Acumen Pharmaceuticals, Inc. (ABOS) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to Acumen Pharmaceuticals R&D Day. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to turn the conference over to your speaker for today, Alex Braun, Head of Investor Relations with Acumen Pharmaceuticals. Please go ahead.

Thanks, Lisa. I'm Alex Braun, Head of Investor Relations. And on behalf of the Acumen team, I'd like to welcome everyone to our virtual R&D Day. Today, we intend to take you on a deeper dive into Acumen's mission and in particular, the scientific rationale, nonclinical and clinical data underpinning our product candidate for the treatment of early Alzheimer's disease, sabirnetug. As a reminder, we'll 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 these risks can be found in our most recent 10-Q filed 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 from Acumen will include Dan O'Connell, our Chief Executive Officer; Dr. Jim Doherty, our President and Chief Development Officer; and Dr. Eric Siemers, our Chief Medical Officer. We're very pleased to also welcome seasoned Alzheimer's thought leaders, who will provide perspectives on sabirnetug's data and its potential as a differentiated treatment option in the landscape. Dr. Steve Salloway is the Founding Director of the Memory and Aging Program at Butler Hospital and Professor of Psychiatry and Neurology at the Warren Alpert Medical School of Brown University. We also have with us Dr. Paul Solomon, Founder and Clinical Director of the Boston Center of Memory, Professor in the Department of Neurology at the Boston University School of Medicine and an investigator at the BU's Alzheimer's Disease Center. He's also an investigator in Acumen's Phase II ALTITUDE-AD study. We thank you both for your time today. We [indiscernible] Alzheimer's disease referred to as AD during this presentation. Then Jim will review the case for targeting amyloid beta oligomers or ABOs highlighting important nonclinical data supporting sabirnetug's mechanism of action. Dr. Salloway and Eric will follow with the Phase I clinical data that advance the story significantly. We'll then hear from Dr. Solomon about the AD landscape and clinical trials, including Acumen's ALTITUDE-AD Phase II study. And we'll conclude with brief remarks from Dan, who will lead us into Q&A. There will be a live Q&A discussion. And in addition, there is a question submission box on your screen that will be open throughout the presentations this morning and during the Q&A session to submit written questions. We'll collect those questions throughout the presentation and take as many as time allows at the end. So with that, for backdrop, I'll hand this over to Dan.

Thanks, Alex. Good morning, and thanks, everyone, for joining us today. I'm Dan O'Connell, Chief Executive of Acumen. And I'm pleased to provide a brief introduction to the company, our opportunity and some background before turning you over to Jim, Eric and our thought leaders. Acumen's mission is central to our culture. Nearly all of our employees, including myself, have been touched in some way by Alzheimer's disease and the devastating effects it can have on our loved ones. We're not alone, at present, Alzheimer is estimated to affect more than 50 million people worldwide. By 2050, that number is expected to grow to more than 150 million people. We, at Acumen, are passionately dedicated to advancing treatments that may preserve and extend quality time for Alzheimer's patients to spend with family and friends and to reduce the burden of care of this terrible disease. I'd like to highlight several of the strengths that we are leveraging in pursuit of this goal. First, our team possesses extensive CNS drug development experience specific to Alzheimer's, both at large pharmaceutical companies and smaller biotechs and involving early through late-stage product development over many years. Second, Acumen is pursuing a differentiated treatment approach that is supported by decades of research which inform the potential treatment benefits of targeting soluble toxic amyloid beta oligomers in Alzheimer's disease. Third, we're capitalizing on this experience and knowledge to develop a potential next-generation product candidate called sabirnetug. Jim will take you through the nonclinical data underlying sabirnetug. Jim will take you through the nonclinical data underlying sabirnetug and you'll hear more from Dr. Salloway and Eric about how the nonclinical data findings have proven to be highly translatable in the clinic based on our Phase I results. Lastly, earlier this year, we launched a global Phase II trial for sabirnetug called ALTITUDE-AD, and you'll hear more about this from Dr. Solomon. I thought it would be useful to provide a brief overview of the dynamics of the Alzheimer's patient population. We all know that Alzheimer's is a serious fatal neurodegenerative disease with limited treatment options. It robs people of their memory, cognitive abilities and ultimately leads to death after escalating care requirements as patient advance. The patient population we focus on in our clinical studies is defined as early AD, made up of patients exhibiting mild cognitive impairment that have confirmed amyloid pathology and mild dementia due to Alzheimer's. This population is estimated around 7 million people in the U.S. today. The prevalence of early AD is expected to continue to grow based on a couple of dynamics, I'm sure you're probably familiar with. First, an aging population, and second, more diagnosed cases due to an improved ability to diagnose the disease