Acumen Pharmaceuticals Inc Stock

Good day, and thank you for standing by. Welcome to the Acumen Pharmaceuticals Investor Day Conference Call. [Operator Instructions] 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 a-beta 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; and 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. And in addition, there is a question submission box on your screen that will be open throughout the presentation 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 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, 2 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 to $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 .

Nevertheless, we see this market is poised for continued growth and large enough to support multiple multibillion-dollar products given the magnitude of the population. One of the primary drivers of market expansion and continued growth in 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 4 approved blood tests for Alzheimer's disease. These are all commercially -- 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. 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, whether such as the recently approved subcutaneous version of LEQEMBI for treatment induction is another way to establish convenience and growth within the marketplace. And then I think experience, 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 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 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 nonclinical data earlier this year and have 2 candidates that we're progressing through IND -- 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. Sabirnetug has already produced compelling Phase I results in Alzheimer's patients, increasing the probability of success for it and future anti-a-beta 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. 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 sabirnetug represents a differentiated opportunity for anti-a-beta disease-modifying therapies for the treatment of Alzheimer's disease. I'm going to touch on 3 related topics today. First, the soluble oligomer hypothesis. Sabirnetug is the first monoclonal antibody targeting the a-beta 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, 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 sabirnetug, how does sabirnetug differentiate from other approved antibody-based anti-a-beta disease-modifying therapies? Well, like other approved anti-a-beta disease-modifying therapies, sabirnetug is an amyloid protein targeting monoclonal antibody. However, unlike the approved anti-a-beta DMTs, sabirnetug 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 anti-a-beta 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. 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 2 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 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 shape amyloid 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 are 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 are 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.

Okay. So next slide, please. So all this leads to this refined a-beta oligomer hypothesis where plaques may be the visible pathology and the original thinking around amyloid biology, but these small hard-to-detect oligomers are the most synaptic 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 soluble oligomers, but no production of plaque. And 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 soluble oligomer hypothesis.

Next slide, please. So all this biology leads to coming up with sabirnetug to target the soluble oligomers. And so sabirnetug 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 a late phase clinical trial. So as you'll hear later from Eric, sabirnetug is currently in a Phase II 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 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, 2 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 2 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, sabirnetug has lower affinity than either of those 2 agents for monomers.

But then if you look at the filled symbols at the bottom, there, you're 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. 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 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 León in the Klein lab at Northwestern University. His team utilized advanced immuno affinity 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 rmab148, which is the mirroring precursor for lecanumab bound preferentially to protofibrillar 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, rmab158 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 sabirnetug 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 2 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 Grenon in Cynthia Lemere's lab at Harvard, comparing the binding profile for sabirnetug with the binding profile for lecanemab in head-to-head in a mouse transgenic model of CAA. So 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 a-beta 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. So that means that both lecanemab and donanemab being IgG1 antibodies signal to the immune system in a slightly different way than the sabirnetug 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 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. So this is now looking at the current incidence of infusion-related reactions with the approved anti-amyloid a-beta therapies, lecanemab and donanemab. 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 2 programs.

Next slide, please. In addition, here are the values for the incidence and severity of ARIA with approved anti-a-beta 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. And of course, there are changes in practice that have been occurring, most notably with donanemab, 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 phospho-tau 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 a 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 ratio. 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-tau181 and p-tau 217, which although are tau markers, they are associated with the pace of amyloid change.

And then a little further 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 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. So 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. So these subjects by this point in time had received 3 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 a-beta 40/42, 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-tau181. And really importantly, we see similar dose associated changes with both neurogranin, a post-synaptic 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 sabirnetug 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 sabirnetug in red, what we're seeing is a fairly rapid change in p-tau181 and also in neurogranin, consistent with the hypothesis that we're seeing a marker of early and significant impact on changes associated with Alzheimer's disease with sabirnetug.

Next slide, please. So I hope I've convinced you of a couple of things. Sabirnetug 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 currently approved DMTs that target other forms of a-beta. 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. 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 II 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 II study. So it's a large Phase II 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 I study. And of course, now we'll look at it in our Phase II 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 3-arm study. So we have 2 different doses of sabirnetug and 1 arm that's placebo. It's an 18-month study with infusions given once every 4 weeks. And after the 18-month period, there is a 1-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 I study, we actually obtained a lot of data that were very good in terms of designing and planning this Phase II ALTITUDE study. So if you look at the lower left on this slide, that's our -- what we call a target engagement assay. So 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. 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 I 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, 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 I 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 on the lower left, and then we did some modeling with it to choose our doses for ALTITUDE. And so we think 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 I 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 sabirnetug 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 neurogranin, VAMP2, p-tau 181, 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 42/40 ratio that tends to go up, which is what you would want to see.

So this is after just 3 administrations of sabirnetug in a Phase I 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 II ALTITUDE study. So -- but these were all from just our Phase I 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 an 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 I study, those are small studies, but the safety appeared to be quite good. We did have 5 cases of ARIA-E 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 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. But if you just want to go ahead and go to the next slide.

So let's talk a little bit more about the iADRS scale and the CDR sum of boxes, just to compare and contrast of it. 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 2 domains. There are some technical differences in how the scales are administered. So 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 6 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 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.

So 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. But the EXPEDITION studies, which looked at a drug called solanezumab 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 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.

But 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. And then finally, the last line there is looking at donanemab Phase II studies. And 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.

Now when they went on to Phase III 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 patients. But 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. And 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. 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, p-tau217 to screen people for the study. So -- and 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 p-tau217 blood test screener was amyloid PET scans.

If you look at ALTITUDE, the largest reason for screen failures was the blood test, the p-tau217. 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 p-tau217 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 U.K. sites, and that always takes a little bit of time. But if we would have just let the U.S. keep running with this, we probably would have even enrolled it a little bit faster. So we are 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 compared with CLARITY. The CLARITY study of lecanemab is -- has a patient population most similar to ours. For those of you who are familiar with the TRAILBLAZER studies of donanemab, 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 p-tau217 screening because when they designed the study, it wasn't available. And so -- and we did have that p-tau217 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 p-tau217, but we ended up with essentially exactly the same patient population as was obtained with the CLARITY study where they did not have the screening with p-tau217. So we feel like we really accomplished our screening process overall in a way that was very, very good. And -- but we did it in a way that was much easier for patients and the sites. 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 iADRS scale. But 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. 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 I 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 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 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 our Phase I study, and we'll 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's a synaptic biomarker.

It's a post-synaptic biomarker and 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 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's sort of an inflammatory marker. So we saw, again, some Phase I data that looked very promising for GFAP. We'll be excited to see the results from a much larger Phase II. And of course, we're going to look at p-tau217, not -- 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'm not going to read all 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 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. So they like being in the study. They like being on the drug. 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 blood-brain barrier with only about 0.1% to 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. So 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-life. 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 give the patient so much drug before we start to see an increase in the 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 antibody 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 2 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 risk 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 2 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. 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 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 and VHH 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 monovalent and bivalent and a range of a-beta binders. So this slide summarizes about 1.5 years 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. And these antibodies, we took through a variety of in vitro and in vivo assays to characterize to end up selecting these 2 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 subcu dosing and that antibodies are released into the parenchyma of 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 ACU301 and ACU401 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. As you can see, after subcu dosing ACU401, you can see that there's rapid uptake, the red line into the blood after subcu 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. And then the subcu 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 suggests 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 cynomolgus monkeys for these studies. And as you can see, we designed a 2-phase study. So in the first phase, animals were dosed subcu 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 2 mg per kg of antibody, the same antibody they received before. And then half of the animals, 3 animals were euthanized 3 hours after dosing and then the remaining 3 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 subcu dosing. On the left, you can see kind of a blowup of the first 24 hours. You can see that very rapidly within 8 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 2 weeks. And what you can see is that after subcu dosing, ACU401 at the end of 2 weeks still has a very good half-life and suggests 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 looked at 3 regions of the brain, the prefrontal cortex, the putamen and the hippocampus, we noticed that the trends with ACU401 were very similar in all 3 brain regions.

As you can see in the prefrontal cortex within 3 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 234. And 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. So we are 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 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 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 subcu 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 dosed with ACU401, we see a robust uptake in the brain with levels as high as 40x 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 subcu 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.

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 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 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 dosing -- 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 4 degrees for an extended period of time. And finally, we saw that there was a very good uptake of drug after subcu dosing and that this should allow us to move into the clinic with a subcu product.

So 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. And then finally, we're developing bioanalytical assays that we'll need for the clinic, 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.

[Operator Instructions] Our first question is going to come from the line of Pete Stavropoulos with Cantor.

First question, 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 lecanemab and donanemab? And when you look at the baseline CDR sum of the boxes for ALTITUDE, it's 2.91, CLARITY 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 the CDR sum of the boxes.

Yes. Well, thanks for that question. This is Eric. I'm happy to take that one. So if you look at -- we'll just start off with the CDR sum of boxes, there's 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, 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 are very, very similar. And to my mind, I don't see anything in there that's a meaningful difference in the 2 patient populations. For donanemab, as I mentioned, those patient populations are a little different. And I think that's because they have this requirement for a certain amount of tau positivity. So if you look across all the various measures, the donanemab studies, the patients are a little bit more advanced or a little bit worse. So it is -- 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 2 different studies, I would say.

And as you noted during the call, there was -- there's 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? And are there any that stand out to you, especially the newer biomarkers as you look at ALTITUDE or incorporate into the Phase III, including biomarkers not listed in your presentation, like perhaps 243?

No, another great question. And yes, the field is moving so quickly. It's a good problem to have, obviously, but especially p-tau243 is one of the ones that is newer and seems to be quite promising. But the first thing that we'll do actually, of course, is look at our altitude results and look at the biomarkers where we do -- that we do have in there. So just for instance, when we designed the ALTITUDE study, there weren't any p-taus 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 4 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 III, should we tweak the screening procedure that worked very well previously with the p-tau217 assay that we use, but now that there's 4 different assays that are FDA approved, we'll need to rethink that for what we do in Phase III. 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. I don't know, Jim, did you want to add something to that?

Yes, 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 know -- we certainly know that there are additional markers that are being evaluated now, and I think that's only going to continue. You mentioned T-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 will 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 the disease well before clinical symptoms have appeared. And as we showed earlier, there's a ton of evidence that there's physical interaction with synaptic circuitry. So 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 could 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 p-tau217. As Eric said, there are now 4 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, 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.

Just one last question on EBD. Let's say that ALTITUDE reads out positively, will that impact your decision to sort of bring sabirnetug versus 234 forward? Positive data would just clinically derisk the binding properties of sabirnetug. Why not stick to sabirnetug rather than introduce risk?

So Jim, do you want to grab that one?

Yes, 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 sabirnetug, 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 it actually even offers some opportunities different than what we get with sabirnetug.

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 I. 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 bring -- 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 biomarkers or in earlier phase of disease. And so we really want to maintain optionality. And so we're interested in profiling both molecules.

Our next question will come from the line of Paul Matteis with Stifel.

This is Emily on for Paul. Just a couple of quick questions for us. So on the EBD profile, we were wondering what's the TPP here. 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 in patients following that mid-2027 IND filing?

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 I 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 we're discussing right now, thinking about the best option for this molecule. And based on data that we get from the ALTITUDE study, will certainly directly impact how we think about the studies that we run, the biomarkers we use, the endpoints of interest. So yes, all of that is still under consideration. And as stated, by the middle of next year, we'll be ready to move forward.

Our next question comes from the line of Jason Zemansky with Bank of America.

Congrats on the great progress. Maybe to start, it's probably fair to say a key determinant of success in 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, yes, 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, 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 lecanemab 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've seen 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. 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. 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 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 homozygous is an important aspect of sort of the overall -- the totality of the opportunity for sabirnetug to differentiate.

Our next question is going to come from the line of Geoff Meacham with Citi.

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 oligomers and the effect for sabirnetug? And 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 do you think these should really get some momentum commercially from neurologists. Does that help you, hurt you, neutral to you? Just wanted to kind of put that in context.

Sure. Maybe I'll lead out and then invite Jim or others to comment. I think in terms of the clinical validation of the oligomer hypothesis, I know personally, I'm looking for a pronounced efficacy signal, and that is 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 4 agents -- excuse me, 4 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 in the population, we see that, that 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 necessitate access to better treatment options.

Yes. I think Dan said it well, but I would just echo, yes, the oligomer hypothesis the target has been validated. Amyloid biology has been validated as meaningful for Alzheimer's disease. And so what 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 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. 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 the signals that we'll see. So 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. 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.

And maybe just one quick thing about the uptake of the diagnostics. 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.

Our next question comes from the line of Tom Shrader with USB/BTIG.

Terrific event. Very related questions. But Eric, is the best -- we're all going to be looking for comparative signals. Is the most likely best comparator CDR sum of boxes versus CLARITY? And then on the oligomer line of questioning, 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.

Yes. 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. But compared to CLARITY, 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. So we'll see what we get, and that will be the scale that can translate best, I would say. So hopefully, that answers your question. I don't know if Jim or Dan, you want to take your second one.

Yes. Just to comment on the second question. I think it's a really good point, Tom. 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 on it 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. 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 a much more complete and a much larger data set from ALTITUDE.

And a follow-up for Paul, 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? And I guess you're obviously very close to the field. Are other people that are -- I mean, there's a huge number of programs there. Are other people finding what you are finding that high affinity TFR binding bivalent does make sense? Just any sense of -- because what you're finding is so different than what we've been reading about for 3 or 4 years. I'm curious if you could give us any help.

Right. So again, we went into this with eyes wide open, not relying too heavily on the dogmas. So 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 Genentech and Denali are similar platforms, both came from Roche Genentech. And in their hands, monovalent looked better than bivalent, antibodies that had a lower affinity seem to perform better than high affinity. And 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.

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 all molecules need to be at a certain affinity to work. So 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 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 parenchyma of the brain and engage a-beta as we would like. So I think it's still early.

Our next question comes from the line of Dev Prasad with Lucid Capital Markets.

I have a couple of questions. One is the slide time frame that Phase III is partnered enabled. So is this a base case rather than self-funding? And another is on subcu. How are you thinking about the role of subcu in late-stage development? And then I have one question on EBD.

So thanks, Dev. Let me -- I'll address the partner question, if I understood it correctly. So 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 and that comes about, I think, is to be determined. But 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 subcu. And I think as it stands, we would envision the subcu formulation for sabirnetug playing into a Phase III strategy and haven't specified precisely how that has -- how that will be incorporated. There's 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 the 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 we see a partnership for Phase III as an attractive way to unlock more value for stakeholders interested in seeing sabirnetug move forward.

Great. 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. 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 40x better than a monoclonal antibody, you can either dose the same to get the same efficacy. So dose 40x less than sabirnetug to get the same efficacy or if there's 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 -- and 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.

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 did have a few come in. One was using AI to assist in analyzing the trial data more quickly for ALTITUDE. So I'll turn that over to, I think, Jim.

Yes, happy to take that one. So 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. 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 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. 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.

Yes. 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. 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 disconnect. Everyone, have a great day.

Day of the Citi Biopharma Back to School Conference. I'm Geoff Meacham. I'm thrilled today to have Acumen. So welcome, guys. The -- there's been a lot of discussion in the Alzheimer's space from a commercial perspective. But maybe, Dan, do you want to give, kind of, a background to where we are in the life cycle, and then we can obviously talk in great detail about the Phase IIb data coming up.

Yes, sure. Thanks, Geoff. Thanks to you and your colleagues for including us in this year's meeting. We're glad to be here. Yes, it's an exciting time for us in the Alzheimer's space, principally as the market continues to develop and reflect the broad and large unmet need of the growing Alzheimer's population. We at Acumen have a pipeline that includes Phase II assets, sabirnetug that will read out later this year. We'll talk more in detail on that in a minute as well as a preclinical or nonclinical program working towards an IND in 2027 that involves some transferrin-directed transport to the brain.

So very excited about our portfolio and pipeline to position new and better treatment options for people impacted by Alzheimer's disease. And I think it is important to recognize we are still in the early innings from a commercial market development standpoint. We have 2 approved agents that have been shown in studies to slow the disease, its progression relative to placebo. Those 2 agents have now achieved annual sales run rates exceeding $1 billion and are expected to be north of $2 billion by 2028 and $3 billion to $4 billion in 2030.

So it's a growing market in demand of better treatment options, and that's really where Acumen is positioned. We're sort of -- we are now at a point where I think there's clinical, commercial regulatory validation of amyloid targeting strategies as sort of a cornerstone to disease modification. And we at Acumen have a unique riff or scientific hypothesis associated with a species of amyloid or A-beta that is potently toxic and one that we think by neutralizing A-beta oligomers, we have the ability to potentially unlock greater efficacy and safety for patients in this population.

And maybe just talk about the science behind the idea of oligomers being the more toxic species. That's -- you guys have some clinical data, Phase I, prior data, Phase II that sort of underpins that. But maybe just for the audience here just to give us a bit of more background or context.

Of course. And just because I'm joined here by my colleague, Jim Doherty, our Chief Development Officer and President, I invite Jim to comment as the neuroscientist in the room and someone that has been tracking this field for a couple of decades.

Yes, happy to do so, Dan. Good morning, Geoff. Yes. So, it's a really good question. And as Dan said, beta amyloid is now a validated target for the treatment of Alzheimer's disease, and that's a huge step forward in any endeavor to find new therapies. But really, when you look at the biology of amyloid beta, look, the protein has a normal function, and it normally exists as monomer single units. But then something happens, and it's not entirely clear yet what that core thing is, but it leads to misfolding and misaggregation of that protein.

So now instead of doing its normal job, it's gumming up the works. And I say it that way intentionally because there's all the things known about the larger things like amyloid plaques, it really the best evidence for true toxicity causing damage to synapses, causing damage to cells, preventing plasticity in the brain and ultimately progressing, interfering with cognitive function is really associated with the small soluble oligomers, at least when it comes to the in vitro and preclinical settings. So a lot of evidence that these small aggregates of amyloid protein are actually interfering with key synaptic function, so messing up signaling.

It's an early element in disease. We all know that Alzheimer's is a progressive disorder. And so this dysfunction associated with oligomers occurs early in the course of disease, and it's persistent. So that's a really interesting place to go from a neurobiological point of view. And given that targeting of soluble oligomers with sabirnetug, we're really excited to be testing the oligomer hypothesis really for the first time by getting cognitive data in the ALTITUDE trial.

Yes. So there's really -- go ahead.

I was just going to say that, yes, as Jim is suggesting, I mean, there's a couple of decades of evidence in support of these A-beta oligomers as being a primary toxin. And of course, the origins of our lead program, sabirnetug. Sabirnetug was designed to neutralize and selectively target these species. So it has a high selectivity for oligomers versus monomer and versus plaques. And based on that mechanism and based on some successful Phase I data, we do think sabirnetug is positioned for success and differentiation through this robust 542-patient Phase II study that reads out later this year.

Great. Yes, let's get into the study. So data is expected later this year, year-end. Maybe just given -- could you walk us through maybe the trial design and what we could expect later this year from ALTITUDE-AD?

Yes. So ALTITUDE-AD is a double-blind, placebo-controlled study, 18-month double-blind period followed by a 12-month open-label extension. There are 3 arms in the study, 2 active arms at 35 and 50 milligrams per kilogram IV, once monthly IV administration relative to a placebo arm. Primary endpoint is the iADRS scale, which is a combined scale of ADAS-Cog, which is a cognitive function scale as well as another scale for activities of daily living. So it really is that combination of cognitive impairment as well as impact that has on daily living.

We have a number of other cognitive scales also in the study, including CDR Sum of Boxes and a variety of others. As I was just saying, this is -- we see the critical test for the oligomer hypothesis. And given that, we really want to as closely as we can, be measuring cognitive performance.

In addition to that, we're also looking at a number of different biomarkers, and I think that's a really interesting area to be talking about these days for Alzheimer's therapies. So we are certainly well represented when it comes to biomarker analysis. So that includes imaging biomarkers like PET scans. We'll be doing amyloid PET as well as a small tau-PET substudy, MR imaging from a safety perspective and a number of biochemical plasma-based biomarkers. So that's the overall design, 542 subjects enrolled in the study, about 180 per arm then. And we are rapidly approaching the conclusion of the study. So we're very excited.

Just a follow up on that. If you think about the differentiation. So, is it reasonable to assume that the efficacy could be sort of directionally maybe better than the current -- if that -- if oligomers are the toxic species, could you see numerically better on obviously, cross-trial comparisons considerations? But then also on the -- talk a little bit about ARIA and the drug and the differentiation from that perspective.

Absolutely.

Yes. And so we do think that there are opportunities to differentiate from existing therapies when it comes to either efficacy and/or safety. And so I think different arguments for both, as you rightly point out. From an efficacy point of view, it's our hope that given the mechanism we've been talking about, we do have that additional benefit by directly targeting oligomers. And so we're expecting to see significant benefit. We're also going to be looking at timing to see if perhaps we see effects at a different time course than what's been demonstrated so far. But our target for what we'd like to see in the study is what we've been saying is about a 30% slowing in cognitive decline. And if you look at the studies that have been conducted to date, the range is somewhere between 27% to 32% slowing depending on the study, depending on the endpoint.

So we feel that anything 30% or better is a really good outcome sabirnetug. Of course, we're hopeful to see even more than that, but that's why you run the study. So we'll wait and see what the numbers look like. But timing is also a relevant thing that we're going to be looking at the rate of any potential improvement.

On the safety side, as you point out, ARIA is a key risk with the class of molecules. And so something to pay close attention to. We've, of course, been looking at safety even in our Phase I studies. And what we saw there was an overall ARIA rate at about 10%, which is at least numerically a little bit of an improvement on what's been seen in much larger studies to date.

So I always talk about the numbers from the Phase I study with the appropriate caveats. It's a small study, but those are the data we have. What we see there is a total of 5 cases out of about 50, so about a 10% ARIA rate. Four out of 5 of those events were nonsymptomatic. So we had one that was mildly symptomatic. And 3 of those 5 were at 60 milligrams per kilogram, which is a dose that we have not taken forward into the Phase II study. So we're hopeful to see an attractive profile when it comes to risk benefit, both on the efficacy side as well as on the safety side.

I guess could we talk a little bit about how discussions are going with regulators as you are approaching later-stage development readouts?

Yes. So we have interacted with U.S. regulatory, with the FDA at the end of the INTERCEPT study, a so-called end of Phase II meeting. And so a very good interaction. There's obviously a lot of activity in the Alzheimer's space. And so there's a lot of good feedback from the agency. We -- one of the critical pieces of that was the understanding that with a well-controlled and robust ALTITUDE study, the one we're running now, that coupled with a single confirmatory Phase III study could support a regulatory submission.

So that is the strategy that we've been following is that we would conduct the ALTITUDE study and if successful, conduct a single confirmatory Phase III study to provide a package to support an approval in the early Alzheimer's space.

And I wonder if I could visit a little bit on the Phase I data, just while we're talking about ALTITUDE and probability of success and what we saw in Phase I and how that translate into Phase II. We used a novel target engagement assay in Phase I that confirmed sabirnetug's ability to bind to and essentially sequester oligomers in a dose-dependent fashion, which was first-in-use novel, but really robust. And what we saw there was really as we pushed the dose a little bit higher, plateauing of the target engagement signal, which said in the context of 60 milligrams per kilogram having 3 cases of ARIA, let's -- we don't need to go that high in Phase II. And so with Phase II, we have the 2 doses that Jim mentioned, 35 mgs per kg and 50 mgs per kg.

And what we did see in addition to target engagement in Phase I were biomarker effects, both on imaging as well as fluid and CSF and plasma. And so with a short duration Phase I with 3 doses of sabirnetug, we're moving multiple biomarkers, imaging and fluid in the right direction. So our expectation, our hope is that chronic dosing over an 18-month placebo-controlled period, we're going to replicate and expand on those biomarker effects and as a consequence, really deliver an efficacy signal on a cognitive functional scale that's meaningful to patients and regulators. So I think that we have a lot of ways to win in ALTITUDE with the 2 doses we have in that study and the way we've enrolled study and conducted the study as a registration quality study.

Jim or Dan, when you think about the baseline of the ALTITUDE study, how would you say, you can compare with either the Lilly or the Biogen/Eisai. Those are more contemporary kind of trials. I think we've learned a lot over the years on how to run an Alzheimer's study. So in terms of who we exclude. So maybe do that compare and contrast with those two?

Yes. So it's a really good question. And you're absolutely right. That has been a robust learning in the space, right? So as we've talked about, it's a progressive disorder. And so finding those patients who are most likely to benefit is a critical issue. And I would say, first up, and this was a key learning from earlier trials, we put a lot of emphasis on really confirming amyloid positivity. So that meant that what we were able to do is use a p-tau217 prescreen.

Now at the time when we were launching the ALTITUDE study, it was sort of early days. So that Eric and the team did a great job of recognizing the potential there. What turned out to be true was that we could significantly reduce the number of failures of amyloid positivity by doing a rapid, relatively inexpensive plasma-based screen to select patients for ultimate confirmation either by amyloid PET or by CSF lumbar puncture.

So it really led to a more efficient entry criteria design and really getting what we think are the right patients. Now the other thing that's critically important is aligning the entry criteria to get patients in the right phase of disease to really maximize your chances to see beneficial effects. And this is where we've sort of taken our cue from those trials that you had mentioned. So we're targeting the -- what's conventionally called the early Alzheimer's population. So that's MCI as well as mild dementia.

And then within that, if you use those 2 donanemab and lecanemab programs as a bit of a benchmark, they're not exactly the same by design, the Lilly program used a tau entry criterion as well, and that resulted in a slightly more severe patient population relative to the lecanemab trials, which was an active choice. In our case, we are not using a tau requirement. And so our study population is probably closest to the lecanemab population when you really come down to it. And in fact, when we were publishing our entry criteria, they're going to look pretty similar to what people have seen previously with the lecanemab study. So a truly early Alzheimer's population, really with a lot of MCI in that sort of balance between MCI and early dementia.

And so even if it's less severe population over the 18-month endpoint, though, you'll have more than enough time to see progression. I think that's the biggest risk, right?

And that's the balance point, right? Because consistently, studies have been showing that the earlier you intervene, the larger the benefit to patients. But that really -- that's, of course, kind of a population argument. So you -- at the same time, you don't want to go so early that you haven't had enough time to see a decline in your placebo group or your untreated group. So it is a balance between early enough to really maximize benefit to patients, but late enough so that you can run a reasonably sized and reasonably powered 18-month trial. And we think we've hit that balance point, but that's really the approach.

Great. Could we talk a little bit about some of the KOL feedback you've been receiving around the trial design and maybe the potential usage of sabirnetug in the future? I guess also with the endpoints you've mentioned, you have more functional endpoints along with biomarkers. Kind of, what are the KOLs looking for here?

So I think we've had great reception from the KOL community on the program. And the program, this is -- I mean, we had first reception on INTERCEPT data, Phase I data, which was encouraging. And now people are sort of on the edge of their seats, knowing we've got a big data readout later this year. I think the biomarker observations in Phase I have been encouraging to KOLs. I think there's a recognition that having more treatment options is desirable in the space. Most of the KOLs that we've talked with are experienced with both agents that are approved today and are finding those to be suitable for a certain number of their patients. But then I think there's a clear interest in more and better options.

The study design is -- has been very well received. I mean I think that we can comment quickly on the overall conduct of the study has been very robust. I mean we enrolled 540 patients in 10 months as a small biopharma swimming in with the big fish in the Alzheimer's space. So really proud of that execution on the part of the team and the study partners. And the overall metrics within the study have been robust. We've had retention in the study that's exceeded our expectations. So we haven't seen high dropout rates due to safety or other considerations that would have been problematic from a powering and statistical standpoint.

And we've had really -- so we have an open-label extension. So after the 18-month placebo-controlled period, patients are eligible to roll into an open-label extension for 12 months. And we've had better than 95% of people eligible to roll into the OLE go into that -- take that next step. And of course, all of this is being occurring in the presence of approved agents. So you can -- it sort of gives you a sense that patients and participants in the study are eager to see other options available to them and have committed their time beyond that to be in ALTITUDE in a fairly encouraging way from where we sit.

Yes. And maybe just to echo what Dan is saying. Obviously, testing a key hypothesis for the field is critically important. This is a key program for Acumen's future. And it's -- but it's not just the science or the ideas, it's about execution. And we are very proud of the team, and it's been exciting to see some of the metrics that Dan was talking about. In addition to that, at the AAIC meeting a couple of months ago in London, we had the opportunity to sit down with a number of the PIs from the study. And in general, the feedback was very solid. People liked participating in the study. They enjoyed the study design, the protocol. And these things really do matter. And that -- so we're glad to see that kind of feedback from the KOLs associated with the study.

I think on the other KOL feedback, I mean, the A-beta oligomer hypothesis has existed for 20-plus years, right? It's been out there. It's been a little bit elusive. I think there have been prior claims and attempts to sort of provide the clinical validation. And I think when the clinicians and KOLs that are active in research in the space recognize that ALTITUDE really is an at-scale robust test of that hypothesis. So we are -- we're hopeful for the result and our confidence is predicated on the success in Phase I, but it's an exciting time for us, which really with a successful altitude, I think it ushers in a new discussion within the A-beta space as to what targets are priority and how best to deliver a better risk-benefit profile to patients.

Definitely. You mentioned this, but could we talk a little bit more about the OLE ongoing? Just how is it progressing? And maybe what could we learn from that trial?

Yes. So as we mentioned earlier, the OLE is a 12-month open-label extension. It is all patients regardless of what their original treatment arm was go on to a 35-milligram per kilogram open-label treatment with sabirnetug. And as Dan was saying, we've had really great numbers as far as percentages of people rolling over into the OLE. In fact, a little bit better than we had even projected. So that's a great sign to see. What it means is we're going to get a lot of data. So that's an important element of the study. We were talking about the 18-month time point to be able to see deviation from the normal decline rate.

And it is true, but there's no question that as a progressive disorder, you really like to have data from even later time points to really see the progression of the effect. So we think that the open-label extension is a really important part of the study and glad to see so many people rolling into it.

Let me ask you just on the differentiation. Although you have the 18-month time point, given the oligomer hypothesis, is it reasonable that you could separate maybe at a faster rate than, say, lecanemab and perhaps donanemab?

I would certainly love to see that. Is it possible? I think so based on the science behind it. Yes, I think you can make an argument that these small soluble oligomers, if they're truly as toxic as the data would suggest, you may be able to see evidence of that even at an earlier time. I think this one really is going to -- we'll have to see the data to really know for sure. But I would say that theoretically, it's certainly possible and something that we'll be looking to see.

Particularly in that early end of the spectrum of early AD, right? I think that MCI population where the oligomer toxicity is sort of central to early disease progression. So if you're intervening at that earlier time point, presumably, there's more substrate to sort of restore or maintain. And so even with the other agents, you've seen the earlier patients seemingly do better with a Kisunla or Leqembi. So with our mechanism, we could really sort of expand on that in a more robust way, but we'll need the data to support that claim.

So you may have patients that are on for 20 straight months if they go from active to open label.

Yes. I mean 30 months, right?

30 months.

I can do the math.

Sorry. But are you going to -- is that ending there? Or do you follow that...

Yes. So our plan for -- yes, let's be clear on that. So we've guided to top line results late '26. And so it's a Q4 event. I don't think it's a year-end event, just to be clear. And we have also indicated we want that to be a robust, informative, actionable data set. So real numbers and real outcomes. And I think we have the ability to do that. It will be material information for the company, so we have an obligation to disclose. And we'll do that, again, inclusive of the primary outcomes of safety, efficacy and secondary outcomes, inclusive of biomarker effects. So that will be focused on the placebo-controlled portion of the study. We don't anticipate a top line informing on the current status of open-label extension, sort of beyond the -- that data will continue to presumably accumulate over time into next year. But we'll focus the top line results on the placebo.

Just on the...

Yes, it's correct.

And let me ask you, too, on the -- you're going to give the full details? Or is this going to be like wait till CTAD...

Yes, yes. We don't have the luxury of waiting. So -- and we've been waiting for these data for a long time. So I shouldn't -- we will be disclosing in a fulsome way that, again, is interpretable and actionable in the moment, not kind of previewing something and holding for a future conference. So yes, no, that's our commitment to all the stakeholders, participants in the study, investigators, investors, and others.

Is it reasonable to assume, though, that, let's say, a patient was on placebo for 18 months and then they switched to active? Is that -- that's sort of a separate kind of question in terms of the OLE.

Well, that's where as Jim is suggesting, and this is an important fact of the way we've been fortunate to have the capital and the resources to do something at scale in a robust way. Like this is a study a big pharma would do typically, right? I mean -- so this is not kind of fly-by-night biotech like sort of cutting corners and otherwise. I mean this is a study that will continue to yield more data beyond the late '26 readout into '27 and so forth. So -- and those data, the biomarker data, the switchover from placebo, once we unblind placebo to active, the longer duration of people that are on for 30 months. I mean, these are really important information that will also inform on differentiation in the future, right? Like maybe not in the immediate moment, but over time, as we contemplate what -- kind of what to focus in on Phase III, in '27, all those data will be sort of informing the strategy going forward.

And just as part of your end of Phase II meeting, I can't remember if you formally have agreed whether this could be a pivotal, if successful, and then you just run Phase III? Or have you had those.

Yes. I think as Jim mentioned earlier, it's very clear from our perspective that we -- the way we've conducted and designed ALTITUDE, it can serve as supportive evidence in conjunction with a single pivotal Phase III, which is an important fact, which I think is easily diligenced for a partner or however, anybody that wants to participate or support a Phase III for sabirnetug. You've got one study to do. And there's not a lot of complexity to what that study ought to look like. It's going to be a 2-arm study, active versus placebo, presumably an 18-month primary outcome, but maybe we see an effect in ALTITUDE that suggests we could win with maybe more patients, but at a 12-month time point.

So there's more -- the data will inform the Phase III design, but we think it's just a bigger version of the 542-patient study that we are running to completion later this year.

Great. I'd love to -- with just -- with the time that we have left, maybe just have some time to talk about the EBD program as well. Could you -- are you planning on announcing a lead candidate from the program in mid-2027. Maybe could you just review the background of the program and potential applications of the tech technology?

Yes. We're also very excited about the EBD program. And it's certainly -- when you think about active transport of macromolecules into the brain, there's a lot of interest and there are a lot of people working on this very exciting technology. And when you think about the reasons for it's, on one level, fairly straightforward, but it's also pretty profound. The brain is pretty good at keeping things out. I mean that's an evolutionary benefit. And so when you're trying to get therapeutics into the brain, you've got the blood-brain barrier that lines all of the blood vessels into the brain and preventing those macromolecules from getting into the brain. It's especially challenging for monoclonal antibodies and other large proteins. The sort of off-quoted number is about 0.1%, 0.1% of the circulating plasma dose is actually reaching your target in the brain.

So anything you can do to materially improve that ratio, we would expect to have a pretty big impact on your treatment. And I think for a couple of reasons, that's especially true when it comes to amyloid therapy for Alzheimer's disease. I can get back into that if you're interested in some of those things. But when it comes to then, if you accept that this is a valuable approach, then it becomes what's the best way to execute that. And we see this fundamentally as it's certainly a bispecific construct, but you're combining a carrier element, which allows you to sort of hit your ride on the transferrin-based system to transport into the CNS, coupled with the cargo you're trying to deliver.

And as we've been talking about, where we think that the soluble oligomers targeting monoclonal antibodies is definitely a robust approach. So combining that with a transferrin-based way to substantially increase brain penetration, lots of benefits. So we have partnered with JCR Pharma in Japan. JCR has spent many years working on this technology, and there are a number of groups that have been. We were particularly impressed with JCR for a couple of different reasons. One of the potential risks generically of the technology is that if you sort of co-opt the transferrin system too much, you can lead to anemia and depletion of reticulocytes. And so what JCR has been able to do is balance the risk for that including in multiple of their development programs, but including in their marketed product for Hunter syndrome. So they don't see a ton of anemia with their approach.

So we worked together and went through a whole list of constructs as a scientist. We -- I can tell you, we didn't just click 2 things together. You do a lot of work to figure out what's the best combination of approaches. And we landed on 2 candidate molecules that we are currently moving through nonclinical development in anticipation of an IND in mid-2027. Those are called ACU301 and ACU401. The difference between the two, ACU301 is the easier one to explain because the cargo is sabirnetug coupled to the carrier technology.

ACU401 is similar carrier technology, but coupled to a molecule that we're calling ACU234, which is from the Acumen library and an analogue of sabirnetug, but with slightly different properties. And so we think that gives us some differentiation or probably better to call it choice, right? So we've got slightly different profiles of the 2 oligomer targeting antibodies. We know quite a lot about sabirnetug, and we're learning about ACU234.

So at the moment, both molecules are moving through nonclinical development. We anticipate choosing one to take into an IND. My hope is that we sort of choose the more attractive overall combination of properties, but that the other molecule remains in the pipeline and in the library for down the road opportunities. So we see opportunity for both molecules, but we're going to be moving forward in 2027 with one.

And earlier this year, we had announced some of the nonhuman primate data for some of these candidates. And as Jim mentioned, we're seeing 20- to 40-fold increases in cortical exposure of the drug relative to unmodified native antibodies. So it's just a huge advantage from a delivery sort of payload ability. Presumably, that has the possibility of adjusting dosing requirements and/or potentially driving efficacy in addition to safety profile.

So this is -- we think of the EBD as sabirnetug may not necessarily need a shuttle per se or an EBD mechanism. But boy, if we have a good result with sabirnetug and ALTITUDE, it's an obvious thing for a future generation life-cycle management to have an EBD version of that or the 234 candidate because it will be a supercharged profile for safety, efficacy and convenience.

And that particular profile, like my ambition would be to see that product really play into this preclinical Alzheimer's population, which I know you're familiar with, which is really the people that are amyloid positive and increasingly, the field is establishing means by way they can anticipate who will likely progress to symptomatic disease within a 3- to 5-year time frame. And those are people -- I mean, you can think about Alzheimer's has been this challenging space for anybody to make headway. I think we've arrived at this moment where we've achieved success. We've learned what not to do. We've learned some of the things what to do. And we're going to see a bit of an inflection in terms of the expansion of options in expanded population that may be amenable to early interventions that afford better quality of life and maybe avert the onset of symptoms.

Jim, Dan, thank you very much.

Thanks, Geoff.

Thanks, Geoff.

Good day, and welcome to the Acumen Pharmaceuticals Second Quarter 2026 Conference Call and Webcast. [Operator Instructions] Please note this call is being recorded.

I would like to turn the call over to Alex Braun, Head of Investor Relations. Please go ahead.

Thanks, Michelle. Good morning, and welcome to the Acumen conference call to discuss our business update and financial results for the quarter ended June 30, 2026. With me today are Dan O'Connell, our Chief Executive Officer, and Matt Zuga, our CFO and Chief Business Officer. They will have brief prepared remarks, and then we'll open the call for questions. Joining for the Q&A session, we also have Dr. Jim Doherty, our President and Chief Development Officer, and Dr. Eric Siemers, our Chief Medical Officer.