in this early stage. Greater availability and adoption of treatment options such as the new anti-amyloid treatments will facilitate the establishment of care pathways and contribute to the growth of the early AD market. We at Acumen like so many others are encouraged by the recent success in the field. After years of trying and learning and persisting, the field has clear clinical validation of anti-amyloid approaches for disease slowing. We now have an established regulatory pathway. It's an emerging payer support for traditional approved products. These successes deserve applause, and yet they also present a great opportunity for improvement with next-generation anti-amyloid therapies and perhaps combination approaches. Turning now, I think it would be useful to Acumen's history. It's worth understanding in terms of the scientific origins and where we focused on A-beta oligomer toxicity as a primary bad actor in Alzheimer's disease. In the l990s, when Acumen was originally founded by researchers from Northwestern and USC, the company acquired exclusive licenses to intellectual property that pertain to A-beta derived diffusible ligands or ADDLs. ADDLs are synthetic preparations of A-beta oligomers which has been discovered in the Acumen scientific founders to be potent neurotoxins. As shown on the left here in one of the seminal papers on the topic, ADDLs are small globular structures, physically distinct from A-beta fibrils, and more toxic due to their propensity to bind to neurons and synapses. Here on the right, it's shown in the same paper that ADDLs rapidly inhibit long-term potentiation, or LTP, an accepted model for synaptic plasticity at typically understood as a surrogate for cognitive function. After only 45 minutes of exposure, ADDLs completely blocked LTP. These and many other discoveries led to the hypothesis that soluble ligand like A-beta oligomers instigate the brain damage leading to Alzheimer's disease. As such, A-beta oligomers represented a novel distinct and attractive drug target to inhibit a fundamental pathophysiological pathway in Alzheimer's and serve as the basis for a novel drug discovery effort. Fast forward to our product candidate, sabirnetug. Sabirnetug was originally discovered in partnership with Merck, who completed robust preclinical studies to confirm the attributes of the antibody, including its high selectivity for A-beta oligomers. Acumen currently holds exclusive global rights to the program and intellectual property with no future financial or other obligations owed to Merck. Sabirnetug is a humanized, affinity matured monoclonal antibody with high selectivity for toxic A-beta oligomers. This selectivity is key to why we believe it could unlock potentially greater clinical efficacy relative to monomer and plaque referring antibodies. Additionally, sabirnetug was intentionally developed as an IgG2 monoclonal with reduced effector function. This lower effector function may in turn contribute to lower rates of amyloid-related imaging abnormalities edema or for ARIA-E, compared with antibodies that bind plaque and have full effector function. From a regulatory standpoint, FDA has granted sabirnetug Fast Track designation. And in the fourth quarter of last year, we had a useful end of Phase II meeting with the agency. As I previously mentioned, sabirnetug yielded positive Phase I results in early 80 patients. And a Phase II study, ALTITUDE-AD, is currently ongoing in North America and Europe. So I'd like to leave you with the reasoning behind why we see the potential for sabirnetug to be a next-generation treatment in early AD. It's pretty straightforward. We've talked about the substantial disease prevalence of Alzheimer's and the escalating disease burden. In 2021, Alzheimer's was estimated as the 5th leading cause of death in individuals over 65. And according to at least one study is estimated to grow a worldwide economic burden of $17 trillion by 2050. The unmet need and desire for better treatment options is thus expected to continue and will grow in the future. Sabirnetug has the potential to offer differentiation from currently marketed AD therapies based on better efficacy or safety or both. The current anti-amyloid treatment options offer clinical benefit of roughly 30% slowing of decline and there is a justified caution about ARIA-E that causes temporary localized swelling in the brain and requires considerable safety monitoring, making these therapies less advisable for certain patients. As I mentioned, we believe sabirnetug's high selectivity for A-beta oligomers provides an ample space to differentiate on either efficacy or safety or both. Given the unmet need and the prospect of differentiated benefit to risk profile, sabirnetug gets the potential to emerge as a treatment of choice for naive patients or as a combination for chronic treatment. This may be especially true for subpopulations at high risk for ARIA-Es such as APOE4, patients who have a higher propensity of developing ARIA-E with current anti-amyloid treatments. And I should also point out that given the early pathology of A-beta oligomers in the disease initiation, sabirnetug has an oligomer directed antibody may have exceptional promise in preclinical AD, though this population is not a current point of focus for us in the clinic. We at Acumen are incredibly excited about the moment we're in the future state of diagnosis and treatment for people living with Alzheimer's. Acumen is fully committed to having an impact on the disease and preserving quality of time for people. And with that, I'll turn things over to Jim.