Before we begin, we encourage listeners to go to the Investors section of the Acumen website to find our press release issued this morning that we'll discuss today. Please note that during today's conference call, we may make forward-looking statements within the meaning of the federal securities laws, including statements concerning our financial outlook and expected business plans. You will see Slide 2 of our corporate presentation, our press release issued this morning, and our most recent annual and quarterly reports filed with the SEC for important risk factors that could cause our actual results to differ materially from those expressed or implied in the forward-looking statements. We undertake no obligation to update or revise the information provided on this call or in the accompanying presentation as a result of new information or future results or developments.

So with that, I'll turn the call over to Dan.

Great. Thanks, Alex. Good morning, everyone, and thanks for joining us today. During the second quarter, our focus remained on disciplined execution as we advanced sabirnetug towards the highly anticipated topline readout from our Phase II ALTITUDE-AD trial, which we continue to expect late this year. We believe this will be an important efficacy readout in the Alzheimer's field. ALTITUDE-AD remains a critical test of our central scientific thesis that selectively targeting synaptotoxic amyloid-beta oligomers may offer a differentiated approach to treating Alzheimer's disease. A substantial body of evidence supports this hypothesis, and we are excited by the opportunity to evaluate that thesis in a well-powered, randomized Phase II study with clinically meaningful endpoints.

Our Phase II results have the potential to substantially expand on our Phase I results, which included demonstration of A-beta oligomer t arget engagement and biomarker changes that we're seeing as early as 3 months of treatment, as we previously reported. We continue to be encouraged with the engagement of patients, caregivers, investigators, and study sites participating in ALTITUDE-AD, as well as in its 12-month open-label extension study. Their commitment has been instrumental in bringing us to this important inflection point. I believe the strong relationships the Acumen team holds with study sites and investigators is particularly supported by Acumen's patient-centric approach.

At AAIC last month in London, we presented patient experience data collected from participants and study partners prior to treatment in ALTITUDE-AD. Results illustrate the diverse ways individuals with early Alzheimer's disease experience, respond to, and cope with cognitive and functional changes, underscoring the importance of capturing patient experience directly to better understand the meaningful benefit at this stage of disease. As we previously described, ALTITUDE-AD was designed to detect a statistically significant difference on its primary clinical efficacy endpoint, iADRS, after 18 months of treatment with sabirnetug compared with placebo. We expect the topline dataset to include results from the primary endpoint, key secondary measures such as the CDR-SB, safety assessments including adverse events and ARIA rates, as well as important fluid and imaging biomarkers.

The study is evaluating two dose levels, 35 mg/kg and 50 mg/kg, compared with placebo. Both these dose levels are within the exposure range previously shown to achieve pharmacodynamic target engagement. While we remain focused on execution and preparation for the readout, enthusiasm across the organization continues to build as we approach this landmark catalyst. We believe that sabirnetug has the potential to demonstrate a differentiated benefit-to-risk profile given its unique product attributes as an anti-A-beta oligomer IgG2 monoclonal. We look forward to sharing the results later this year.

In the second quarter, we announced the nomination of two enhanced brain delivery candidates for the treatment of Alzheimer's disease, representing the only program combining a validated blood-brain barrier penetrating technology with an anti-A-beta oligomer-selective therapeutic antibody. Building on robust preclinical data from both in vitro and in vivo studies, we exercised our options with JCR Pharmaceuticals and will advance two candidates, ACU301 and ACU401. ACU301 is a bispecific antibody incorporating sabirnetug, and ACU401 incorporates a novel next-generation A-beta oligomer-selective antibody with differentiated properties. This is known as ACU234. We view our EBD program as expanding the optionality in our pipeline and will continue to evaluate both candidates in the lead-up to support a filing of an IND. Confirming our mouse data in non-human primates is a pivotal step in this work.

At last month's AAIC conference, we presented data showing that after intravenous dosing, all three EBD bispecific antibodies achieve greater brain exposure than unmodified ACU234 alone. ACU401, in particular, achieved up to a 40-fold greater frontal cortex exposure in non-human primates and significant increase in exposures in deep brain regions. The degree of brain penetration observed in cynomolgus monkeys, combined with preserved soluble A-beta oligomer selectivity and a clean hematological profile, exceeded our expectations and gives us confidence in the differentiated potential of our EBD program's approach. We continue to anticipate an IND filing for our lead EBD candidate in mid-2027.

Coming up, I'd like to flag for investors an anticipated virtual Investor Relations Day to be held on September 16. Please mark your calendars to view live or as a recording, as we hope this will be a helpful review for the Acumen investment thesis prior to ALTITUDE-ADPhase II data readout. The advance of sabirnetug and our next-generation blood-brain barrier EBD candidates underscores the strength of both our scientific platform and our ability to execute, positioning us well for a significant, eventful remainder of 2026. I look forward to updating you on our program and on our Phase II results for sabirnetug late this year.

And with that, I'll turn the call over to Matt.

Thank you, Dan. As a reminder, our second quarter of 2026 financial results are available in the press release we issued this morning, and in our 10-Q we will file later today. We ended the second quarter with $110.2 million in cash and marketable securities on our balance sheet, which is expected to support our current clinical and operational activities into early 2027. R&D expenses were $27.8 million in the second quarter. The decrease over the prior year was primarily due to reductions in manufacturing and materials costs as well as CRO costs as we get into the final leg of our clinical trial.

G&A expenses were $4.7 million in the second quarter, roughly flat for the same period in the prior year. This led to a loss from operations of $32.6 million and a net loss of $32.7 million in the second quarter. We are confident in our scientific innovation and strong track record of execution as we work toward our Phase II ALTITUDE-AD readout later this year and advance our EBD program. We remain dedicated to building value with our portfolio of A-beta oligomer-targeted antibodies for Alzheimer's patients, caregivers, and stakeholders.

And with that, you can open the call for Q&A. Operator?

[Operator Instructions] Our first question comes from Paul Matteis with Stifel.

This is Matthew on for Paul. I guess another company doing an oligomer-specific approach read out some blinded data recently. Maybe can you talk about like what are the differences between their approach versus yours and trial design, and how much can we, you know, kind of read through on their clean safety to your upcoming data?

Hey, Matthew, thanks for the question. Yes, we saw the announcement of the blinded interim assessment, but this is really early-stage data. So there's not too much we can conclude from that reporting or that announcement. And we'll be interested to see how that study reads out sometime early next year. We reported Phase I results in 2023, which, to our view, established a really robust clinical target engagement of A-beta oligomers. And with just 3 doses in that Phase I study, we're seeing effects on both fluid and imaging biomarkers that sort of exceeded our expectations and underpin our confidence in why in a large study, in an efficacy-based study such as ALTITUDE-AD, sabirnetug is positioned for success.

Okay. And maybe a quick follow-up. In the selection of your EBD candidates, what were the parameters that you sought to optimize? And where do you think your second molecule might be better than the bispecific sabirnetug?

Thanks. I can quickly comment. I mean, I think for our EBD program, we envision from a product profile standpoint, subcutaneous administration as a convenient form for delivery, as well as preserving the oligomer selectivity, potentially enhancing that selectivity, and an efficient transport across the blood-brain barrier using the transferrin carrier technology as partnered with JCR. So I think we're looking at safety, efficacy, and broader exposure in a format that would lend itself to convenient sub-Q dosing. So both of the candidates have, at least so far, demonstrated all of those attributes, and some of that data has been presented at meetings, and we'll continue to report on findings in that program as we march towards an IND filing on a lead sometime in mid-'27.

Matthew, this is Jim. Maybe I can add a little bit to what Dan has been saying. Of course, when you see the candidates that we announced, those represent the sort of culmination of a process. And we had a really robust collaboration with JCR. And what it allowed us to do is really look at a bunch of different parameters for optimizing for the right fit to match the carrier and the cargo to come up with the final product. And so we looked at a number of things. We looked at affinity for TfR. We looked at valency, monovalent versus divalent. We looked at a bunch of parameters around the potential risk for anemia and things like that. And so it really represents the culmination of a whole campaign to optimize for what we think is the best fit to deliver these oligomer-targeting antibodies into the CNS.

Our next question comes from Jason Zemansky with Bank of America.

You described ALTITUDE, I guess, as designed to detect a stat-sig difference in iADRS, but with two active doses, can you clarify the framework and whether each dose is independently powered against placebo? If only one succeeds, under what circumstances would constitute a statistically robust positive study? And then a quick follow-up, please.

Thanks, Jason. Good question. As we have not specifically provided details on the powering and the analysis. I think, I don't know that we can go into greater detail on that this morning. Yes, we do have both doses, both of which have demonstrated target engagement. We think both of these doses could emerge as efficacious doses, and we'll be looking forward to providing more information as we get closer to the data readout later this year.

Got it. And then maybe without getting too much into the efficacy bar, can you speak to the work you're doing now to minimize the interval between the Phase II results and the initiation of a Phase III? Any regulatory engagements, CMC, partner discussions, site planning? Which activities are sort of gated until the data?

Thanks, Jason. Well, you can imagine there are elements of everything that you mentioned that are ongoing now, with the exception perhaps of regulatory interactions in terms of establishing the Phase III design and so forth. But there's a lot of activity and anticipation to minimizing the white space. And we're hopeful for a successful readout in ALTITUDE-ADthat really will help facilitate and accelerate our ability to move sabirnetug into a single pivotal Phase III.

Our next question comes from Pete Stavropoulos with Cantor.

Hi, this is Samantha on the line for Pete. My first question is there are biomarker data that suggests certain tau fragments like p-tau217 can be used as a marker for amyloid pathology, while markers like MTBR-tau243 identifies tau tangle pathology in Alzheimer's disease. I know that you've incorporated and will look at p-tau217 in the ALTITUDE-ADstudy, but can you talk about tau243? Do you plan to look at it in ALTITUDE, and how could you incorporate it into a Phase III? Can it be leveraged to help or expedite patient selection?

Thanks, Samantha. Go ahead, Eric.

Yes, so this is Eric Siemers. Maybe I can take that one. So, yes, the biomarker world in Alzheimer's is moving really quickly, especially with regard to blood-based biomarkers. As I think you probably know we use p-tau217 as part of our screening procedure actually for enrolling people into ALTITUDE, but it'll also be an outcome measure that we'll look at after we're unblinded at the end of the study.

MTBR is relatively newer, and so it really wasn't being discussed at the time we designed ALTITUDE. But one of the things that we have talked about is that, we have, a large number of patients and a lot of actually plasma samples that will be stored. And so we have the opportunity to look at things like MTBR, new biomarkers that, especially the blood-based biomarkers, that become interesting after we actually complete the study.

So yes, MTBR is one of the things we talk about, but I think it's not just that. Any other new blood-based biomarker that may look interesting, we'll have the opportunity to look at.

And Samantha, this is Jim. Maybe just to add a little bit onto what Eric is saying. I think he's totally right. It's really an exciting time in the field for looking at these fluid-based biomarkers. And the reason for that is it really provides a lot of information about patients. And so I think what we're seeing is people are beginning to measure these multiple markers in a lot of different studies, looking at a lot of different things. It potentially gives you the opportunity to look at where a person is in their progression with disease. It has the ultimate potential, I think, to start identifying patients who might be better candidates than others.

I think we're too early days for those kinds of applications, but I do think that's where the field is going. And so what we'll do exactly as Eric is saying, is as we go along, we'll continue to monitor all this. We'll use these tools as we can in our trials, and we have the opportunity to go back and measure some of these things, even in a post hoc fashion. So I think this is going to continue to be an important part of Alzheimer's trials moving forward.

Awesome. And just one quick follow-up. In July, there was an announcement of a collaboration with Unlearn utilizing digital twins. Can you help us understand what this tool is and how it's incorporated into the Phase II, and how can you possibly leverage it for Phase III?

Yes, absolutely. This is Jim again. I'm happy to take that one. As you say, we have partnered with a company called Unlearn.AI to use these digital twins. And we see it again as another tool, another emerging tool that potentially provides some value. Essentially, these are almost individualized digital models relying on the data from thousands and thousands of patients who have been studied for the progression of their disease in clinical trials and in other formats. And so at this point, there's a tremendous amount of data about how disease progresses over time. And of course, it's incredibly complex and differentiated patient to patient. But what these tools do is allow for using baseline data to predict how their individual course of disease will progress over time.

It's a model, and I think there have to be lots of questions about how robust the models are, what you can say about them, what you can't say about them, but potentially, they have the opportunity to do things like allow you to refine your patient selection. They have the opportunity to do things like be used as a prognostic covariate in analyses following trials. And I think there are a number of potential applications, but honestly, the only way to really evaluate how much value these things have is to begin to get in there and work with it yourself. And so that's effectively what we're doing.

We're using this at this point as an exploratory endpoint. We're trying to understand how these tools might be useful to us in the future. And I think, as I was saying, there are several potential ways they can be used. So that's what our evaluation will be to understand which ones are the best ways to apply this technology for Acumen.

Our next question comes from Thomas Shrader with BTIG.

A little background or next steps on the EBD franchise. Do you anticipate you would take both candidates into humans? Do you have to start with healthy volunteers? And any sense of how many patients or people you would need to get a read on anemia?

Thanks, Tom. Jim, why don't you take that one as well?

Yes, happy to. Some great questions, Tom. These are things that the team is actively working on at this point. To the first question, we have identified and nominated two candidates, ACU401 and ACU301. We're doing work on both molecules, and it really is intended to identify which one offers what we think is the best overall profile. So what we would intend to do is move into clinical development with one molecule, and that'll be the one that we think offers the best of possible profiles.

As far as additional work that we're doing, there's a tremendous amount of work on CMC and on tox study preparation in preparation for our plan to file an IND in mid-2027. And, I think we're still working on study design. There's a lot of active discussion around it. We've got a lot of experience from the INTERCEPT-AD study with sabirnetug that is going to help us identify what's exactly the best trial design to use. I think what I could say at this point is it's really going to come down to what's the most efficient design. We are going to try to get as much information as we can as we did in the INTERCEPT-AD study, but we also wanted to move this exciting program forward as quickly as we can. So more details later on what those design choices are going to turn out to be. But I can tell you there's a lot of active discussion right now with the program team trying to land what is going to be the most efficient design.

And are you going to start in healthy volunteers or are you not saying?

So, that's one of the things that we're going to see. I think the goal is to transition to patients as quickly as we think is practical because you get a lot of valuable information from patients, as in INTERCEPT-AD. But I think, exactly when that would be is honestly one of the things that we're still talking about. So, yes, I just, we haven't really made a final decision yet.

And one quick one for Dan. Do you expect to go radio silent at some point? And any guidance about when?

So, Tom, we continue to be convinced we'll have the topline results for ALTITUDE-AD late '26, consistent with our guiding for some time now. We have mentioned, as I mentioned on the call, we'll have an Investor Relations Day, September 16. And that'll be a forward-looking public-facing discussion. We anticipate participating in some of the early fall activities. So we'll be visible and accessible at some point as we get closer to the end of the year. In the fourth quarter, I think we will probably have to shut down some of our public-facing engagement in anticipation of results. But the timing and specific dates for that, can't comment on.

Our next question comes from Geoff Meacham with Citi.

I have two quick ones. The first, I know the focus on oligomers obviously differentiates you from Kisunla and Leqembi, but how would you set expectations on safety and tolerability and the differences there? I guess, particularly as we get more real-world experience with these two agents in the industry commercially.

Second question, I want to get your view of the recent competitor tau data when you kind of think about the post-ALTITUDE-ADdata. Is there a way to fast track perhaps a combo proof of concept if you think that's a viable strategy?

Thanks, Geoff. Good questions. I think in terms of safety, tolerability, and sabirnetug, as we described, ALTITUDE-ADwith two active doses is intended to demonstrate a clinical efficacy signal and a risk-benefit profile, both inclusive of the clinical efficacy relative to safety that is differentiated from existing treatments. So we're hopeful and enthusiastic about that possibility. And really just the magnitude of the study, the duration of exposure, we think it's a well-designed study to underpin and validate the oligomer hypothesis as we've positioned it. So that's sort of our expectations for sabirnetug and ALTITUDE.

I think that you mentioned the, I think that you're referring to the Biogen BIIB080 program that was reported at AAIC in July. And I think those are interesting data. It looks as though they'll move into a Phase III study for that molecule. And I think it serves as, depending on how you view it, the first clinical validation of a tau-directed approach. Ultimately, I think we take the view that Alzheimer's is a disease that will be more adequately addressed with combination strategies. So we'll continue to evaluate ways to leverage not only our portfolio of A-beta oligomer-directed approaches or treatments with other potentially synergistic combinations whether it be tau or anti-inflammatory approaches, but it just sort of underpins sort of the stage we're at in terms of establishing better treatment options for patients.

We think the future is quite bright for safer, more efficacious, and more robust treatment for the early stages of the disease. And as I'm sure folks on the call are aware, the move into the preclinical population, and hopefully a way to avert or otherwise delay the onset of symptoms. So it is a really robust innovation ecosystem right now in the space, and we think that will continue to accelerate both commercially with products being adopted and grown in the marketplace and then with further research innovations that will continue to build on better options for patients.

Yes, and this is Eric. If I could just expand on that a little bit. In terms of safety and tolerability, there's sort of two aspects of that that are differentiated with sabirnetug. So first of all, it's the target. It's very selective for oligomers rather than plaque, and we think that that has some potential benefits in terms of safety. And the other thing that is important to keep in mind, I think, is that this is an, what's called an IgG2 antibody rather than an IgG1 antibody. Without going into too many details, the IgG -- all the other monoclonal antibodies are IgG1s, and they have more what's called effector function.

In other words, they call in your immune system to get rid of things that you don't want there. In the case of these monoclonals, it's typically plaque. And that can lead to problems like ARIA. But for an IgG2, there's less of this effector function, so it's less effect on calling in immune cells. And for our mechanism, targeting oligomers, you really don't need that to happen anyway. So there's two reasons to think that our safety and tolerability could be quite good. One is that we have this differentiated target, oligomers, and the second is that we have an IgG2 antibody with less effector function and less immune system activation. So we're looking forward to seeing the data from ALTITUDE, obviously.

Our next question comes from Dev Prasad with Lucid Capital Markets.

Just a couple of follow-up questions. First is to follow up on the biomarker data question. Will that biomarker data be in the topline release or will it follow later? And the second is, what should we expect from September 16 IR Day? Will it include new EBD data or a preview of ALTITUDE-ADanalysis plan or a venue to select EBD lead candidates?

Thanks, Dev. So for your first question, the topline results, as I mentioned in the prepared remarks, will include the primary outcome, the iADRS, which is a composite including both cognitive and functional measures involving the ADAS-Cog as well as the ADCS Activities of Daily Living. We'll also have the CDR Sum of Boxes, again, another cognitive functional endpoint familiar to the agency and others in the field. We intentionally will include both fluid and imaging biomarkers as part of those topline results. We really want the ALTITUDE-ADreadout to be a robust readout that really determines sabirnetug's safety and clinical efficacy as part of the study design. So, yes, we do anticipate having both imaging and fluid biomarkers with the topline results late this year.

And then for IR Day, yes, so I would expect that to be more of a review of the investment thesis of Acumen. So whoever would like to get up to speed on sabirnetug and our EBD program prior to that Phase II data, that would be a good event for, viewers to tune into. So, yes, please keep it on your calendar.

I'm showing no further questions at this time. I'd like to turn the call back over to Alex Braun for closing remarks.

Thanks, Michelle, and thanks to everyone for tuning in today. As always, we are at the company for follow-up questions, and I hope everyone has a wonderful day.

Thank you for your participation. You may now disconnect.

Last day of Bank of America's Annual Healthcare Conference and a very, very warm Las Vegas. My name is Jason Zemansky. I'm one of the SMID-cap analysts here at BofA. And I'm very pleased to have join me on stage Acu Pharma (sic) [ Acumen Pharmaceuticals ], Dan O'Connell, Chief Executive Officer. Dan, thanks so much for joining us.

Thanks, Jason. Thanks to you and your colleagues for having us to the meeting.

Perfect. Maybe just to start at a higher level for those less familiar with the story. Can you briefly describe sabirnetug and its mechanism of action.

Sure. So just to introduce Acumen, real briefly, Acumen is a clinical stage company that is committed to advancing better treatment options for people living with Alzheimer's disease. Sabirnetug is our lead program. It's a humanized monoclonal antibody that has high selectivity for soluble toxic A-beta oligomers and that mechanism and for sabirnetug is one of the ways we think it has the potential to really differentiate on safety and efficacy measures for patients. That program is in Phase II study that will read out late this year. We can go into more of the details on that. But it's a very exciting time in the field and for Acumen. A second program that we've described in the last 12 months involves using enhanced brain delivery, so taking some of our therapeutic cargoes, sabirnetug and sabirnetug-like antibodies and using receptor-mediated transcytosis to deliver more of that payload into the brain and interstitial space. So that is slated to go to hit an IND milestone mid-'27, but really excited about that part of the portfolio as well.

Maybe if we could go a little bit deeper on the rationale for targeting specifically the oligomers versus other subspecies like the monomers, protofibrils, insoluble plaque.

Sure, Jason. So as our Chief Medical Officer is accustomed saying, amyloid is not monolithic. It has -- it comes in a variety of shapes, forms and aggregated states. So A-beta monomer is a normal physiological peptide that's produced with high rates in the body, accumulating aggregated A-beta has had a pathological consequence. It's really sort of the hallmark of Alzheimer's disease. In terms of therapeutic strategies, we think because these soluble aggregates or oligomers have, over a couple of decades, been shown to be potent toxins to synapses and neurons that they represent a distinct and attractive therapeutic target for slowing down disease progression in Alzheimer's disease.

And so some of the hallmarks of oligomer toxicity involve more circuit disruption, synaptic loss tau hyperphosphorylation and induction of calcium into cells and essentially initiating and propagating the neurodegenerative processes in Alzheimer's disease, which is distinct from monomer, which is really not toxic and shown really the strategies that have interacted with or targeted monomer have been ineffective, safe, but ineffective for the most part. And then there's obviously a lot of emphasis right now in the field on plaque reduction as a mode of getting to a clinical benefit. And we think sabirnetug and oligomer-directed approaches really offer a different approach that could yield improved efficacy and safety relative to those plaque-directed approaches that are kind of the current class, if you will, today.

Excellent. So it goes without saying a recent Cochrane review raised questions about the efficacy of the class. When you look at the results, how would you kind of -- what were your takeaways there? And again, kind of thinking about the evidence behind sabirnetug, what's your rebuttal?

Yes. Thanks, Jason. Yes. So for those of you that might not be familiar the Cochrane report was a meta-analysis looking at over a decade of A-beta-directed strategies towards clinical benefit for Alzheimer's patients. And that meta-analysis included a number of agents that have been shown to be failed and essentially shifts the conclusion towards those other programs, which didn't yield the results that -- at least the first 2 approved agents in well-designed controlled Phase III studies have shown clinical benefit of between 25% and 32% slowing on clinical measures and also other biomarker effects.

So I think the report itself, the methodology has been called out by many experts in the field. The Alzheimer's Association has sort of highlighted some of the flaws in the approach and the underlying conclusions that the report asserts. So we do think that it's been my own experience to sort of observe how the field has cumulatively learned what not to do in terms of more monomer targeting strategies and other things and has really found a path towards designing studies with the right population and now with agents that are really more prone and designed to target pathological species.

Maybe this is a good time to pivot to your INTERCEPT results. Can you briefly summarize what those were? And then looking ahead, what gave you confidence to move into the ALTITUDE Phase II?

Sure. So our INTERCEPT-AD study was the first-in-human study, Phase I single ascending dose and multiple ascending dose study in early Alzheimer's patients. And we deliberately included patients in both the SAD and MAD cohorts in order to assess key attributes of sabirnetug, including its safety profile, the ability to engage oligomeric target and to assess any impact on both imaging and fluid biomarkers. And in the study, the results of the study -- it's a short duration study. So the single ascending dose had 4 dose levels escalating over time, single administration of the drug, IV, I should mention. And then the 3 MAD dose cohorts had 3 different dose levels, again, where there were only -- excuse me, there were only 3 doses administered in that MAD portion of the study. And what we found in the study was robust target engagement and sort of dose proportional elements of engaging oligomeric target as measured by a novel assay assessing that complex of sabirnetug bound to oligomers in the cerebrospinal fluid of patients.

And corresponding with the target engagement, we also observed effects on imaging biomarkers of the amyloid PET, in particular, at the high dose levels, which moved the PET signal consistent with what's been shown for agents like lecanemab at a 3-month time point. In addition to the imaging biomarkers, we had assessment of CSF and plasma biomarkers. And there, though we hadn't had sort of overzealous expectations to see effects with such a short duration study, we actually moved kind of the standard fluid biomarkers of the AB of 42 to 40 ratio elements of phospho tau, so phospho-tau181 as well as ptau-217 in plasma. And intriguingly, we did actually see also on synaptic markers, neurogranin and VAMP2, again, achieving almost a statistical significance at some of the higher dose levels. So those are -- the totality of those results in Phase I gave us confidence to move into Phase II and kind of underpin our optimism for a successful result later this year in ALTITUDE.

Obviously, a very exciting year. We'll see the results of ALTITUDE at the end of this year. Can you help us frame expectations going in? What do you -- what would you like to see on the primary endpoint, the iADRS?

Sure. So in terms of ALTITUDE-AD, it's a robust Phase II study. We have 2 active doses versus placebo. The 2 dose levels are 35 mg per kg and 50 mg per kg, and this is Q4W dosing IV. There we have designed that with 180 subjects per cohort. So in as short as 10 months, we enrolled 542 patients in that study across 5 countries and with fewer than 80 sites. So there was a robust enrollment in the study. And I think it was attributed to the Phase I results, I think, enthusiasm for our mechanism advancing the field in terms of oligomer-directed approaches. The study is an 18-month placebo-controlled period, and the primary outcome is the iADRS, which is a composite score that includes aspects of the ADAS-Cog as well as the ADCS-ADL measure, so both cognition and function.

And what we would -- a clear win for us on the primary would be something in the 30% slowing over 18 months in this particular early Alzheimer's population. It is -- we'll also be looking at the CDR sum of boxes. We also have both imaging and fluid biomarkers. So the totality of the results are going to inform the next step for sabirnetug. But we -- the study conduct has been great. The early terminations have been consistent with our forecast and expectations. And last November, we had the first patient enrolled into an open-label extension. And that open-label extension has attracted high rates of conversion from the placebo into OLE in the upper 90 percentile in terms of people willing to stay in the study and know that they will be on sabirnetug for the open-label portion of the study.

Excellent. Well, I did want to pivot to your developmental -- more development portfolio. Can you tell us a little bit about the enhanced brain delivery system? What made you partner with...

JCR.

JCR. And what the potential sort of added benefit is there?

Yes, sure. So the field of receptor-mediated transport of larger molecules into the brain is something that's been evolving over the last couple of decades, again, where different targets on the blood-brain barrier have the ability to transport larger molecules, payloads or cargoes are the terminology that we use. JCR Pharma is a Japanese company that's been a pioneer in the field. They have an approved product using a transferrin-directed enzyme replacement therapy for Hunter syndrome. And we -- about 2 years ago, as the proof-of-principle data were coming out on a program that Roche has in Phase III now, it became apparent that these delivery modalities afford the potential sort of supercharge or enhance a product profile. So potentially greater efficacy, lower dose requirements, potentially improved safety and convenience. So those fundamentals were what kind of got our attention about sort of what should our strategy be.

And engaging with JCR, we found that their clinically validated approach, for instance, their IZCARGO product has not shown any anemia either in development or clinically. And we think anything that is directed towards the transferrin receptor has a potential vulnerability to inducing reticulocyte count drop and anemia in patients. And that's -- some of that has been observed with some of the ongoing programs. So we really like the validated clinical transparent-directed approach from JCR. And then we're delivering the payload of sabirnetug and another Acumen antibody called 234, which has similar potentially enhanced properties such as sabirnetug, so it had a little bit higher selectivity for oligomers over monomer even than sabirnetug. So we think both -- each of these agents and payloads are part of the candidate portfolio that we are close to designating -- 2 candidates as our -- exercising our option under the JCR agreement and looking to have a single clinical candidate to file an IND in the middle of next year.

If you look at your competitor data, I think a couple of things that we saw certainly better overall efficacy but more intriguing, I think, greater brain penetration. So is the idea that sabirnetug -- is there a potential for an overall synergistic effect going much deeper into the brain? Or is it a chance just to extend more linearly the efficacy?

So what's been shown with other agents, and we're doing work to sort of confirm this. We've already demonstrated in nonhuman primates that we get somewhere between 14 and 40-fold elevated levels of drug in the cortex relative to the unmodified antibody. So there, that's a pretty massive and very competitive enhanced exposure profile. I think the other element is that it's understood that using this transferrin delivery modality, a lot of the transference in delivery is through small capillaries. And so you're actually -- it's not just higher levels, but it's a more broadly distributed delivery of the payload or cargo. And in our case, oligomers have -- it's kind of interesting where oligomers sort of present early in hippocampal and other areas.

And so to the extent that we have not only enhanced broader exposure, but also within more diffused and harder to reach large parts of the brain anatomy, we think that could be very synergistic therapeutically. The only other -- another sort of mechanistic thing that I think is of some interest is there are transparent receptors on neurons, and there's also been evidence that there's interneuronal A-beta and whether you could actually get an antibody or a payload into a neuron and address underlying A-beta pathology, oligomer pathology with one of these enhanced brain delivery approaches is of interest to us.

That's great. We have about a minute left, so I'm going to ask probably the most challenging question for you. But you've maintained that anti-amyloid antibodies are likely to be foundational in Alzheimer's. And obviously, we had some news this morning on an anti-tau approach. So just can you give us your overall sort of high-level thoughts here?

Yes. So we do subscribe to the belief that anti-beta strategies are going to be a cornerstone of treatment for Alzheimer's patients for the foreseeable future. And that, that population of patients, not only the early AD population that we're working on right now in ALTITUDE and would anticipate in Phase III, but also the preclinical population. So I think the landscape or the opportunity is expanding. And it's being enabled by novel technologies, diagnostic technologies, plasma-based diagnostics. So that we would anticipate as sort of a cornerstone strategy. That field will continue to adopt new agents with differentiated mechanisms and better enhanced profiles, if you will. And we see that is really where sabirnetug and EBD play into that cornerstone approach. But I don't think anybody believes that Alzheimer's is a disease that is going to be most efficaciously treated with a monotherapy that there will be combination strategies.

And the news this morning on the Biogen tau program is -- sounds encouraging potentially. So we'll need to see more of the data. But to think that Biogen would be declaring a willingness to move forward based on what they've seen. And I think they probably do have a high bar internally for why they would continue given the nature of some of the things the company has experienced over the last bit of time. So I guess I'm optimistic that they're seeing something. We haven't had clinical validation of a tau strategy heretofore. So if they really do have evidence that they are on the right path, I do think that's a positive development for the field and something that puts us one step closer towards this combination strategy that ultimately may be the greatest benefit to patients. So hopefully, that was -- a tough question, but I'm optimistic that the future is still bright in the space, and we at Acumen have an important contribution to make.

It was a great answer. Really looking forward to the readout later this year. Dan, thanks so much for joining us.

Thanks, Jason.

Good day, and thank you for standing by. Welcome to the Acumen Pharma First Quarter 2026 Conference Call and Webcast. [Operator Instructions] 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 Braun, Head of Investor Relations. Please go ahead.

Thanks, Didi. Good morning, and welcome to the Acumen conference call to discuss our business update and financial results for the quarter ended March 31, 2026. With me today are Dan O'Connell, our Chief Executive Officer; and Matt Zuga, our CFO and Chief Business Officer.

They will have brief prepared remarks, and then we'll open the call for questions. Joining for the Q&A session, we also have Dr. Jim Doherty, our President and Chief Development Officer; and Dr. Eric Siemers, our Chief Medical Officer. Before we begin, we encourage listeners to go to the Investors section of the Acumen website to find our press release issued this morning that we'll discuss today.

Please note that during today's conference call, we may make forward-looking statements within the meaning of the federal securities laws. Including statements concerning our financial outlook and expected business plans. Please see Slide 2 of our corporate presentation, our press release issued this morning and our most recent annual and quarterly reports filed with the SEC.

For important risk factors that could cause our actual results to differ materially from those expressed or implied in the forward-looking statements. We undertake no obligation to update or revise the information provided on this call or in the accompanying presentation as a result of new information or future results.

With that, I'll turn the call over to Dan.

Great. Thanks, Alex. Good morning, everyone, and thanks for joining us today. I ended last quarter's call by emphasizing the progress we've achieved with sabirnetug and our next-generation blood-brain barrier EVD candidates and highlighted the important work and upcoming milestones that lay ahead. That message has not changed. In the first quarter, we continued to advance sabirnetug through our Phase II ALTITUDE-AD trial, building on the clinical momentum established over the past year.

The study remains a critical proving ground for our central scientific thesis that selectively targeting synaptotoxic a-beta oligomers rather than amyloid plaques may constitute a more effective and/or safer path forward in Alzheimer's. Execution has stayed on track, participants have been transitioning smoothly into the 12-month open-label extension study and the conversion rate remains high. We see this disciplined progress is bringing us closer to a potentially differentiated treatment option with people living with Alzheimer's. We expect our top line results for ALTITUDE-AD late this year.

As we've described, ALTITUDE is designed as a well-powered study to detect a statistically significant difference after 18 months on our primary clinical efficacy end point, the amount of slowing as measured by the iADRS. We expect to also report on key secondary endpoints in the top line results, such as the clinical dementia rating score some boxes, certain safety measures such as adverse event rates, including ARIA rates and key fluid and imaging biomarkers.

The study is designed to evaluate safety and efficacy of 2 dose levels, 35 and 50 milligrams per kilogram compared to placebo. Both of the active doses are within the range of exposures shown to have exhibited pharmacodynamic target engagement in our INTERCEPT-AD Phase I trial.

Our enhanced brand delivery EBD program is also advancing nicely. We are conducting additional preclinical work to fully establish candidate profiles and are very pleased with the output. We intend to submit a notice to exercise our option to license 2 compounds developed as part of our collaboration with JCR Pharma in the second quarter of 2026.

So this development is imminent. We expect to discuss those candidate profiles in greater detail at a future medical meeting and continue to anticipate an IND filing in mid-'27. We view EBD as a way to enhance our antibodies, enabling the potential to develop treatments with increased penetration and distribution in the brain while maintaining a favorable safety profile and allowing for patient-friendly subcutaneous dosing.

We recognize there is competition in this space. However, none with an a-beta oligomer targeted therapeutic cargo. This is where we see the potential to push the therapeutic index even further, attaining efficacy by engaging the soluble toxic species of a-beta throughout the brain. Also, JCR, our collaborator on our ABD program has clinically validated transparent targeting blood brain barrier receptor-mediated transcytosis technology. JCR has an approved therapy in Japan, which incorporates their technology and has exhibited little to no anemia. This anemia safety profile offers us further potential for differentiation with our carriers plus cargo EBD product strategy.

Taken all together, our EBD program adds optionality to our pipeline as an additional oligomer-targeted therapeutic strategy. While not currently contemplated in our immediate clinical development plans and anti a-beta oligomer EBD therapeutic could also potentially be studied in preclinical Alzheimer's. A population earlier in the disease course that could benefit greatly from a next-generation oligomer-directed approach. The progress we've made with sabirnetug and our next-generation EBD candidates reflect the strength of our science and ability to execute and sets a solid foundation for an exciting remainder of the year. I look forward to updating you on the imminent candidate selections in our EBD program and on our ALTITUDE-AD Phase II results in late '26.

And with that, I'll turn the call over to Matt.

Thank you, Dan. As a reminder, our first quarter 2026 financial results are available in the press release we issued this morning and in our 10-Q we will file later today. We ended 2025 with -- we ended March 31 with $128.4 million in cash and marketable securities on the balance sheet, which is expected to support our current clinical and operational activities into early 2027. This increase over the prior quarter is due to the private placement we completed in support of our EBD program that grossed $35.75 million, in which we announced in March of this year.

R&D expenses were $16.5 million in the first quarter. The decrease over the prior year was primarily due to a reduction in manufacturing and material costs as well as a reduction in CRO costs associated with our ALTITUDE-AD clinical trial, which completed enrollment in March 2025.

G&A expenses were $4.7 million in the first quarter, the decrease primarily due to reductions in legal fees as well as reductions in accounting, consulting and insurance expenses. This led to a loss from operations of $21.1 million and a net loss of $20.7 million in the first quarter. We are confident in our scientific innovation and strong track record of execution as we work toward our Phase II ALTITUDE-AD readout later this year and advance our EBD program. We remain dedicated to building value with our portfolio of a-beta oligomer-targeted antibodies for Alzheimer's patients, caregivers and stakeholders.

And with that, we can open the call for Q&A. Operator?

[Operator Instructions] And our first question comes from Pete Stavropoulos of Cantor Fitzgerald.

Congratulations on the continued execution of ALTITUDE. A question sort of about ALTITUDE. ALTITUDE is looking at Alzheimer's disease, similar to the approved amyloid beta antibodies. However, there are ongoing studies for preclinical Alzheimer's with a Phase III readout starting in 2027, assuming that ALTITUDE is positive and you move forward with sabirnetug. Could you just give us your current thoughts on which populations or patient types you would target in Phase III studies, what would trigger you to expand the preclinical Alzheimer's?

Thanks Pete, I can address that real quickly. In terms of our focus, we remain focused on the early AD population such as we've enrolled in ALTITUDE-AD see that as the path forward for sabirnetug in a future registration study. I think our interest in the preclinical population remains quite high. And as I mentioned, potentially part of the future opportunities ahead for -- principally for a EBD candidate.

So that's not an immediate part of our plans. But certainly, I think the science and mechanism neutralizing toxic oligomers in the early course of the pathogenesis of disease is something that is promising on the horizon.

And another question, please, on the EBD program. You do have different versions of 193 and 234. They have different PK profiles at least which we've shown to date. What are sort of the key properties and preclinical data that will drive you or drive the decision on candidate selection. And with an IND targeted, I believe, mid-2027, could you just walk us through how you're thinking about development plans and trial designs?

Sure. That's a lot, Pete. So I think, as you know, we've explored a lot of diversity in the EBD program, both from a carrier and cargo perspective, and we like sort of the -- having the ability to evaluate a series of candidates. We are down to the short list. And as I mentioned, we anticipate exercising our option for 2 candidates in the second quarter and remain confident that we will be filing an IND mid-2027. I don't know that we can go into the details of specific PK properties. But as we have characterized, I mean, the advantages of EBD you really have to do with broad brain distribution, potentially a wider safety margin and the subcutaneous dosing convenience.

So those are elements of what we are using as part of the filter for prioritizing candidates in that program. Jim Doherty, who's on the call. I don't know, Jim, if you want to add some additional color to comment on Pete's question.