Thanks, Dan, and good afternoon, good morning, everyone, depending on where you're sitting today. Thank you for joining us today for Acumen's first R&D Day. We really appreciate you taking the time out of your schedules to join us. This is certainly an exciting time for the treatment of Alzheimer's disease with 2 disease-modifying therapeutics now approved for use in the U.S. Still, it's just the beginning. With the rapid advancements being made in the use of biomarkers to study disease progression, most notably imaging and fluid biomarkers to more precisely map the course of disease in individual patients, it will become increasingly possible to match the right treatment with the right patient. To achieve that opportunity, we'll need the next generation of AD therapies. Although there's still much to learn about the pathophysiology of AD, one of the key hallmarks of disease is the splicing misfolding aggregation and accumulation of a protein abundantly expressed in the brain, the amyloid protein. In normal physiology, amyloid beta plays a role in synaptic function and plasticity. In Alzheimer's disease through a process of enzymatic cleavage that you produce alternative forms of A-beta that are prone to misfolding and aggregation. The resulting protein complexes take multiple shapes and sizes, including soluble oligomers. In this talk, I'll describe some of the key properties of soluble A-beta oligomers as well as some of the roles they can play in the pathophysiology of Alzheimer's disease. I'll also describe some of the functional consequences of removing soluble oligomer with either sabirnetug or its rodent predecessor, ACU3B3 in nonclinical studies before doctors, Salloway and Siemers, describe our clinical results with sabirnetug from the INTERCEPT-AD study. Sabirnetug is a monoclonal antibody, as Dan mentioned, targeting amyloid beta, specifically raised against soluble oligomers, and we hypothesized that the specificity will provide benefits to patients suffering with Alzheimer's disease. So in the slide titled Soluble Oligomers Beta -- Soluble Amyloid Beta Oligomers, you can see some cartoons describing some of the individual profiles of amyloid beta, starting with the small monomers that in disease can aggregate into multiple forms. And those forms include the oligomers and protofibrils shown in the center, smaller species continued aggregation producing much larger structures, the fibrils and plaques that are certainly hallmarks of the disease and that Dan was showing earlier. And I think the important point to make here is the relative abundance of these various species. You can see on the right some numbers around CSF concentrations. And the point I'd like to make is that the oligomer and protofibrils, those fractions are relatively low abundance targets. And despite that fact, they're also highly toxic targets. So if we can go to the next slide, please. So why would you focus on soluble oligomers? There are a number of reasons to do so. First is that it's a low abundance target that's been demonstrated to produce acute synaptic damage and neurotoxicity. There's a robust correlation between synapse damage and cognitive impairment in Alzheimer's disease. A little bit deeper. You can see on this slide a whole host of studies that have demonstrated different effects of soluble oligomers, everything from disrupted synaptic plasticity and synaptic function, which we'll talk a little bit more about to impacts on astrocytes and microglia, which we'll talk a little bit less about and a variety of other facts. So clearly, these proteins are having meaningful effects in the pathophysiology of disease. But what I'd like to focus on today are the concepts of synapse dysfunction and loss, a little bit about tau hyperphosphorylation and functional impairment. So if we go to the next slide, one of the most important insights has come from Alzheimer's disease research over the past few decades, has been the understanding that many biomarkers can show the onset of pathophysiology years or decades before the onset of clinical symptoms. And this very powerful insight has led to a temporal model of Alzheimer's disease progression, which is summarized on the left panel and allows us to place individual targets into that context. And as you can see, I won't go through the individual elements, but a number of readily measurable markers are showing changes from the normal state well before clinical disease presents. This allows us an opportunity to better understand disease and target individual components. That context has been used on the right in a recent study looking at the specific levels of soluble oligomers and put into the continuum of disease using the model on the left-hand side. And what you can see, the 2 curves to focus on are the red and green curves, which are the levels of soluble oligomers. The red curve is the concentration of soluble oligomers in APOE4 carriers and the green and noncarriers. And although the absolute magnitude is different, I think the central point is the same. This is a target that is increasing in concentration in the prodromal phase, in the preclinical phase and also peaking somewhere in the MCI phase of disease. So highly relevant in early stage Alzheimer's disease to be targeting soluble oligomers. So if we go to the next slide, a little bit more about the soluble oligomers. So quantitation of oligomer levels in a variety of tissues. So the point of this slide is to show using density gradient centrifugation experiment that you can recognize a whole variety of sizes of these amyloid proteins. Those fractions correlate to a variety of sizes. So fractions 4 and 5 correlate to 60 to 150 kilodaltons or so and fractions 9 to 10, somewhere over 400 kilodaltons. It's a large scale on the y-axis. So you can see there's substantial amounts of these various protein fractions that are being generated. Also important on this figure, you can see both from murine models as well as from human Alzheimer's tissue, that you get this elevation in