Yes. No, I think that sounded great, Dan. I guess, Pete, the only other thing I would add, you asked about clinical program. I mean it's early days. So we're still thinking about what the early phase clinical program is going to look like. But I think we have a huge benefit in having conducted the INTERCEPT study with sabirnetug, it really gave us quite a lot of data, not only the safety and tolerability and PK data you typically get in the Phase I study. But since we were looking at Alzheimer's patients in the mad phase, we're able to collect data on PET imaging for a-beta, for biochemical biomarkers for a number of different things. And that's really helped us with the sabirnetug program. And so we're actively discussing how to incorporate that kind of thinking into the early clinical studies for the EBD program.

So more to come, but we're modeling what we've done on the sabirnetug program as a way to go forward.

And our next question comes from Geoff Meacham of Citi.

This is Mary Kate Davis on for Geoff. Just was wondering, could you please walk us through the early physician interest and feedback of sabirnetug, especially given the unmet need in early Alzheimer's and mechanism of the treatment. And then as a follow-up, could you just walk us through the ongoing regulatory interactions in anticipated discussions for the late-stage development of the program?

Thanks, Mary kate. Actually, Jim, why don't you take that. Jim and Eric, I think on the feedback we've received, we've done a lot of work at meetings and visited with a number of KOLs and other clinicians that have provided a broad set of feedback on the sabirnetug program in particular.

Yes, happy to do that, Mary Kate. And as Dan says, we've spoken to quite a number of KOLs about the sabirnetug program. And I think there's a lot of interest, obviously. I mean, we're testing a hypothesis that is slightly different than what's been tested so far with the approved therapeutics. And I think we can talk about both what those therapies have been able to do in treating patients and where there's opportunity. And we do think that the sabirnetug approach offers a differentiated opportunity from what's been done to date.

And I think that's generally understood by KOL. So I think everyone is very much looking forward to seeing the data as we release the results for the ALTITUDE trial in late 2026. But I think at this point, there's a level of anticipation to see that potential for a differentiated response.

Yes. And I might just add, we have spent a lot of time thinking about the differentiation of sabirnetug. And I think to sum it -- well, obviously, we don't have the data right now. We're in a blinded trial. But when we get the data one of the things that we'll look at, number one, would be efficacy because, again, we target oligomers which is different than the 2 approved drugs. And then the second thing is we'll look to see if we can differentiate on safety because our antibody is an IgG2, the 2 approved antibodies or IgG1s, igG1s have more effector function the potential for more ARIA. And so we're going to look at the safety data very carefully when those become available.

Yes. And other question Yes, go ahead.

Yes. And to your question around regulatory interactions, the ALTITUDE study, of course, is running in multiple countries across multiple jurisdictions. So we're obviously speaking to regulatory agencies in the U.S. and Canada and in Europe as part of all that. And then thinking strategically about the program we're, of course, engaging with regulators about the overall progress of both of our programs, both the sabirnetug program as well as our EBD programs.

And so that's something we'll continue to do. Obviously, it's quite important to stay in contact and to keep them apprised of progress. And so that's just the fundamental thing that we're always doing.

And our next question comes from Paul Matteis of Stifel.

This is Emily on for Paul. I wanted to say congrats on the quarter and just 2 quick questions from us. As it relates to the upcoming Phase II readout, what do you think would be a clear win that would prove out to sabirnetug to be a unique alternative to donanemab and lecanemab. And do you see kind of different scenarios at the different doses? And then as a follow-up to that, assuming success in Phase II, would you be able to incorporate a subcutaneous arm in a Phase III program? And maybe any color on the subcutaneous timelines would be helpful, too.

Thanks, Emily. So I think in terms of a clear win in ALTITUDE-AD would be an efficacy signal. At least a 30% of flow, which is sort of the maximum or the upper end of the boundary, I think, for the current approved agents. So we are hopeful and anticipating that by targeting toxic species in a directed fashion, selective fashion that it will unlock greater efficacy. I think the safety profile, I think there's now a real world evidence to sort of suggest what the overall rates of ARIA. And of course, those rates of ARIA differ by genotype. And so those are some of the other elements of what we'll be looking to establish in terms of ARIA.

So it's -- I think it will be the totality of the ALTITUDE data and really this sort of the risk-benefit profile sabirnetug with the combination of efficacy and work safety is positioned as the primary means of differentiation relative to the current approved agents. And in terms of subcu, I think we've previously guided that we will be looking at the Phase II data, particularly in respect of the 2 active doses that are being investigated in ALTITUDE to inform precisely where and how we would advance the ongoing work in subcu as part of the Phase III program.

And I might add, Emily, I think you asked an interesting question as well around doses. As you know, there are 2 different doses included in the ALTITUDE study. And those doses were chosen to sort of bracket the range of oligomer clearance as measured by our target engagement assay in Phase I. So we think we've got an interesting range of doses chosen. And it will be -- I'll be very curious to see how that impacts the results both from a point of view of efficacy and safety, as Dan said. And so that's an interesting feature of the ATTITUDE study is that we've got both of those doses to investigate.

Yes. And just one other point about the ARIA. I think one of the concepts that's across the field now that's being better appreciated is that it's really symptomatic ARIA that you're really concerned about. And even if the symptomatic ARIA it's serious adverse events that you really worry about. So those are nearly as common, but obviously, they have a bigger impact. And so that's one of the things that will be benchmarking pretty carefully when we do get our data.

Our next question comes from Jason Zemansky of Bank of America.

Congrats on the great progress. I wanted to ask a question maybe from a different perspective here. But over the last several weeks, we've seen both the Cochrane report questioning the value of the anti-amyloid class. And I guess, a few days ago, there was an article that detailed that use of the current commercially available anti-amyloid antibodies has been slower than expected. So -- as we kind of take a step back and think about both the overall unmet need and sort of the overall sort of view of the classic itself, what do you think is necessary from ALTITUDE and any sort of Phase III you do to really demonstrate that there's a level of differentiation here as well as overall efficacy to the point that it sort of turns back some of the skeptism.

Jason -- so I think in terms of the Cochrane report, I think there's been a good bit of follow-up in terms of the methodology there. And I think there's your question about kind of the merits of the approach from a methodology standpoint. I do think that I'm familiar with the stat article as well. And I think it speaks to sort of 2 things, the unmet need and the demand for better options and the fact that there is -- the clinical infrastructure is now -- has been established and continues to adopt and progress the make available these first couple of agents and build out essentially the marketplace. I think what the market is looking for is a more clear value proposition in terms of the risk-benefit profile. And that's really where reading out ALTITUDE and validating the oligomer hypothesis. I think Acumen and sabirnetug stand at really attractive position from a timing perspective sort of reenergized the space and position next-generation treatment options.

I think the field has progressed over a number of years to develop better insights into clinical trial design, which patients to treat underlying aspects of the pathophysiology of the disease. And so we view sabirnetug as sort of that next position advancing the field forward on the basis of positive data.

And I might just add, I was recently at the American Academy of Neurology meeting in Chicago. And these are practicing neurologists for the most part. There was a great deal of interest and enthusiasm for information concerning the 2 approved drugs, lecanemab and donanemab. So even though there have been these relatively negative analysis, and again, as Dan mentioned, the Cochrane report was pretty flawed and a lot of people's opinions in terms of how they did the analysis. I think if you actually talk to neurologists, they understand that the infrastructure has been rate-limiting but that infrastructure is going to continue to improve. And so there is a lot of interest from neurologists at the AAN meeting.

And our next question comes from Tom Shrader of BTIG.

This is Jimmy Kim on for Tom Shrader. At ALTITUDE-AD approaches the late 2026 top line readout, could you give us some additional color on the blinded operational metrics are tracking things like protocol deviation rate, site level dropout patterns or any shifts in enrolled patient population profile relative to your original assumptions. More broadly, what distinguishes the quality of this data set relative to prior anti-amyloid trial?

Thanks, Jim. Jim, Do you want to lead out on that and Eric provide some color?

Yes. Jenny, I'll give you a first pass and then ask Eric to weigh in. I think probably the best thing to say is that we, at this point, have been very pleased with the progress of the ATTITUDE study. Any of these studies is a 542 subject study. There's a lot of data and a lot of information flowing in the study. But we've been relatively pleased with the conduct of the study. It's a great team that is working extremely hard across multiple geographies to deliver the data. And I think to date, we have been tracking to the assumptions that we built into our study design.

So we are -- we have confidence in our study design as well. And I'll turn it over to Eric to give you any specific commentary.

Yes. So thanks for the question. The study is progressing quite well. I think as you know, we completed enrollment in a very short period of time in 10 months. One of the things that we did in our study, which is being done in other studies, that is quite innovative, I think, was to use this plasma p-tau217 test as part of the screening procedure.

So in other words, when we did our Phase I study to get into the study, you had to have a positive PET scan and it turned out that about 60% of the time, the PET scans were negative. When we added this blood test, simple blood test as a screening step before you got to PET scans, the rate of negative PET scans drop from, again, around 60% to under 20%.

So it made the screening process much better. We heard feedback from the sites that they really like that approach. I think that's something that could be used in clinical practice. And actually at the American Academy of Neurology meeting, there was a lot of discussion about how you would use these plasma biomarkers as part of your screening process for patients.

So we were really very pleased how that worked out in our trial, and we're looking forward to seeing that utilized in clinical practice.

Our next question comes from Dev Prasad of Lucid Capital Markets.

Congrats on the progress. Just following up on the previous question regarding Phase II doses how much separation between 35 mg and 50 mg do you expect? And what would you need to see to select a Phase III dose? Also on EBD program. Can you provide more detail on 14 to 40x higher brain exposure that you observed in the primates. What differentiated those exposures such as dose, route, brain, distribution, et cetera?

Thanks, Dev. Jim I'm going to direct those straight to you.

Yes, Dev, so happy to take those questions. So when we think about dosing for the ALTITUDE study first. The doses are 35 mg per kg and 50 mg per kg. And I was mentioning earlier, the doses were sort of chosen with the idea in mind that, that is what looks to be a key part of the dynamic range and exposure of soluble oligmers, which, of course, is our key primary target. And I think there's the opportunity to see effects differential effects of the 2 doses in a couple of different ways. I mean we'll have to wait and see what the data actually show.

But one possibility is differences in efficacy. You might expect to see dose-related differences in efficacy. Although I think part of what we're testing there is what the role of the soluble oligmers is and how that's different from what you've seen to date with more plaque targeting antibodies. So in some ways, the lower dose may give more of an oligmer-specific signal. Although we do expect some contribution from other species of a-beta even at that dose. And then certainly, as you go to a higher dose, you would expect some additional effects on larger species as we've seen in the INTERCEPT study in Phase I. And I think also, one might expect there could be some differences in tolerability, right? I mean that would be again, consistent with the Phase I data.

So very excited to see the study at the end of the year, and we'll be looking at all of these things for differential effects at multiple doses. And then I think your other question around the EBD programs. So of course, what we're trying to achieve is both an improvement in brain penetration, but also the brain distribution of our oligmer targeting antibodies by coupling with the carrier technology from JCR. And so what we've done is we've investigated multiple candidates is we've been able to vary both sides of that equation.

So looking at the changes to the carrier choices from JCR as well as modifications on the cargo side. And really, the quick way to summarize it is what you're seeing is a range of substantial improvements in brand exposure. And that's in both rodent studies using humanized [ tranferrin ] receptor. And then also in primate studies. And so we're looking at multiple brain regions and so in the primate study.

And so we're seeing really substantial improvements and you quoted the range between 15-fold and 40-fold improvements in exposure. And so we're seeing both that improved brain penetration as well as distribution. And we really think it's both properties that are part of what makes this technology so exciting for the treatment of Alzheimer's and specifically for soluble oligomer approach.

So that's what I can say to date. We are keeping a close eye on which are the best candidates to give us the broadest distribution in multiple brain regions.

Thank you, this concludes our question-and-answer session and also today's conference call. Thank you for participating, and you may now disconnect.

Ladies and gentlemen, thank you for standing by. Welcome to the Acumen Pharma Fourth Quarter 2025 Conference Call and Webcast. [Operator Instructions] Please be advised that today's conference is being recorded.

I would like now to turn the conference over to Alex Braun, Head of Investor Relations. Please go ahead.

Thanks, Michelle. Good morning, and welcome to the Acumen conference call to discuss our business update and financial results for the year ended December 31, 2025. With me today are Dan O'Connell, our Chief Executive Officer; Dr. Jim Doherty, our President and Chief Development Officer; and Matt Zuga, our CFO and Chief Business Officer. They will have brief prepared remarks, and then we'll open the call for questions. Joining for the Q&A session, we also have Dr. Eric Siemers, our Chief Medical Officer.

Before we begin, we encourage listeners to go to the Investors section of the Acumen website to find a press release issued this morning that we'll discuss today. Please note that during today's conference call, we may make forward-looking statements within the meaning of the federal securities laws, including statements concerning our financial outlook and expected business plans. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements.

Please see Slide 2 of our corporate presentation, our press release issued this morning and our most recent annual and quarterly reports filed with the SEC for important risk factors that could cause our actual results to differ materially from those expressed or implied in the forward-looking statements. We undertake no obligation to update or revise the information provided on this call or in the accompanying presentation as a result of new information or future results or developments.

In that, I'll turn the call over to Dan.

Thanks, Alex. Good morning, everyone, and thanks for joining us today. 2025 can be defined as a year of execution and expansion at Acumen. We made demonstrable clinical progress for our lead program, sabirnetug in our Phase II ALTITUDE-AD trial, which we consider an important test of our core hypothesis that synaptic toxic amyloid-beta oligomers play a pivotal role in the development and progression of Alzheimer's disease. ALTITUDE is a well-powered Phase II study that is investigating sabirnetug, our monoclonal antibody with high selectivity for a-beta oligomers. Sabirnetug selectivity for toxic oligomers is central to why we believe it could unlock potentially greater clinical efficacy and improved safety relative to amyloid plaque directed antibodies.

We are closely tracking to plan with ALTITUDE. We completed enrollment about a year ago, and the participant transition into the 12-month open-label study that started last November, continues to be smooth and with a higher rate of version. In 2025, we also expanded our pipeline in our persistent pursuit of innovation along with our mission of improved treatment options for people impacted by Alzheimer's. Our enhanced brand delivery or EBD partnership with JCR Pharmaceuticals which combines acumens a-beta oligomer targeted therapeutic cargo with JCR's validated blood brain barrier carrier technology holds potential to produce a true next-generation differentiated therapy for Alzheimer's disease.

We think of EBD as supercharging our antibodies to significantly brain penetration and distribution with potentially lower safety risks and in a convenient subcutaneous dosing format. We believe our EBD approach is well suited for study in a preclinical or presymptomatic AD population and though not contemplated in our immediate clinical development plans, we foresee that population as an attractive opportunity for the future.

2026 is poised to be a transformative year for Acumen. We expect to read out ALTITUDE-AD late this year, inclusive of key clinical efficacy and safety measures. We believe the study results will inform our development strategy in the field more generally, in terms of better understanding of the impact of clearing a-beta oligomers in Alzheimer's patients.

Our optimism for the success of ALTITUDE is based in part on imaging and fluid biomarker data from our Phase Ib INTERCEPT study. For instance, after just 3 doses at the final 3-month time point, sabirnetug showed positive effects on pTau181 and neurogranin levels in CSF. These are competitive indicators in the AD space and continue to gain acceptance as diagnostic and clinical markers of disease. We view these data as supportive of sabirnetug's potential in Phase II, which assesses safety and efficacy of sabirnetug over 18 months of treatment.

We're obviously very excited to see these data later this year. Our EBD program is also gaining momentum. Just last week, we announced preclinical data, including in vitro, in vivo and nonhuman primate study results that support multiple potential development candidates in the program. Jim will speak more about these results in just a minute. Importantly, the profiles achieved exceeded our target product profile for the EBD program and catalyzed a roughly $36 million private placement.

As of now, we are targeting a filing of an IND for a clinical unit in mid '27. A final look on the sentiment in the AD field. We just returned from the ADPD conference in Denmark, where the energy and momentum in the Alzheimer's space was palpable. Between real-world data supporting the currently marketed therapies, the growing evidence that targeting a-beta is clinically beneficial as well as the adoption of blood-based biomarkers to streamline development diagnosis and treatment, this is a hopeful time for Alzheimer's patients and their families. It's also important to realize we are still in the beginning of the treatment elution in AD and ample opportunity exists to provide improved benefit risk options for patients.

Between sabirnetug's ALTITUDE-AD results in our next-generation EBD program advancing this year, we at Acumen believe our commitment to scientific innovation and track record of execution will enable us to deliver differentiated treatment options for Alzheimer's patients.

And with that, I'll turn the call over to Jim.

Thanks, Dan, and to everyone on the call. Happy to be here with you today. At an said, we're very pleased with the candidate profile is generated in our preclinical EBD program and impressed with the level of expertise contributed by our partner, JCR Pharmaceuticals. Each EBD candidate consists of 2 elements: a cargo in this case, inhibited oligomer targeted antibody and a carrier, which is JCR's transferrin based blood-brain barrier receptor-mediated transcytosis technology.

Sabirnetug has demonstrated robust fluid biomarker results in the INTERCEPT Phase I study, as Dan just meant, and also showed relatively low rates of REE and IRRs. JCR has clinically validated their technology, which is used in an approved therapy in Japan with little observed anemia. By combining these components, we aim to develop a therapy for AD with enhanced efficacy, low REE and anemia risk and subcutaneous dosing. We've been working diligently with our JCR colleagues over the last 18 months to combine our soluble AB targeting monoclonal antibodies with their EBD technology to develop novel EBD candidates that significantly enhance brain distribution while maintaining a soluble A-beta oligomer targeting profile.

Our testing cascade included measures of transferrin receptor affinity, single chain or VHH architecture, balance, stability and functional selectivity of our antibodies for oligomers following attachment of the JCR carriers. We brought a number of these candidates into a nonhuman primate study, which demonstrated between 14 and 40-fold higher brain levels when compared to the native antibody control at a time point of 24 hours post dosing.

Hematology data in nonhuman primates indicate potential for anemia with no observed change in red blood cell count, hematocrit, hemoglobin or reticulocyte counts at 24 hours after subcutaneous dosing. Stability was also favorable and supportive of subcutaneous dosing with low-volume devices. These profiles exceeded our expectations for a target profile in our program meaning that we now have diversity and flexibility in nominating an IND candidate, which is targeted for mid-2027.

With optimized cargo and carrier components, we believe we are on a path to developing a potential next-generation EBD treatment for people living with Alzheimer's disease.

And now I'll hand the call over to Matt.

Thank you, Jim. As a reminder, our full year 2025 financial results are available in the press release we issued this morning and in our 10-K we will file later today. We ended 2025 with $116.9 million in cash and marketable securities on our balance sheet, which is expected to support our current clinical and operational activities into early 2027.

R&D expenses were $104.9 million in 2025. The increase over the prior year was primarily due to an increase in manufacturing and materials associated with our ALTITUDE-AD clinical trial, as well as personnel-related costs and research expenses, including EBD research.

G&A expenses were $18.9 million in 2025, the decrease primarily due to reductions in recruiting expenses, corporate insurance expenses and consulting costs. This led to a loss from operations and a net loss of $121.3 million in 2025. As Dan mentioned, on March 16, 2026, we closed a private placement in support of our EBD program that grossed $35.75 million before offering expenses, which were minimal. We believe this involvement from committed institutional investors strongly validates our portfolio and our enhanced brain delivery strategy. Proceeds from the financing are expected to primarily support our EBD program, including ongoing preclinical development work to support the nomination of a lead clinical candidate molecule and for working capital and other general corporate purposes.