amyloid proteins in both conditions in both the models as well as certainly in the human Alzheimer's disease condition. So highly abundant targets and very different fractions, very different sizes. So targeting specific types of oligomers should have functional consequences. So a little bit about where the soluble oligomers actually are being expressed. You can see on the next slide, a set of immunohistochemistry studies. And I think what's really interesting about this slide, on the left-hand side, you're seeing a study from 2004 and what was observed at that time using confocal like microscopy is a colocalization of applied soluble oligomers. So this is 500-nanometer of ADDLs, as Dan talked about earlier, the synthetic oligomers. And what you can see is that you get colocalization of those oligomers, which is the green signal with postsynaptic neurons that are positive for CaM kinase II, a postsynaptic kinase associated with plasticity and synaptic function. And so what you're seeing is localization of that soluble oligomer, right to the synaptic context. A much more recent study using dSTORM analysis and a more detailed analytical method is reinforcing that initial observation but extending it as well. And what you can see on the right-hand side is a figure from the paper where A-beta oligomers are actually forming nanoscale clusters around excitatory synapses. And so this is really demonstrating that these oligomers are interacting with excitatory synaptic synapses. So there are consequences of those interactions. If you go to the next slide, this is a preparation of human iPSC cells that have been derivatized to form neurons and, therefore, synaptic actions. If you apply those same synaptic ADDLs to the preparation, we can see is that you get a significant loss of synapses on these neurons. That's quantified on the right-hand side, a dose-dependent loss of synaptic contacts in the presence of soluble oligomers. And very likely, given the important role that synapsis play in plasticity and cortical function very likely related to the impaired memory functions and other disorders associated with Alzheimer's disease. All right. But it's -- I wouldn't want to leave you with the impression that soluble oligomers are only found at synaptic context. In addition to that fact, if you go to the next slide, please. Soluble oligomers are also associated with amyloid plaques themselves. Typically in a halo around the dense core plaques. So the cartoon on the right-hand side is intended to give you that visualization. There's a dynamic equilibrium it's thought between the concentration of the soluble oligomers and small protofibrils with the more solid dense core plaques. And so at any given time, that is -- that's existing in equilibrium. All right. In addition to those effects on localization to plaques. If you go to the next slide, another effect of soluble oligomers is the induction of tau hyperphosphorylation. Again, this is in an experimental condition showing that directly applying ADDLs, soluble oligomers leads to a substantial increase in tau hyperphosphorylation in neurons. In the micrographs it's at a particular site, the pTau, the 205 site, [indiscernible] 205. Well, you can see the quantitation on the bottom shows that, in fact, the ADDLs actually cause phosphorylation at multiple residues in the tau protein. So as we get to the clinical studies, of course, you'll be hearing more about phospho tau labeling from the INTERCEPT study. All right. So turning then to sabirnetug on the next slide. With all that context in mind, what is sabirnetug binding to? So what you can see is some internal experiments at Acumen on the left, showing size, fractionization and size exclusion chromatography. And what you can see is that sabirnetug is actually recognizing multiple of these species of A-beta, both the small 3 to 8 mers as well as large protein complexes in the 10 to 100 kilodalton space. So that's what is being recognized by sabirnetug. Another important point from preclinical studies is on the right-hand side, where you're seeing a dose-dependent binding of soluble oligomers from brain tissue of transgenic mice in the TG2576 model and systemically delivered sabirnetug is leading to binding dose-dependently to A-beta oligomer in the mice. So this is a study that led to progression of sabirnetug, and I think you'll see the direct consequence of that in Dr. Salloway's talk when we look at the target engagement study in the human brain from patients being treated with sabirnetug in the INTERCEPT-AD study. If you go to the next slide, I mentioned before the impact of acutely applied oligomer on synaptic contact. So what does sabirnetug do in that case. What you can see from the study on the left, the A-beta oligomers are labeled in red, neurons in blue and synapses in green. And what you can see is that in the presence of sabirnetug that negative effects on synaptic density triggered by soluble oligomers is reduced. That is quantified on the right-hand side. And so you can see that there is a significant neutralization by sabirnetug of that effect of A-beta oligomers on synaptic contacts. All right. As I mentioned earlier, if you go to the next slide, now we're looking at the staining of sabirnetug in human brain from Alzheimer's disease. So showing that some of the effects I've been mentioning from animal studies is also paralleled in the Alzheimer's brain. What you're seeing is labeling in red this time for sabirnetug with -- throughout cortex but not associated directly with Thioflavin-S positive plaques. So these are those amyloid oligomer populations that are associated potentially with synapses but certainly not with the plaques themselves. However, as I said, you do also get a second population of oligomers that is associated with plaques. And you can see that a little bit on the merge slide on the bottom right corner, there's a little bit of yellow staining. But these experiments are not showing it to the best advantage. So on the next slide, you can see 2 different