We are confident in our scientific innovation and strong track record of execution as we work towards our Phase II ALTITUDE-AD readout later this year and advance our EBD program. We remain dedicated to building value with our portfolio of a-beta oligomer targeted antibodies for Alzheimer's patients, caregivers and stakeholders.

And with that, we can open the call for Q&A. Operator?

Michelle, are we ready for Q&A?

[Operator Instructions] Our first question will come from Pete Stavropoulos with Cantor Fitzgerald.

This is Samantha on the line for Pete. So my first question related to the ALTITUDE-AD study, how is patient retention been so far? How is it trending relative to your initial assumptions? And you previously announced that the first patient enrolled in the OLE in November. Can you give us a sense of how roller into the OLE have progressed overall? Any details you can give would be very helpful? And what, if anything, does the retention rate and rollover rates suggest to you about safety, tolerability? And how do they compare to other studies such as lecanemab, and donanemab?

Thanks, Samantha. Jim, do you want to take a first pass at that?

Yes, absolutely. Happy to give you a response, Samantha. I'll ask Eric to comment when I'm done. Yes. So you asked about retention and rollover rates for the ALTITUDE study. And really, as Dan said in his prepared remarks, we've been very pleased with the overall progress of the ALTITUDE study, and that includes what we're seeing both in terms of retention in the study, which we think our numbers are in line with what's been observed in a lot of the other major Alzheimer's trials that have been conducted recently.

And from a rollover perspective, we've been very pleased with the rate at which people are rolling over into the open-label extension. So in both cases, metrics consistent with the trial progressing nicely.

And then to your other question around how those numbers relate to things like overall safety and conduct in the trial. Of course, as you know very well, a blinded study, and we don't try to take too many interpretations away from those metrics other than to say, given that those metrics are well in line with other studies and that consistent with the overall progression in the study, where we're not seeing anything that we feel to be out of line based on those numbers. So basically, at this point, the study continues forward.

Eric, anything you'd like to add?

Yes. No, that's a good summary. As you mentioned, this is an ongoing blinded study. And so a lot of the answers to the questions you're asking, we'll see at the end of the study, but so far, the study is run remarkably smoothly, I would say. I mean, we've not had to order the protocol for dosing and that sort of thing. The retention rate has been good. And again, the rollover rate of people going into the open-label extension has been very satisfying. I think it's a good sign that people sort of like the study and are satisfied or happy with the safety profile.

So we're looking forward to the results at the end of this year. There's a limited amount that you can know for an ongoing blinded study, but especially, for instance, how we would compare to clarity, which is the pay population that's probably closest to what we're studying we'll make those comparisons at the end of the year when we're on blinded.

And if I could just sneak in one more question. the EBD came. So you've generated different versions of sabirnetug with JCR EBD as well as another anti-A-beta oligomers antibody 234 from your portfolio. What have you seen in preclinical studies thus far in rodent models and primate studies that suggest you have viable candidates and that one candidate may ultimately have better efficacy over others? And what gives you confidence that you're on the right track?

Yes. Thanks, Samantha. We're -- as I said, we're really pleased with the progress we've been seeing. We -- as you go through a typical discovery program, you make a lot of analogs. And given that there are several, what I would call, flavors that JCR has of their transparent targeting technology, we really were looking at how to best combine the 2 pieces. I talked about the cargo in our case, either sabirnetug related oligomers targeting antibody and then various flavors of the JCR technology. And you can imagine the matrix, you match and you look to see which has the best overall profile.

And having done that, I think one of the most attractive things from my perspective, having done this for a long time, is there are actually multiple candidates we like. Often the case, you're really looking to identify which one is the one you want to take forward. We're actually in the happy position of liking the profile of a number of these candidates. And so it's a combination of the enhanced brain penetration. So I mentioned in my remarks that in a study, we're seeing 14 to 40-fold improvements in overall brand exposure, which is a substantial change in brain levels, and we believe that, that's going to have multiple positive implications.

Beyond that, it's also the overall profile and things like and the sort of distribution that you get of the antibodies. So all that together, kind of well for the overall profile. And really, multiple candidates met not only our target profile for progression, but what we are calling sort of an idealized profile. So we'll see plenty of work left to be done. But where we are today, we think we're in a good position with multiple really robust candidate.

Congrats on the quarter.

And our next question is going to come from Paul Matteis with Stifel.

This is Matthew on for Paul. Congrats on the progress. I guess for my first question, are you planning to present additional NHP preclinical data for your EBD program in the near future? What should we expect there? And for my second question, we appreciate there's more brain penetration with the EBD program. But with sabirnetug already being pretty selective in targeting oligomers. How much more room do you think the EBD can improve on this?

Yes, please.

Yes. So to your first question around the -- what we presented in more data. So over the last few major scientific meetings, we've been increasingly presenting data from the EBD program. So now we've sort of shown data from the humanized mouse with the humanized transferrin receptor expression. We've also -- we have some mouse constructs. And I'm sure you know, one of the challenges with doing experiments around these transferrin targeting constructs is transferrin itself is very species-specific. And so it's difficult to do experiments with the candidate molecules in a mouse or rodent system.

So you can either use humanized mice or analogs that have the mouse transparent receptor, so not your candidates, but sort of the mouse version. We've done both kinds of experiments, and we started to publish on those. We've talked about some of the data that we've seen so far in the nonhuman primate study. I think as we go along, we've got some more work to do in our preclinical program ahead of the IND, and we continue to be publishing more of the overall data set in support. I don't know whether we'll pick out individual is, but I think we'll continue to tell the story in upcoming scientific meetings.

And then to your second question, do -- certainly, we already really like the profile of sabirnetug. And so as Dan called it, we think that this is sort of supercharging that profile. And one of the words that I said when I was talking about our EBD program is we really think that we're going to improve the distribution of antibodies with the technology. So of course, just that absolute change in magnitude that 14- to 40-fold improvement in the overall brain levels, we think is beneficial.

But beyond that, because the transferrin receptors are localized in small capillaries that run throughout the brain, where the antibody gets into the brain is different with these EBD constructs. And we think that's also an additional value that you don't see with a non carrier-mediated antibody. So -- and you can see that in multiple presentations that multiple groups are making showing that you get a much broader pattern of distribution with this EBD technology. So yes, multiple reasons to think that you can see a supercharger enhanced profile with our EBD program.

And our next question will come from Jason Zemansky with Bank of America.

Congrats on the great progress. Maybe just a follow-up to your previous comment. As you think about the potential of an EBD enhanced molecule. What is your sense now, and I appreciate this may be somewhat theoretical of the distribution within the brain of the different A-beta species. Is there a sense that the oligomers are deep in the brain, where an enhanced antibody might penetrate?

And then secondarily, I was hoping you could speak to why you think you're seeing lower rates of the impact on the reticular sites and anemia that or the other transferrin antibodies have shown?

Yes, absolutely, Jason. So to your first question, distribution of the oligomers, yes, you're right, that it is somewhat a theoretical topic. But I think probably a couple of [indiscernible] if you look at things like immunohistochemistry, it's pretty good evidence that you've got broad distribution of soluble oligomers across multiple cortical and subcortical regions, and there's been a lot of work published around the pattern of a-beta distribution overall. And I think that the soluble oligomer pattern is not terribly different than that overall.

I think there might be a -- because it's a small soluble form of a-beta, you get an even wider distribution than you have something like plaque. So pretty broad throughout cortical and subcortical regions, which I think is part of the reason why an EBD delivery is attractive because since you are going in through the fine capillaries, there's really sort of no part of the brain fragment that's not within a couple of hundred microns of some capillary. So you do get broad overall distribution.

At the recent ADPD meeting, there were some very nice presentations looking at sort of entry of antibodies of a-beta targeting antibodies into the brain that don't have EBD technology. And what you're seeing is it's not only the areas of the brain, we're getting in, but it also tends to penetrate from leaky parts of the broad brain barrier for one of more time for a longer answer. And so you see things like superficial layers where you're getting antibody in, but the deeper cortical layers you don't get as much antibody in. So it's not only regional distribution, but it's sort of the parts of the cortex where your antibody is penetrating. So obviously, anything that can prove that is likely to have a beneficial effect on function.

And your second question, sorry, remind me, Jason?

The lower rates of anemia that have, I guess, less apparent in the preclinical data.

Right. Thank you. Yes. So part of the reason that we decided to work with JCR is they do have a tracer from their clinical programs with a drug called cargo, where they were able to deliver enzyme to the brain for the treatment of Hunter syndrome in Japan, but they did see lower rates of REA -- or sorry, lower rates of anemia with their study. And so we do think that JCR's technology has reason to think that you'd have lower anemia rates. I think it's likely to do with the specific epitopes that they're targeting on the transferrin receptor, but that's why we were so pleased to see in our nonhuman primate study, a similar pattern where at 24 hours, which is where you'd expect to see the most robust effect on things like reticulocytes head count, we were not seeing much impact quite consistent with what they've seen clinically.

And our next question will come from Tom Shrader with BTIG.

A lot of good questions on the shovel. You're quoting numbers for uptake that are significantly higher than your competitors, I think Roche quotes numbers around 10. Are you sure you're better and you're quoting ratios, do you have data on amount that you're getting in? Because obviously, the ratio depends a little bit on where you start. And then I have an OLE follow-up.

Yes, Tom. So when we are -- you're correct when we're quoting numbers, we're quoting the ratio relative to brand penetration from the nonenhanced antibodies. And I think that's the appropriate way to do it. I try to shy away from statements like better or worse. I mean these are not head-to-head comparisons. But what we can say is we're seeing robust increases in levels of antibodies relative to the unlabel controls. And so that's how we look at it.

We're seeing robust improvements. And I think that compares well with what other people are seeing. I think I try to stay away from direct head-to-head numbers unless those studies have been done together.

Fair enough. And in your OLE study, what are you going to continue to measure? Are you still going to do a-beta scans? And I understand you don't have a ton of data, but is your expectation that after 18 months, based on the plaque clearance you've seen, most patients will have cleared plaque? Or do you expect a lot of them might still be clearing plaque? I'm just wondering if you've made those calculations, what your summary is?

I think Eric is probably best positioned to answer this one. So Eric, do you want to take this one?

Yes, sure. So for these open-label extensions, typically what's done and this is what we've done is, you measure the same things, but you do it generally less frequently. And that's just a matter of patient boot basically. I mean, obviously, everybody is on drug at this point. There's no placebo group. So you do want to measure the same things and you want to look at a couple of things. One is the people who are originally on drug, how they do as they continue for a longer period of time.

Then we also have 1/3 of the patients in ALTITUDE originally on placebo. And that will be interesting to see the effect once they go on active treatment. As far as the question about plaque reduction, it's a great question. And I don't know that there's any way that we can really know what to expect at the end of 18 months. Now we know in their Phase I study after 3 months at the highest 2 doses at 60 mg per kg and 25 mg per kg every 2 weeks. We did see some plaque reduction. And the amount of plaque reduction at 3 months was about the same amount of plaque reduction that was seen for lecanemab after 3 months. But what what our plaque reduction will be at 18 months, I don't think we really can say at this point. I mean, that's why you do the study to get the data. And -- that's one of the things, obviously, that we'll be very much looking forward to is to finding out.

Does the plaque load continue to decrease or to the plateau out because in our case, we target oligomers. We don't target plaque. So plaque production isn't necessarily needed in our case, but it will be a very interesting part of the readout when we unblind the end of this year.

And our next question is going to come from Geoff Meacham with Citi.

This is [indiscernible] on for Geoff. So just first question, was an IND targeted for mid-2027 for your EBD program. Could you walk us through how you're looking at maybe trial design for an early-stage trial here? And then a separate question on sabirnetug, as you guys approach DIN Phase II later this year. Could you walk us through the type of feedback you're receiving from physicians on where sabirnetug maybe addressed the unmet need in the space here?

Yes, of course, [indiscernible]. So I'll take your first question around trial design for EBD. And again, I'll ask Eric to jump in around feedback around how sabirnetug might fit. From a sabirnetug perspective, I think the first thing to say is still early days. We are in the midst of working on trial design. We do think that we can take advantage of the fact that we've got quite a lot of clinical experience now with sabirnetug in designing our study. And in particular, we've got quite a lot of value out of including Alzheimer's patients in the Phase I study for sabirnetug. And so that's likely to be a feature for the EBD program as well. both from the point of view of safety tolerability, but equally important, I think, is we were able to generate quite a lot of biomarker data, both imaging and fluid biomarkers in the INTERCEPT study.

And in the couple of years since that study was conducted, that field only continues to expand. So there's actually quite a lot of interesting information. I think that one can glean from those fluid and imaging-based biomarkers. So those are the kind of the key thoughts. I think the other thing that we'll think about is perhaps the length of the study. That's one thing that we might look at in the INTERCEPT study, as I'm sure you recall, multiple ascending dose was a total of 3 doses spaced at a once-monthly interval. So we'll have a look at the whether it makes sense to dose for longer than that. But I think as I said at the top, the final decisions haven't been made in design yet. But we do intend to take full advantage of what we've learned from our ongoing sabirnetug studies.

And then for your second question around -- feedback around positioning for sabirnetug, let me turn it over to Eric and let him speak.

Well, yes. And in terms of how this would be positioned, I'm not sure what exactly you're including in all this. But obviously, there's 2 drugs that are approved right now in the U.S. And so we'll -- once we have our data, we'll make some comparisons with those. But we do think that there's really and I think everyone would agree, there's room for improvement with the currently available drugs. And one of the things that the field has actually learned over time is that, in particular, with regard to ARIA and safety is that when this was sort of a new event that the field hadn't seen before, it was certainly concerning, but over time, what the field has learned is that what you really worry about is symptomatic ARIA. And actually, it's just the people with severe symptoms.

So in other words, most cases of ARIA symptomatic. It's just a radiographic finding on an MRI. There are roughly, roughly 20% of people who have ARIA do have some symptoms of those people, most of those are fairly model. You may have a headache for a few days, some difficulty walking for a couple of days, but nothing that's -- I've said, nothing that's really problematic. The ones that you really worry about are the rare cases of people who have serious symptoms. And those include things like status epilepticus, macro hemorrhages, there actually have been some fatalities unfortunately.

And so even though it's a small percentage of patients that have those kind of serious adverse events, those are the ones, obviously, you really worry about. And so I think as the field progresses and as we read out our data, one of the things that we'll want to look at is do we see people with serious adverse events? And how does that compare with the other drugs that are available, we're in IgG2 and the other drugs are IgG1s. And IgG1 has more of what's called effector function, so it triggers more of an immune response. IgG2 has some effector function, but not as much as an IgG1. So again, when we read out our data at the end of this year, we'll find out whether that differentiation of an IgG2 versus an IgG1 makes a difference. So I hope that answers your question.

And our next question comes from [ Dave Prasad ] with Lucid.

Congrats on the update. I have couple. One is the oil is dosing at 35 mg per gig rather than 50 mg per kg. Can you remind us and maybe add some color around what drove the dose selection? And if ALTITUDE-AD is positive, what are your current thinking on the Phase III design? Would you plan single pivotal trial or to or would you pursue 2 dose are single? Then another question is on NHP. So the exposure shows 14 to 40x range. Can you help us understand what's driving the variability? And is the 40x candidate also done with the best anemia profile?

Yes. Thanks, Dave. Happy to take the questions. Maybe we'll take them in reverse order, and I'll take the first 2 and then ask Eric to comment on the choice of the 35 mg per kg dose for the OLE. First, to the variability question in the EBD. I think there's a couple of things at play here. So we are looking at brain levels across multiple regions. And so in a summary like this, where we're just giving you the overall range of numbers. So there's also looking at the levels in front cortex versus Hippocampus versus other brain regions. And so I think there's always going to be a little bit of variance between those numbers.

But I think what you see more than anything across multiple candidates in the primate study, there's generally some pretty good consistency. So the variability is more between candidates than between brain regions for a single candidate, which is kind of nice. And then I think really, all of the candidates we saw had low risk for anemia as measured at the 24-hour time point after subcutaneous dosing. So were actually part of the reason I said earlier that we think that we're in a really good spot is multiple candidates have a really attractive overall profile. And so it's going to be an interesting decision for which ones are the best ones to take forward.

To your question around Phase III design, we do think at this point that ALTITUDE-AD design that we're using is a good robust design. And so obviously, you always make decisions based on data and we'll see where we are when we have the readout from ALTITUDE, but our assumption at the moment is that we're looking at a trial design similar to the ALTITUDE design, probably with a larger population.

Our expectation, our base case at the moment is that we think that one additional Phase III study should be sufficient to be able to file a BLA for early Alzheimer's disease, and we have had some interactions with the FDA that lead us to that conclusion at this point. Obviously, nothing is decided at the moment, but our base case is one additional Phase III study with quite a similar design to the ALTITUDE study.

And then to your question around the choice of dose level for the OLE, I'll turn it over to Eric to answer that one.

Yes. So thanks. And just one additional comment about the Phase III sort of strategy is just to remind you that for donanemab for the TRAILBLAZER studies, it was a little -- kind of similar to our situation. So the TRAILBLAZER study was a Phase II is actually smaller than our ALTITUDE study, but that was followed by a single TRAILBLAZER II study that was a larger Phase III, and that led to their regulatory approvals.

So I think we're kind of in a similar situation to that. As far as the dose selection, so I love the question, and this gets into the [indiscernible] pretty of drug development. But -- so we generated from our Phase I INTERCEPT study, a lot of good data on target engagement. In other words, first of all, how much antibody crosses the blood-brain barrier, but then does it actually bind to the target, does it bind to oligomers. And we had some really good data that showed over the dose range that we used in the Phase I study, we actually reach saturation.

In other words, call the Emax curve. But we reach that saturation we're going higher than, say, 60 mgs per kg really wasn't useful. But we also did a lot of modeling on those data. And what the modeling led us to is that at 35 mgs per kg, you actually have good target engagement at both peak and trough. And we think this is a really good test of the oligomer hypothesis, actually. The 50 mgs per kg was a little bit of an insurance policy in my mind because maybe you need some plaque production, and we'd be more likely to see that at 50 mg per kg, but the point is both of those doses are viable in terms of potential efficacy.

And then obviously, we'll compare safety to 2 doses at the end of the study. So the 35 mg per kg dose is a very viable dose. And actually, there was one study that was done several years ago now in monkeys, where they used a 20 mg per kg dose. And based on lower ratios of the antibody in oligomers in spinal fluid, even 20 mgs per kg in that monkey study looked like a viable dose. So we think 35 mgs per kg is really a very viable dose. And obviously, we're looking forward to seeing the results.

And I am showing no further questions in the queue at this time. I would now like to turn the call back over to Alex for closing remarks.

Thanks, Michelle, and thank you to everyone for tuning in and spending time with us today. Any other questions that you have, we are always available at the company. So please contact us. With that, have a great day.

This concludes today's conference call. Thank you for participating, and you may now disconnect.

Good day, and welcome to the Acumen Pharma Third Quarter 2025 Conference Call and Webcast. [Operator Instructions] As a reminder, this call may be recorded.

I would now like to turn the call over to Alex Braun, Head of Investor Relations. Please go ahead.

Thanks, Michelle. Good morning, and welcome to the Acumen conference call to discuss our business update and financial results for the quarter ended September 30, 2025. With me today are Dan O'Connell, our Chief Executive Officer; and Matt Zuga, our CFO and Chief Business Officer. Matt and Dan has some brief prepared remarks, and then we'll open the call for questions. Joining for the Q&A session, we also have Dr. Jim Doherty, our Chief Development Officer; and Dr. Eric Siemers, our Chief Medical Officer.