studies on the top, a transgenic mouse model of Alzheimer's disease. And on the bottom, Alzheimer's brain tissue. And in both cases, what you can see is this halo of sabirnetug standing in red surrounding Thioflavin-S positive plaques. And so again, the cartoon on the right is extending what we were talking about earlier, looking at this halo of soluble A-beta oligomer around plaques, but now being labeled with sabirnetug. All right. Given those findings, let's talk a little bit about sabirnetug and its selectivity. So if we go to the next slide, I want to describe some studies that have been done in Acumen as collaborations between Acumen and the Fraunhofer institute in Germany, looking at a technique called SPR, or Surface Plasmon Resonance, as a way of measuring binding kinetics between soluble oligomers and sabirnetug as well as a number of other related antibodies. I'm not going to go into detail on the technology itself, a little bit beyond the purpose of today's talk, but we certainly can talk about that in more detail at another opportunity. But in short, it's in vitro methodology using the properties of light and the changes in the properties of light associated with binding activities, give you a very rapid and highly precise measure of binding kinetics between 2 proteins. So with that context in mind, on the next slide, the first study that was done with a panel of antibodies, including sabirnetug but also a murine donanemab as well as recombinant forms of aducanumab and lecanemab, looking at A-beta 1 to 40 monomer binding. So this is not a oligomer binding, this is monomer binding. And what you can see is that sabirnetug has less affinity for A-beta monomer than either 3 other antibodies, the murine donanemab, aducanumab or lecanemab. The reason why this is important is that A-beta monomer levels, as many of you know, are significantly higher than the low abundance oligomer levels found even in the disease brain. So approximately 7,000 fold higher. So substantially higher levels of monomer in the brain relative to oligomer. And so therefore, higher affinity for monomeric A-beta is going to reduce functional selectivity, because more of the antibody will be binding to monomer. All right. So how does that then impact aligner binding? If you go to the next slide, this is now looking at a comparison between sabirnetug binding versus aducanumab binding on the left and versus lecanemab binding on the right. What you're seeing, I'll interpret the curves for you, the open symbols are a repetition of the data I just showed you, which was the monomer binding. So you can see that in both cases, sabirnetug has less binding to monomer than either aducanumab or lecanemab. But importantly, then looking at oligomer binding instead of monomer binding, you see the opposite effect where sabirnetug has a significantly higher affinity for oligomer than either aducanumab or lecanemab. And of course, when you consider both of those findings together, functionally, you've got a highly different selectivity between oligomer between the antibodies, about 8,000 fold selectivity in the SPR format for sabirnetug versus either the other 2 antibiotics. All right. Let me finish up then with what are some of the functional consequences of sabirnetug binding soluble oligomers. On the next slide, you can see an example of a long-term potentiation experiment. So Dan mentioned in his opening that LTP studies have shown impairments in the presence of soluble oligomers. So in this setup, that finding has been replicated. So as you see in the red curve, if you try to induce Schaffer collateral LTP and hippocampal slices from transgenic animal -- or sorry, this is not transgenic animals, this is acutely applied oligomer A-beta 1 to 42, 50-nanometer. You do impair long-term potentiation. However, in the presence of sabirnetug, that is rescue, essentially then normalizing plasticity in this experiment. Right. And on the next slide, an example from a chronic transgenic mouse model, demonstrating that chronic administration systemically, of ACU3B3, the murine predecessor for sabirnetug has a number of beneficial effects on the mice. What's being shown here is an increase in Drebrin staining, which is a marker for postsynaptic density. So this is saying the animals that have been treated with sabirnetug are showing an increase -- a significant increase in postsynaptic density in the cortical circuits being studied. So you also do see a reduced amyloid deposition as well, although that effect is much more permanent in the younger animals than it is in older animals. All right. So that's a quick turn through the rationale for the use of sabirnetug to clear soluble oligomers and the beneficial effects that, that can have for the treatment of Alzheimer's disease potentially. So just a summary of what I've told you about, first, soluble oligomers are low abundance, highly toxic target in the pathophysiology of Alzheimer's disease. Oligomers exist in a range of sizes from tens to hundreds of kilodaltons. And there's evidence that they bind to excitatory synapses to form a nonscale clusters that can disrupt synaptic plasticity and impair network function. Oligomers also increased during early Phase AD and are associated both with those excitatory synapses, but also a separate population associated with amyloid plaques themselves in this halo around the dense core. Oligomers -- sabirnetug binds to soluble oligomers with a high affinity, and it's highly selective for soluble oligomers relative to monomeric A-beta. And finally, sabirnetug delivered either acutely or chronically, can reverse pathophysiological effects on plasticity in nonclinical models of Alzheimer's disease. So with that in mind, I just want to quickly thank all of our collaborators, who contributed to the studies as well as the Acumen scientists and clinicians who contributed to the work and to the presentation. And I will now hand over the presentation to Dr. Stephen Salloway, who will discuss the results of the INTERCEPT-AD study. Steve?

Yes. Thanks, Jim. Thanks for that excellent presentation. I want to thank the Acumen for inviting me to present today. By way of disclosure, I've been involved in testing and consulting on amyloid immunotherapy with a number of companies, and I serve on the Scientific Advisory Board for Acumen. I'm also an expert in ARIA, which I'll be talking about briefly with this -- in this Phase I study. Next slide. So briefly, the INTERCEPT-AD study was a randomized placebo-controlled old trial in early Alzheimer's disease. There were 4 cohorts in a single ascending dose starting at 2 milligrams per kilogram going up to 60 milligrams per kilogram. There were 8 participants per cohort and dosed in a 6:2 ratio of drug versus placebo. There was also a multiple starting at 10 milligrams per kilogram every 4 weeks, for 3 doses, a second cohort, cohort 6, 60 milligrams per kilogram every 4 weeks and cohort 7, 25 milligrams per kilogram every 2 weeks. And those were dosed in an 8 or 10 per group in the multiple ascending dose study, and it was dosed 8:2 in favor of drug versus placebo. Basically, this population is early Alzheimer's disease, age range of 55 to 90, a mini-mental state range of 18 to 30, they could have a clinical dementia rating global score of 0.5 or 1. They had to have amyloid pathology on -- evidence of amyloid pathology and amyloid PET. APOE testing was done. There were a number of clinical measures obtained during the trial. It's obviously a Phase I, and so we don't expect to see a major change there. The baseline demographics, patients were in their early 70s. It was largely a Caucasian population and the majority were APOE4 carriers with in the teens for homozygous carriers APOE4, you can see the mean mini-mental is 24, which is in the NPI mild dementia range. And you can see also there's a numerical difference between those on treatment versus placebo, slightly higher baseline amyloid levels and the amyloid level of centiloid value of 65 in the treatment group and 49 in the placebo group. The -- in terms of amyloid inclusion, the SUVr quantitative measure was obtained and those that were above an SUVr of 1.2, were considered amyloid positive, those that were less than 1.0 which was a low centiloid value of 8.7, below 8.7 were considered negative. And those that were between 1.2 SUVr went on to have a visual read and a decision was made, whether or not they should be included. Now there are also -- I'm not sure we put this slide in here -- there were patients who had evidence of cerebral amyloid angiopathy, which have been used in other amyloid immunotherapy trials were not included in this trial. Now the important feature of this study was a measure of target engagement using an antibody, a Meso Discovery Scale antibody, a turbo immunoassay that recognizes the complex of sabirnetug with the A-beta oligomers. So when those -- it combined to that, and it really helped direct dosing and measuring target engagement for this trial. So that was an important innovative aspect of the study. Next slide, please. You can see that looking in the CSF, measuring target engagement with this antibody showed that there was a dose-related -- dose proportional increase in target engagement in both the single ascending dose and especially in the multiple ascending dose cohorts. Next slide, please. Now this is important, because it appeared that doses approaching maximal target engagement help guide dose selection for the next phase of development. And it looked like that the doses of 60 milligrams per kilogram every 4 weeks and 25 milligrams per kilogram every 2 weeks, we're approaching that maximal target engagement. And probably higher doses were not required to get a robust target engagement to test this molecule. And Eric may have more to -- Eric and others may have more to say about this and Paul, in their talks or in the Q&A. Now it was encouraging, and we really didn't know what to expect about amyloid lowering. So repeat amyloid PET scans were done. And there were some evidence of amyloid lowering in both the SAD and the MAD studies. And so overall, there was a 21% reduction in the SAD study in amyloid burden on PET and [ 26% ] in the MAD study. So there is some effect. We don't know the extent of it because it's a very short trial on amyloid plaque causing some reduction. Next slide. And again, this is not a head-to-head comparison, but just putting it into some context, the -- in this time frame, the amyloid lowering was tracking along with the amyloid lowering that we saw with other antibody trials that target amyloid plaque more specifically, and so we'll have to see in a longer-term study how this plays out, but there is a component of amyloid lowering with this -- with sabirnetug. Next slide, please. Okay. And it looked like sabirnetug serum exposure is dose proportional without accumulation in both components of the study, the SAD and the MAD study. And also sabirnetug CSF exposure is dose and dose-regimen proportional. And you can see that quite clearly in the MAD study. So it looks like drug is binding to target in the way we can measure it and also there's evidence of the drug in CSF. Now one area we didn't know if there would be ARIA with this treatment since it targets oligomers and not plaques specifically, but there were 5 cases of ARIA abnormalities that we've seen with the plaque targeting antibodies such as lecanemab and donanemab. So in 5 out of the 48 patients that were treated with sabirnetug ARIA did develop, and I'll talk briefly about those cases, 4 were APOE4 for heterozygotes, 1 was a noncarrier, and of the 6 patients who are treated, who are E4 homozygotes, none of them developed ARIA. So it's an interesting finding. Again, it's a small sample but certainly worth exploring in future trials. So just a little