Before we begin, we encourage listeners to go to the Investors section of the Acumen website to find our press release issued this morning that we'll discuss today. Please note that during today's conference call, we may make forward-looking statements within the meaning of the federal securities laws, including statements concerning our financial outlook and expected business plans. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements.

Please see Slide 2 of our corporate presentation, our press release issued this morning and our most recent annual and quarterly reports filed with the SEC for important risk factors that could cause our actual results to differ materially from those expressed or implied in the forward-looking statements. We undertake no obligation to update or revise the information provided on this call or in the accompanying presentation as a result of new information or future results or developments.

So with that, I'll turn the call over to Dan.

Great. Thanks, Alex. Good morning, everyone, and thank you for joining us today. In the third quarter, we continued our track record of operational execution on 2 fronts: the steady progression of our Phase II ALTITUDE-AD trial and the generation of additional nonclinical data supporting our Enhanced Brain Delivery or EBD program.

Our core hypothesis remains that synaptotoxic A-beta oligomers play a pivotal role in the development of Alzheimer's disease, and as such, stand as a highly attractive therapeutic target for safe and efficacious treatment of AD. ALTITUDE is investigating sabirnetug, our humanized monoclonal antibody with high selectivity for A-beta oligomers. Sabirnetug's selectivity for toxic oligomers is central to why we believe it could unlock potentially greater clinical efficacy and improved safety relative to antibodies targeting amyloid plaque.

We've made rapid progress in the substantial 18-month study. Some of the 542 participants enrolled in the trial are already beginning to complete the placebo-controlled phase with the first participants scheduled to be dosed in the open-label extension as soon as today. In the open-label extension, all participants have the opportunity to receive sabirnetug at 35 milligrams per kilogram every 4 weeks for up to 52 weeks.

The OLE represents not only our commitment to the participants involved in ALTITUDE, but will also provide us with valuable long-term safety and additional efficacy data to supplement the broader data package supporting sabirnetug. Based on our strong execution, we continue to expect top line results for ALTITUDE-AD in late 2026, inclusive of the key efficacy and safety measures.

For our EBD program, we recognized for some time that pairing a differentiated A-beta oligomer-directed cargo with a validated blood-brain barrier carrier technology could offer an attractive next-generation product opportunity in Alzheimer's. As you heard on our Q2 call in August, we announced a strategic collaboration, option and license agreement with JCR Pharmaceuticals to develop an Alzheimer's disease product combining our A-beta oligomer selective antibody expertise with JCR's transferrin receptor targeting blood-brain barrier technology.

As part of this effort on the cargo or effector side of the construct, we are evaluating sabirnetug and other oligomer selective antibodies from our library, including an antibody we're calling ACU234 that may have even greater selectivity for oligomers over monomers as compared with sabirnetug. For the carrier portion, we're exploring both single chain and variable heavy domain antibody constructs from JCR's extensive TfR targeting libraries, which we consider cutting-edge approaches in the BBB space.

The program is progressing nicely, and we expect to present mirroring data using some of our constructs at upcoming medical conferences. We continue to anticipate a nonclinical data package, inclusive of a nonhuman primate study in early 2026, which will inform our decision to advance up to 2 development candidates under our exclusive option agreement with JCR.

Finally, I would like to highlight the addition of Dr. George Golumbeski to our Board as Chairman. With his addition, the Board has increased to 8, and George brings more than 30 years of experience in the biotechnology industry and is a highly recognized and experienced biopharma leader with a strong track record in business development, licensing and strategic initiatives. His deep expertise aligns well with our current goals as we continue to advance our ongoing Phase II trial and EBD program to drive value for shareholders and Alzheimer's patients alike.

And with that, I'll turn the call over to Matt for the financials.

Matt, I think you might be on mute.

Yes. Apologies. Thank you, Dan. As a reminder, our third quarter 2025 financial results are available in the press release we issued this morning and in our 10-Q we will file later today. As of September 30, we had $136.1 million in cash and marketable securities on the balance sheet, which is expected to support our current clinical and operational activities into early 2027.

R&D expenses were $22 million in the third quarter. The decrease over the prior year was primarily due to a reduction of CRO costs associated with the ALTITUDE-AD clinical trial, for which we completed enrollment in March 2025 following dosing of the first patient in May 2024.

G&A expenses were $4.5 million in the third quarter. The decrease primarily due to reductions in legal fees, audit and other accounting services expenses and recruiting expenses. This led to a loss from operations and a net loss of $26.5 million in the quarter. 2026 will be a very exciting year for Acumen. We are confident in our strong execution of ALTITUDE-AD, and we look forward to sharing top line results in late 2026.

Our EBD program also offers optionality and further unlocking the potential of targeting synaptotoxic A-beta oligomers for improved outcomes in treating Alzheimer's disease, and we will have more to share on that in early 2026. Through this 2-pronged approach, we remain dedicated to delivering potential next-generation treatment options for the benefit of patients, caregivers and shareholders.

And with that, we can open the call for Q&A. Operator?

[Operator Instructions] And our first question comes from Jason Zemansky with Bank of America.

Congrats on the progress. Two, if I may, please. Can you disclose what you're looking for in the early transferrin data in terms of a go/no-go decision? I mean, what does it take to feel confident the delivery mechanism is efficient enough? And then maybe secondarily, can you talk a little bit about the evoke trials, the Novo studies of Wegovy in Alzheimer's? And if it's positive, how does that impact the space and your approach?

I'm actually going to invite Jim Doherty, our Chief Development Officer, to comment actually on both of those questions. I think Jim is a good source of response.

Yes, happy to, Dan. As we think about the EBD program, we do see an awful lot of opportunity and potential by really being able to increase the penetration of sabirnetug or sabirnetug-like antibody in the brain. And there's not an absolute number that we think about as a target for the fold increase that we're looking for or something like that. But I can certainly tell you, as we look at the profile of sabirnetug, we remain very confident in sabirnetug's overall profile, and we're excited about where we are in Phase II. So as you think about a next-generation approach, we're really just looking at enhancing the overall profile for sabirnetug.

So given the relatively low penetration of any monoclonal antibody into the CNS, a moderate increase in exposure level could have beneficial effects in multiple different dimensions. And we see opportunities when it comes to efficacy, when it comes potentially to safety, given the findings so far with monoclonal antibodies being used with EBD for Alzheimer's disease, and even for things like drug delivery when it comes to total volume delivered and things like that. So as we think about it, we're looking for a meaningful increase in the overall exposure. And we can achieve that at relatively low levels because of the potent effects of sabirnetug already.

On the evoke side of things, we are watching -- as with everyone else, watching very closely to see what's happening with the GLP-1 studies from Novo. We think the science is really pretty interesting and it's certainly an evolving space and clear that improving metabolic profile overall is having effects in a number of different patient populations. And I think there's really good science behind the concept that improved metabolic profile could have a real effect for Alzheimer's patients.

So we're interested to see the outcomes. I think the key questions always come down to, in a specific trial, how well the agent is going to be delivered into the CNS? And I think that's a fair question for evoke and evoke+. But we're just really glad to see activity going for other complementary mechanisms of action in treatment of AD. It's clear that there are a lot of patients who need help, and I think some of these other alternative approaches could be interesting to pair with amyloid approaches like sabirnetug.

Our next question comes from Tom Shrader with BTIG.

You made an interesting comment about possibly replacing sabirnetug with something that's more oligomer focused. Maybe you can outline your thoughts there because what the shuttles allow you to do is remove plaque safely. So the other approach is to use something that's more plaque focused, because if you can do it safely, you might as well. So I'm just curious the thoughts of insiders.

And then for early data for the shuttle, is the sense that the -- it's all about anemia. Is the sense that the anemia goes entirely with the shuttle domain so that your anemia should really be based on data from your partner? Or is the anemia potentially also related to the actual payload, your actual antibody?

I'll make a quick comment and then Jimmy might like to add on it. I think one of the important facets of the JCR collaboration was for us to explore diversity of constructs. And so that's really where -- we're not seeking to replace sabirnetug, but we're looking to explore what other possibilities exist as we sort of work through this discovery phase effort. So I think that's the principle at play in terms of things beyond sabirnetug.

So we think that's an interesting -- gives us some redundancy and diversity in that early-stage program. And so far, we're seeing some interesting results and are excited to complete the data package by early next year. Jim, do you want to take the other question from Tom on anemia and how we're thinking about epitopes and selectivity?

Yes, happy to, Dan. Tom, we, as well as others, are really excited about the technology, and I think it's -- there's a lot of opportunity. It really comes down to framing it the way Dan's framed it earlier in the call around the combination of cargo and carrier. So obviously, the final product is going to have elements of both, but that also means that your overall profile is going to be dictated by the components.

So when you think about things like the risk factors, I mean, the risk factor for ARIA that has been associated with transferrin-based approaches comes with the technology. So no reason for us to think that the profile to date with sabirnetug shows any sign of such considerations, but it certainly is the case with the technology. So our ways of thinking about it are at the moment, we are very much focused on understanding what the combination of pairing a monoclonal A-beta for soluble oligomers with transferrin.

So as we do testing for individual constructs, we're looking at the risks or potential for seeing anemia-related effects with the constructs. But we do think that it's likely -- if we see anything like that, the contribution will be coming from the transferrin-based construct. Ultimately, at the end of the day, this is why you do testing and select a particular candidate molecule to sort of maximize benefits and minimize risks. But from first principles, that's our thinking and that's where the expectation would be, is that it would be a risk carried by the transferrin technology. And part of the reason that we selected JCR as a partner is they've got a track record in the clinic of being able to minimize that risk with their constructs.

Our next question comes from Geoff Meacham with Citi.

It's Ross on for Jeff. We had a question on the nonclinical data package. Specifically, we're curious what data we could expect to see and specifically in regards to what biomarkers you would be looking at.

Jim, you want to take that?

Yes. Yes, as we think about data package, I guess there's a couple of ways that we think about that. One would be the data package that goes into a candidate selection decision which we're targeting for the early part of 2026. And there, you can expect to see a number of preclinical studies looking at both the target profile for the new construct. So we want to make sure that the sabirnetug-like profile that we have is not negatively impacted by adding the cargo and the carrier construct.

And then, of course, we're also very much interested in the impact of the carrier construct on PK profile, both looking at the increase in brain penetration, but also looking at the pharmacokinetics. That is one place where there is diversity from candidate to candidate. So we'll be looking at PK profile. We'll be looking at binding to oligomer and other A-beta targets. And we'll be looking at some murine animal models as well to see if we can see profiles consistent with what we've demonstrated to date with sabirnetug.

So that's the -- and of course, very importantly, we'll also be including a primate PK study because, of course, the murine stuff is very important, but no substitute for looking at what's happening in the primate brain, especially with the transferrin receptor constructs, which the primate version of transferrin is a little different than the murine. So that's how we're thinking about delivery of the package for selecting a candidate to move forward with.

The program moving forward after that, we benefit very much from the fact that sabirnetug is currently in the mid-stage clinical trials. And we've spent, as you know, a lot of effort in understanding biomarker profiles for the original sabirnetug. And so we see a real opportunity as we go into early phase clinical developments to build off of that.

And so what you'll see is a lot of the same biomarkers that we've looked at in the sabirnetug program. So thinking about the plasma-based biomarkers, looking at A-beta 40, 42 levels, looking at pTau levels, including pTau217, and then also including the downstream synaptic markers like neurogranin and VAMP2. And really, it gives us a lot to build on from our lead program to be able to understand how the carrier-enhanced sabirnetug program is doing.

Our next question comes from Paul Matteis with Stifel.

This is Matthew on for Paul. Congrats on the progress. I guess on the shuttle program, I was wondering will these candidates -- will both candidates be advanced in unison? Or is there a chance of advancing one and then waiting for the ALTITUDE results before advancing the other? And in terms of selecting the other non-sabirnetug candidate, other than specificity, were there other things you considered that might be optimized?

I think it's too early for us to say whether we'll be advancing 1 or 2 and which of the 2 might move forward. So I think this is going to be data dependent in early '26. I do think we're looking at a combination of factors around the sabirnetug, the 2, 3, 4. I mean we're still generating more data around selectivity and other properties, but are intrigued to think that there's other profiles even still beyond primary sabirnetug that could be candidates for further development.

Our next question comes from Pete Stavropoulos with Cantor.

This is Samantha on the line for Pete. Congrats on the progress. So my first question, I know we're about a year or so away from ALTITUDE data, but I'm wondering what your current thinking is in terms of the bar and what's the minimum you'd like to see out of this study to move forward from both a clinical scale perspective and biomarker data? And then I just have a quick follow-up.

Jim or Eric, do you guys want to provide a primary response on that?

Yes. So let me start, and I'll invite Eric to jump in. Great to hear from you, Samantha. And I think the answer to the question is this is -- we talk a lot about testing the oligomer hypothesis, and we think for a lot of reasons, there's a vast amount of evidence that speaks to oligomers having an important role in the pathophysiology of Alzheimer's disease. And I think our Phase I data so far supports that. But the value -- the key value in the ALTITUDE study is it's the first true demonstration looking at clinical scales. And so obviously, the major impact for the study is to understand the effect on those clinical scales.

So we're, of course, looking for a clear and demonstrable effect when you come down to change from progression rate. But we're also going to be looking at what the overall impact of that is and looking at the effects of sabirnetug on multiple scales. So we certainly have -- iADRS is our primary, but there are a number of scales that are going to go into that. And really, in addition to just looking for a clear signal, we're going to be looking for what's the type of response in those various scales.

And I think the same kind of thing around the biomarker work. We're very excited with the biomarker signals we're seeing after 3 months of dosing from the INTERCEPT study. And so this gives us much more data over a much longer period of time with an 18-month primary endpoint. So that's kind of how we're looking at the readout itself. But let me turn it over to Eric and see if he has any other color that he wants to add.

Yes. Well, it's a great question. Because at the end of a study like -- a fairly large Phase II study like ALTITUDE, it's really a matter of safety and efficacy. And as Jim mentioned, our primary outcome is the scale called the iADRS, which is a combination of cognition and function. So that's going to be our primary outcome in terms of efficacy, although, as Jim mentioned, we've got a lot of secondary measures in there, too. And then you have to combine that with safety. And it's the 2 of those in combination that give you the therapeutic index. And in a study as large as ALTITUDE with 542 people, you really can get a sense of what that therapeutic index is.

Now beyond that, as you know, in our Phase I study, we actually had some, I would say, fairly impressive biomarker responses, which really tells us not only do we have target engagement in terms of binding to oligomers, but we're also having effects on the downstream pathology in Alzheimer's disease. And of course, we'll look for those kind of biomarkers in ALTITUDE. But based on the fact that we saw those even in our small Phase I study, I think that could give us a real potential for being differentiated from other treatments.

I'm showing no further questions at this time. I'd like to turn the call back over to Alex Braun for closing remarks.

Thanks, Michelle, and thanks to everyone who tuned in today to listen to our Q3 update. We are always available at the company for any further questions. So please don't hesitate to get in touch. With that, have a great day.

Thank you for your participation. You may now disconnect.

All right. Here we go. Welcome to the webcast of the Acumen Pharmaceutical session. So Dan O'Connell, CEO, joining us. also Jim Doherty, Chief Development Officer; Alex Brown from the IR team. So guys, welcome. Thanks for doing the back-to-school conference.

[indiscernible] thanks for having us. Pleased to be here.

Awesome. Well, Dan, maybe just kick it off with the -- your -- maybe your vision for -- in Alzheimer's, given the launch of LEQEMBI and Kisunla today, maybe how would you grade that? And how would you look at this as a long-term opportunity? Like what differentiation or what rooms -- opportunity for improvement do you see from the current standards?

Sure. Thanks, Geoff. I think we're encouraged at some of the progress that's been achieved in the space. And the fact that we now have 2 approved -- traditional approved disease-modifying treatment options available to patients. I mean, our view -- we have been pursuing and developing Sabirnetug as an A-beta oligomer-directed antibody. So we think that is a distinct way to address disease pathology and potentially offer a better treatment option for patients in respect of efficacy and safety. And what's unique, Sabirnetug has, from its origins, been intentionally developed to neutralize these toxic species. And so we do think that, that -- our vision is that the field will continue to evolve and grow and that Sabirnetug and oligomer-directed treatment approaches may ultimately be sort of the best approach for patients.

Have you seen anything in terms of the science of how the identification of oligomers being deemed the toxic species, has the literature kind of evolved to where that's becoming more apparent? Or are you aware of studies ongoing outside of Sabirnetug that could also that could also help support that?

Sure, Geoff. So there's a large base of research and evidence in support of oligomers being distinctly toxic species of A-beta aggregation. And this is I mean this goes back over 20 years, even at some of the founding science around acumen. I think the -- that base of evidence has continued to grow. I do think we've also, as a consequence of what's been observed with these first couple of agents, there's been a fixation, if you will, on plaque clearance and in particular, driving up a reduction in the amyloid PET signal, as a means of correlating with a clinical benefit or essentially a treatment benefit for patients.

We think the A-beta oligomer hypothesis has yet to be fully clinically validated, but we think we at Acumen with Sabirnetug, are well positioned to provide conclusive evidence, proof-of-concept evidence and evidence and so forth taking treatment and development strategies towards preferentially targeting this or exploiting the mechanism, if you will.

That makes sense I think in a lot of it's diversifying the opportunities, right? So we know that Alzheimer's disease is complex disorder. You were asking earlier about the drugs that are out there and it's fantastic for patients it's the milestone that we finally got into after a tremendous amount of work and investment to treatments that can treat Alzheimer's disease. But I think we're also seeing that no one therapy is going to be able to treat all patients at all stages of disease. And so -- in a lot of ways, this differentiated mechanism of action by going after the toxic oligomers is adding a real opportunity overall to the treatment.

And just given the data that you had thus far, Sabirnetug, the kind of the tolerability and the risk benefit. I think when you -- most people think about this indication having another mechanism added on would be helpful. And so -- what's your view of the combined ability, I guess, as you look forward, obviously, you have to wait to get the data results next year.

Yes, that's of course, that's right, Geoff. And I think -- part of our confidence -- much of our confidence, I should say, in Sabirnetug, is predicated on the Phase I data, right? The INTERCEPT-AD study we ran in 2022 through to 2023 was exclusively in Alzheimer's patients, and it was designed really as a proof of mechanism study. And in that study, we confirm target engagement. So the antibody hitting its intended target being oligomers, a safety signal consistent with a competitive safety profile in respect of tolerability and including RAE. And then we have these biomarker effects, which both on the PET imaging results, we had a modest sort of comparable reduction in the amyloid PET signal, but we also observed a modification of a series of different fluid biomarkers, both in cerebrospinal fluid and plasma.

So on a short duration study in a patient exclusive study, we think all of that data holds together and puts us in the path to that optimize product profile in terms of risk benefit with Sabirnetug. And that's the evidence we're seeking to generate in ALTITUDE-AD. I think the future state of treatment will probably involve more than one agent that there are a variety of different sort of points of intervention that physicians and patients will be seeking for optimized treatment. So I think layering on -- there's -- as I know you're aware of this, there's this debate right now between the 2 commercial products of chronic treatment versus treat to clear.

And we do think that the disease progression -- the disease pathophysiology continues even in the absence of amyloid -- of a PET signal. And so chronic treatment and addressing some of these other biological mechanisms such as oligomers or tau or inflammatory approaches as we sit here today, would -- I think it's safe to assume that they will be -- there's a future for that -- those types of multiproduct combination strategies.

Makes sense. Well, Dan, you mentioned the blood-based biomarkers. So I wanted to ask you on the sort of the diagnosis angle of it. Is it helping you think, raise the awareness, maybe stage patients? Do you -- how do you see it helping you guys? Is it more just helping with enrollment -- the speed of enrollment? I just want to get a view of that. The way it could play out clinically and then also commercially.

Sure. I'll take a first stab at that, and then Jim, I'm sure can follow on. So I think right now, the fluid biomarkers are fundamentally enabling, right? They're creating greater awareness in the population that if you have a suspected case of Alzheimer's disease, there's research that can be done. There are products that you could be -- you could be going on or you could be entering a research study such as we had with ALTITUDE-AD. And we employed of plasma-tau 217 plasma biomarker as part of the screening process. So we do think that, that contributed considerably to the sort of speed and efficiency that we were able to enroll the study.

I think we're in the middle of kind of step change in the precision that we've got around being able to diagnose in Alzheimer's disease. You saw that for the first time with the [indiscernible] right? So you went from a truly clinical diagnosis dementia, and what we found when the [indiscernible] came around that many times, those were not truly Alzheimer's cases. It was dementia for another reason. And it was that precision and that ability to see more data that made such a difference.

Same thing is happening again with the fluid-based biomarkers. There are a number of them. There are markers that are more associated with the target amyloid-related A-beta 42:40 ratio be the obvious example. There are the tau markers, which are also a core pathophysiology in Alzheimer's disease, and then we and others are also looking at downstream synaptic markers.

So you're getting an awful lot of data on what's happening in the brain for a patient. And it really creates the opportunity to in many ways, stage patients in a way that hasn't been possible before. So to understand where they are in the course of disease, and perhaps create a situation where you can craft the right treatment for the right patient. We know that Alzheimer's disease is not diverse. It's not the same pathophysiology for every Alzheimer's patient.

So I think that's where the field is going. There's been explosion of work in biomarkers, both in the number of biomarkers but also in the types of studies that are being done, to really understand where you're seeing signals, what the signals are correlating with. And so I think you're going to see a real improvement in staging and diagnosing individual patients. And I think that only benefits being able to target new treatments.

I think it's going to be more patients seeking more treatments. And essentially, if you think about the funnel and the logistics of the way the commercial products have rolled out, I mean having the ability to prioritize patients from a blood test is a much more efficient when -- way to get the right people into the funnel to go through steps to come on an anti-beta or anti-amyloid product.

Have you guys seen anything? I mean this is genuinely the last real frontier it has been for decades. In terms of unmet needs and the science. Have you seen anything that's maybe noticeable on the AI or machine learning angle to try to put together all these data points, everything from cognition to biomarker data to mechanism data to clinical data like that's even reliably predictive or that could enhance the chance of success?

Well, I think there's a lot of interest in sourcing the data sets that would inform those models. And I think that's the real question the quality of the data set, and there's a massive amount of it. We were just talking about this at lunch, actually. Because and it's like multimodal, whether it's EEG, it's biomarkers, it's clinical assessments.

So I think that AI or machine learning will have a contribution to those advances in the future, a lot of interest nothing that I can point to you today off the top of my head that says like these folks haven't figured out.

There's no new discovered like a mechanism or correlation or anything like that through...

No. But I mean the progress of technology, I mean even in the biomarker space, we've seen rapid evolution of a series of different [indiscernible] whether it's [indiscernible] 181 to 217, there are a couple of others that are in mix. As those diagnostic platforms continue to be able to multiplex across a bunch of different targets, you're going to -- you'll extract the things that are most pertinent to a disease population such as Alzheimer's disease.

So on that same thing with a diagnostic test. I guess, what are you hearing from physicians using it? Obviously, you guys have accredited that use of the two accelerate the enrollment process and also get the trial up and running a little bit faster, I guess, what are you hearing from actual kind of physician usage?

So I think it's increasing is the short answer. Certainly, our trial is kind of a real-world example of the benefit that having that kind of quickly accessible data can offer. I think that as i was saying a few minutes ago, we're really in the midst of a lot of studies ongoing. Looking at how these various markers can be correlated. And I think as more of that data comes around, coupling that with the ease of use and the sort of rapidity of getting results back, I think more and more physicians are going to continue to use the data. You're already seeing that, but I think that, that's only going to increase as more of the survey data comes in.

At the AAIC meeting in Toronto earlier this summer, we presented a poster on some of the economies and efficiencies that using the 217 assay yielded in the ALTITUDE-AD study. And I mean the cost differential between the blood test and a PET scan is a factor of 10 or more. And so that -- that alone is just a good indication of how the progression of these better diagnostic, more efficient and yet it's precise measures come to open up the clinical market.

And then moving forward, obviously, with the diagnostics using for p-Tau 217, are there other biomarkers that you guys are looking up behind the scenes? Or do you think it's going to say to say that p-Tau 217 is kind of like the clear real winner here?

I certainly think 217 is the one that's drawn the most attention, and it does seem to be a very sensitive marker and there's a lot of work trying to understand how well it correlates with the drug effects and things like that. There are also a lot of studies looking at as patients progress in disease, how the 217 signals change. So definitely a lot of interest in that market.

And I think in the short term, that does mean that's the one that we're going to learn about the most about in a short period of time. But I do think there will be other markers that kind of get added to that list. I mean one of the real opportunities with a plasma-based system is you don't have to do a single marketer and you can get multiple signals from the same sample from a patient. And so I think you're going to see rather than things supplanting 217 because I do think it's going to turn out to be one of the most sensitive and most useful markers. You'll see other things added along with it.

Yes. And [ equipment ], I mentioned the fluid biomarkers in Phase 1 and the ALTITUDE-AD. I mean some of the -- we looked at A-beta, some of the tau species, but also some of the synaptic markers of neurogranin and [ BAM2 ]. And as we think about the toxicity of oligomers, the evidence over 20 years suggests that they have a propensity to bind neurons, induce calcium influx, disrupt neuronal signaling and essentially result in the loss of -- synapse loss.

So as we see like a short duration study such as INTERCEPT and Sabirnetug at the higher dose levels, demonstrating not only significant changes, on a dose dependency on neurogranin and [ BAM 2], I mean that's really at least compelling in terms of our mechanism, how ultimately that might yield the differentiated efficacy profile that we look for Sabirnetug.

And along those same lines, we talked about combined ability. I mean, everyone says beta amyloid and tau are probably the 2 toxic species that you want to get rid of sooner than later, but it doesn't -- so far, it doesn't look like tau is as effective. I mean, any updated thoughts of whether that is still a viable strategy in your view or whether tau is simply more of a biomarker and less of a disease kind of modifier?

Well, I'd first offer that tau is still a promising therapeutic target in the disease, presumably. I think what we have observed or experienced is in the A-beta spaces taken us 25 years to get to where we are right now, and we're still debating about plaque clearance versus proto firewalls versus oligomers. And tau biology is an order of magnitude more complex than A-beta.

And so I think we've learned -- if you're tracking tau, we've learned kind of what not to do, which is what we also did in the amyloid space with Monomer targeting agents and so forth or pan-amyloid targeting agents like [indiscernible]. There are a couple of studies. There are some ongoing programs that might read out in the next 12 to 18 months in the tau space that would help inform what to do in terms of a tau-directed intervention. So I think it's -- the jury is still out, but it is a consequence of learning what not to do and then ultimately focusing in on the thing that is most therapeutically beneficial.

Yes. And those -- they talk about -- sometimes talking about A-beta being the trigger and tau being the bullet. The fact that we have an oligomer-directed agent that's had downstream effects on tau species again, is sort of encouraging, but to think that you could be doing both in oligomers-directed agent and then augmenting with tau directed product or treatment is that possibility still is very much exists.

And just to follow up, you hit the nail on the headwind. I mean it's just taken a long time to get to where we are with just beta amyloid. Do you think that the tau biomarkers are from a regulatory standpoint are they robust enough or they would take maybe shorter-term kind of changes to p-Tau 217. Like is there -- because I look at like the HEP C angle, right, like that went from 48 weeks to basically 4. Right, is that's -- the 4-week was predictive of what you'd see. We're not going to go on that speed.

But like is there a 3-month or a 6-month biomarker trial in Alzheimer's that you could feel confident in using biomarkers that you drug -- a drug has an effect?

For drug effects, probably yes, for regulatory purposes, I don't know that I'm ready to -- or I would be willingness to say that agency is willing to accept or extend the label. But I do think those biomarkers are faster turns on what's working and what's not from a development derisking standpoint.

Yes, I think it's fair to say we're not there yet. But I would also say this is part of the promise is that there's enough data emerging and individual markers that assuming enough data gets generated, you could see making an argument to the regulator to do something like that. And they're certainly paying close attention to the science that's emerging and they are engaging in conversations. But I think they're appropriately going to be pretty conservative, and they're going to want to see a lot of data before they go down road like that.

And on the AI and machine learning piece, is there other -- is it the company that don't -- why is the data quality not there? I guess there's not maybe a third-party repository of data that could everyone could look at? I'm just trying to think of like the companies want their own access to their own data and they're not going to share.

Well, there's an interesting -- let me see -- so there's an interesting dynamic now that the space has gone commercial and I've been in this space for an extended period of time longer than I might care to admit. And it had been a very collaborative work, data sharing, impetus and precompetitive strategies were kind of maybe in the last 10 years, we're kind of more than normal. I think there's a little bit more of a proprietary siloing now, where people don't want to enable a competitor unnecessarily in the space.

But so I don't know that there's a quality -- it's the data sets, it's quality, but it's also scale, diversity, how well characterized those data sets are. So some companies that have been in the space for an extended period of time, they have unique insights applying AI to those...

And maybe will we learn anything from the commercial, if we do follow on the...

Yes, the real-world evidence, absolutely. I mean we're already starting to see some of that and kind of most prone to do -- to benefit from all of that stuff gets back translated, I think, into really kind of stepping closer towards a personalized medicine for like getting the right patients on the right drugs.

And I know you're not in the prediction business, but if you had a win for ALTITUDE-AD, what would you say that will look like? Is it preliminary? Is it numerical? Is it what -- I mean you're probably not going to get too much stats on it, but I don't know, just help us out.

I mean it's a reasonably powered Phase II, intended to be a proof-of-concept study. We're prepared for all outcomes, including an upsized success one, where that extended dosing of a oligomers-directed -- oligomers-directed antibody yields a pronounced efficacy benefit and does not have the ARIA liability associated with plaque clearance. So mean, yes, I'm not -- I can't predict, but I'm certainly encouraged to think that we have a real possibility of having that outsized success with ALTITUDE.

Yes. And I can't remember. I think we've talked about this, but if you think about the Lilly's strategy of only having the drug onboard and removal all the plaque then that's it versus the Biogen strategy of having on board 18 months and the clinical trials are indefinitely commercially. Is there evidence for keeping it on board while you clear plaque completely?

Yes. I mean I think if you look at the Lilly data or the Eisai and Biogen data, chronic dosing with the right agent seems to be until a patient progresses out of a particular stage of disease seems to be appropriate. I mean the best evidence, I think, in support of chronic dosing is that gap period that Eisai had with LEQEMBI, which was they stopped dosing, they weren't sure if they were successful, and then when the study was successful, they put people back on treatment after, I think, on average about 12 or 18 months.

And the PET signal increased over that period of time, modestly, but other the p-Tau 181, some of the A-beta 42:40 ratio, all of the other biomarkers sort of came back online, if you will, in the absence of the intervention. So that would suggest that keeping people on treatment while they're not whether they have an advanced to moderate disease or frank [ dementia ].

And where you can keep -- and this is where being able to monitor the biomarkers becomes clinically relevant where you're sort of assessing progression not only on clinical measures, but on the biomarkers and not relying exclusively on an amyloid PET, right? I mean that's the one of the -- if you take a step back and you look at Donanemab as a pyroglu A-beta directed antibody that's designed to clear plaque, I mean they deplete target. So it doesn't make sense to actually keep people on Donanemab in the absence of plaque.

And yet there's other A-beta biology that continues to advance the disease as supported by the ASI data.

So it could be that you have, say, a foundational oligomer that maybe has not picked up on a PET scan, but constantly being clearing it out.

I mean that -- I mean at that level of description, I can assure you that's the case. I think the complexity of which is at protofibrils or large oligomers or small oligomers. I mean, there's a variety of different species. And these things, they do work kind of in an equilibrium.

So I do think that plaque clearance does have secondary effect on reducing presumably a secondary effect on reducing oligomer levels. But I think most of the evidence that we've seen would support chronic dosing again, while a patient is kind of within that early AD space.

Now the other area that's of great interest to us in the near -- at some point in the future is this preclinical Alzheimer's population where they're A-beta oligomers pathology is pronounced. Like that's really the initiation phase of disease as aggregation is starting and where you're having presumably like subtle effects on neuronal and synaptic health, that don't present as clinical symptomology yet and essentially, the horse is leaving the barn and sort of the process has started, and we'll continue to advance in the absence of some intervention.

Makes sense. I guess changing gears a little bit, I guess, over the weekend,LEQEMBI subcutaneous formulation was approved for maintenance dosing. We know that you guys are developing a subcutaneous formulation yourselves, I guess, if there's any color around that, how the company is thinking about the subcutaneous formulation or kind of greater what do you think it means for the field as a whole?

Yes, absolutely. And as you say, there is now an approval for maintenance for subcutaneous formulation. And I think we, like everyone else thinks that one of the major things you gain with a subcutaneous formulation is much more flexibility and ease of use to administer the drug. And so there are likely to be patients who will want to retain an IV approach, but there are probably a lot of patients who would like to be able to switch over and use a subcutaneous strategy. Some recent studies were just discussed at AAIC suggesting that for a number of patients they're readily able to do that and master themselves. So definitely, we feel like that's going to be a value to any treatment is to have that ability.

And so as you say, we have run a Phase I study in healthy volunteers with a formulation that a [ Comex ] formulation that will allow for larger volumes to be delivered. And we -- based on the results from that study, we're continuing forward with our approach with subcutaneous -- we really kind of want to see the results from the ALTITUDE-AD before making too many next steps with a subcutaneous approach. So what we've been saying is we're likely to complete that study and then based on results, look at including an arm or component in our Phase III study that we will be doing to follow on with the subcutaneous formulation.

That's sort of our first approach to subcutaneous. We've also announced recently a collaboration with JCR Pharmaceuticals. I know you guys know about for a blood-brain barrier approach. We're calling it enhanced brain delivery or EBD. So in our view, in the EBD approach, we already love the profile of Sabirnetug, as James been saying, but if we are able to increase the fraction of a drug that's being delivered into the CNS, that gives us a lot of flexibility with dose and with formulation and with amount delivered. And so that would be a second opportunity to go to a subcutaneous administration.

Awesome. Also on your collaboration with JCR. There are some other players looking at transferring -- in the transfer I guess, what do you think differentiates I guess, your now new approach as opposed to other players field?

As we looked pretty thoroughly at the opportunities that are out there and the strategies that are out there. And as you say, a number of people who are targeting transferring as the shuttling mechanism to get into the brain. There are -- just as an aside, there are a number of other proteins that form -- play a similar role. So there would be other possible targets as well. But we landed on transferring because there's the most clinical validation for transparent in these sorts of products. And then in the case of JCR, they have clinical experience. They have a marketed product called IZCARGO that's approved in Japan for Hunter syndrome.

And we like their experience and we like the epitope that their technology binds to. What they've seen with this cargo is they have not seen signs of anemia with their drug. So that's something that we'll, of course, will need to be played out with the collaboration to see if that holds, but we're definitely attracted by their approach to targeting transferrin receptor and the lack of anemia that they've seen with their IZCARGO product.

What's aspirationally using a transport or transferrin or however mechanism you get across the blood-brain barrier? What's your view of where this theoretically could go in terms of the dose? Could you cut the dose half by 90% -- Like, I don't know the number. It seems like I don't know -- I think it's less about, in my opinion, the dose and more about maximizing the effect size. Because you can run into, I mean, ARIA, et cetera. How do you think that, that will all kind of shake out from the transport side of things?

Yes. Well, I mean, as Jim is suggesting, I think having that greater fraction of drug in the central compartment in the brain interstitial space through this receptor-mediated transport has advantages. I think with Sabirnetug, we don't -- relative to plaque-directed antibodies we're not running into a dose limiting ceiling. In the Phase I, I think we conclusively showed that. So for us, it's really more about these EBD approaches seem to have a combination of potentially an intrinsic safety benefit just in terms of avoiding all CAA plaque because of the capillary delivery, the lower dose requirements to get -- achieve an equivalent efficacy and all of the safety and thereby just the convenience of doing that in a subcu format.

So I think there's -- yes, there's -- the those pieces as you look around the it's sort of like a somewhere between a 3 or fivefold reduction in the dose levels that are equivalent to IV is sort of, I think, the benchmark out there.

Okay. And what sort of time frame do you think you can get to, say, a proof of concept?

Well, we've guided to preclinical candidate designation early '26. So we're actively working with our partners at JCR, a profile -- different carriers in different cargo's or payloads. So the JCR transferrin carrier technology, there are a variety of different configurations on the front end of that. And then we're looking at Sabirnetug and Sabirnetug-like payloads or cargo's. And we have under the terms of agreement, which I would say, really capital-efficient way for a small company like ours to get into validated space fiscally responsible deal that we think we'll have the preclinical data sets early next year, to then, in a perfect world, those are adequate to help us move towards IND and then getting in the clinic in '27.

Yes. Okay. So that makes sense. Just from the landscape, I know the recent Prothena data sort of not optimal. That's another company in the space that people had a lot of hopes for. Any like higher level of views of that I mean that's the way the is in the...

I think you putting it in the category of Alzheimer's is a challenging and occasionally humbling space to be active in. And I think that we have -- we definitely have a very different epitope and mechanism and feel like we're on the right path with Sabirnetug in terms of that risk benefit profile for patients.

Yes. What's your view of the -- because I know the Denali's and [ Electors ] of the world that have had novel mechanisms of action. I mean -- I mean, as we talked about earlier, it's not like this is a completely met -- medical need. I mean, so but you're adding risk on top of an already high risk indication if it's not a proven sort of validated mechanism. But there is still a need to do something different, right? Is there a mechanism that you think is -- looks interesting that's outside of the beta-amyloid kind of tau access, either inflammatory. I mean people are talking about the GLP-1.

GLP-1 is going to be -- could be very interesting this year with the EVOKE readouts. I mean that -- I don't think I'm not in the business of making predictions, but if that were positive or directionally -- even just directionally positive, I think it would usher in a lot of enthusiasm for [ complementoring ] A-beta tau strategies with GLP-1 approach. I think the TREM2 space is still -- still has some potential, I think there's more learnings to be had there, but this whole inflammation component of Alzheimer's pathology, certainly an area of -- that we should continue -- the field should continue to pay attention to.

Got you. Okay. Ross, do you have any? No. Okay. Any final thoughts? Are you good? You cover everything?

Well, I think we covered a lot of ground. I do think it's -- it really is an exciting time for the space. And even on that last question, I think there are so many possibilities when you consider inflammatory approaches, for example. But one of the challenges is -- there are a lot of different possible combinations to look at. So when we talked earlier about biomarkers and how that's going to be useful you can envision efficient trials in the future are going to allow you to look at combinations in a different way.

Yes. To me, it seems like this is ripe for sort of AI and like let's try to check that box in the next couple of years to see, if we can uncover a novel mechanism or staging or some element.

And you think about that technology coming on, Geoff, in a situation where the population -- the unmet need will persist, right? This isn't going to go away overnight. I don't think anybody is going to sort of steal the bacon here. So I guess it's sort of continued progress and exciting time in some of those enabling technologies, whether it be the AI and/or biomarkers or some combination. Certainly improves probability of the success in the future and better options.

Thank you, guys.

Thank you very much.