more detail about the cases of ARIA. There was one case in the SAD study at 60 milligrams per kilogram. It was a moderate degree of ARIA, was asymptomatic. There were -- there was one case at 10 milligrams per kilogram every 4 weeks in the MAD study and in APOE4 heterozygote. This was after the third dose, it was mild and asymptomatic. There were 2 cases in the 60-milligram per kilogram every 4 weeks, one in APOE4 heterozygote, one in a non-carrier, only 1 of these 5 was symptomatic. There were some right leg dysfunction in that patient, which was transient. The ARIA occurred after the first dose and the plan was not to continue treatment in this Phase I trial after ARIA occurred. The second 60-milligram per kilogram every 4 weeks occurred after the third dose was mild and asymptomatic. And there was one case at 25 milligrams per kilogram every 2 weeks. And all cases of ARIA -- there were no serious cases and there were no deaths. All cases of ARIA showed radiographic resolution. Now interestingly, and we've seen this with some other of the amyloid lowering trials. There was amyloid lowering in the 5 patients with ARIA on the follow-up PET scan, some of them was pretty prominent. So you can see one patient there had a reduction of 47.4%, 42 centiloids, that's pretty significant in a short time frame. Another had centiloid lowering of 30. So there in at least a couple of the cases, there was some prominent amyloid lowering following ARIA-E, ARIA edema. So that ends my overview of the INTERCEPT-AD Phase-I trial, and I'm going to turn it over to Eric about fluid biomarker results and the [indiscernible].

Okay. Well, thanks very much, Steve. And thanks to all of you for taking time out of your busy day to join us. So I'd like to give you a little additional data from our Phase I study, in particular, talking about the fluid biomarkers and then a couple of other points in terms of what led to our Phase II study design. So in this slide, where we have a cartoon of the various biomarkers that we are looking at, you can see that there's a variety of things. We obviously, of course, look at amyloid plaque that's based not only on PET scan, but also on CSF A-beta 42 or 40 ratios. We look at the various pTau species and we'll talk more about that. We look at this astrocytic marker, GFAP in plasma. And importantly, and this goes back to some of the material that Jim presented, is we look at 2 synaptic biomarkers, a presynaptic biomarker, VAMP2 and a postsynaptic biomarker neurogranin. And so this is a lot of material to look at in a Phase I first-in-human study, but we thought it was important to do, and it's one of the reasons why we did our phase study in patients rather than in volunteers. So to get to the results then, this slide has the spinal fluid results of the A-beta 42 over 40 ratio, pTau181 and also pTau217. One thing I will mention, of course, is a very small Phase I study. We do have some values or some differences that reach nominal statistical significance, we are not correct for multiple comparisons. But I think when you look at the data together, directionally, it's actually all very consistent and is in the direction that you would want it to go. So for the A-beta 42 over 40 ratio, you can see as we get to the higher doses, and this is in the MAD cohorts. But as you get to the higher doses, it's increasing. So it's going back towards normal. For pTau181, you see the nominal statistical significance actually at the 60 mg per kg dose. But directionally, even at the 10 mg per kg dose, you see a reduction in pTau181. And then similarly for pTau217, directionally, it looks very similar to the pTau181, and you see this reduction after drug. One thing I should probably also point out is this is after just 3 administrations of drug, we really didn't know whether we would see any changes in these biomarkers in spinal fluid. We did the assay primarily to get experience with the assays to understand the variability so we could apply them in our Phase II study. But when we saw these results in the Phase I study, after just 3 administrations of sabirnetug, we were actually very pleasantly surprised, or at least I was. So we wanted to dig in this a little bit deeper. And one of the things that's kind of an obvious question is, is the amount of reduction in pTau181 and pTau217 related to target engagement. And you can see, and again, with various degrees of statistical significance, but directionally, you do see that with greater target engagement, which, of course, you have at the higher doses, you see a greater change in pTau181 and 217. So I think this is interesting sensitivity analysis just to confirm that what we saw in the previous slide, is really a real finding. One of the other interesting things we found in the study is that there did seem to be an effect of the duration of treatment. So in the cohort that was dosed every 2 weeks. So that was 25 mg per kg every 2 weeks. They were dosed then at week 0, week 2 and week 4. But the every 4-week cohort were dosed at week 0, week 4 and week 8. So they actually had a longer period of exposure to sabirnetug before they had their follow-up LP. And what we found here interestingly enough is that, that duration of treatment seem to make a difference. So if you look at the Magenta diamonds, that's the every 2-week 25 mg per kg cohort, they actually appeared to have sort of a smaller effect than you had even with 10 mg per kg, but every 4 weeks. So this is going to be something that we'll want to watch very carefully with our Phase II study, our Phase II study is 18 months long. And so, we'll see whether that duration of dosing leads to even a greater biomarker response in the Phase II study. So -- and again, we really had an emphasis on the synaptic biomarkers, and this is just cartoon that illustrates both VAMP2 and neurogranin. But the results that we got we're, again, I think, quite interesting. For VAMP2, we actually had nominal statistical significance versus placebo for all 3 cohorts, this assay performed quite well without a lot of variability. So you can really see the differences there. For neurogranin, we, at the highest dose, have nominal statistical significance. But again, it's the direction of these changes is quite consistent. And then when we looked at these 2 synaptic biomarkers versus target engagement, again, we see with a greater degree of target engagement, you have a greater effect on both VAMP2 and neurogranin. And then to get to this question about duration, we saw exactly the same thing. We saw -- if you look at the Magenta diamonds, the 25 mg per kg every 2 weeks dose group a little bit less of an effect than the every 4-week dose groups. And so again, we'll be looking forward to seeing what these biomarker changes are after 18 months in our Phase II trial. And then finally, we also looked at plasma. There's been a lot of advances in the field, as I'm sure you all know it in terms of plasma biomarkers, plasma for whatever reason you tend to have more of a GFAP signal than spinal fluid in a lot of different study. Now here, the results were more variable and in particular, for the 25 mg per kg every 2-week group, you see more variability. That's partly because of the timing of the blood draw was after the completion of the dosing. But again, just as in the other results, directionally, it's all very consistent with an improvement in these biomarkers in plasma with just 3 administrations of drug. So obviously, we're going to do a lot of this testament in our Phase II study, and we'll have, of course, a much bigger sample size and more time points to look at. So just to summarize this, I think we've seen a lot of evidence already today that there's the potential for differentiated efficacy. We have this selectivity for oligomers. We showed you some biomarker results that says that not only did we hit the target, but it's a good target to hit, because in only 3 administrations of drug, you're on these downstream effects on biomarkers. And then in terms of safety, as Dr. Salloway already mentioned, we are intrigued by this finding that of 6 E4 homozygotes, none of them had ARIA. Now obviously, this is a small study. But we'll be looking carefully at our Phase II data to see whether that finding holds up, even if it's just a matter of being E4 carrier is not such a great risk factor, would be a differentiating point for this antibody for sabirnetug. So just a couple of other points that comes from human genetics. And so this slide from a mutation that was actually sort of led to the founders of the company, looking at oligomers as a target. And so what you see is that these are 2 patients with this mutation. People with this mutation have very little plaque, but they have an ongoing dementia, and they have oligomers in spinal fluid. So what you're seeing these are 2 different patients, the top skins are FDG PET. And you can see that there is a loss of FDG PET that goes along with their loss in cognition. The bottom scans are clear. So that's looking for plaque and you don't see any actual neuritic plaque. So it tells you that you can have the pathology and the clinical symptoms of the disease without any plaque at all. And then this slide then is the Christchurch mutation. And this is a more recent finding. It's a really interesting -- there was an initial single case report, but since then, there's been another publication looking at Christchurch heterozygotes and they basically replicated the findings with a larger sample. But this initial case report was based on a kindred that was being looked at in Colombia, who had a presenilin mutation. So with those presenilin mutations, those are essentially 100% penetrant. And so these people with the mutation will have the onset of clinical symptoms late 30s, early 40s. And in many ways, they look like other people with sporadic Alzheimer's disease, it's just a much earlier age of onset. So they have plaque followed by Tau, followed by actual neurodegeneration. But there is a woman in this kindred who was known to have this presenilin mutation, but her cognitive measures remained intact for probably a couple of decades after when she should have been going -- starting to have problems. So this woman was extensively evaluated at MGH. And what you see on the top here is that the very top scans, you see that this woman has a lot of plaque, even more plaque than you might expect based on just having the mutation. And then if you look at the second row on the top, this is looking at the amount of tangles looking at tau PET. And what you can see on the right-hand side, the person with the presenilin mutation, but not the Christchurch mutation, you see lots of plaque. I'm sorry -- lots of tangles. But in the woman with the Christchurch mutation on the left, even though she has all this plaque doesn't have much in the way of tangles, which sort of goes along or preserved cognition. So you dissociated having plaque from having the downstream effects of that tangles and cognitive decline. And then at the very bottom, this actually shows FDG PET, which correlates well with cognitive function. And it's the same story that you see in the person just with the presenilin mutation, they have a loss of FDG PET, but it's preserved in the woman with the Christchurch mutation. And so -- in some ways, we think of sabirnetug as being a way to try to kind of imitate what happens with the Christchurch mutation, because you're binding these toxic oligomers, you should get less tau, you should get less neurodegeneration, and slow disease progression. And so we found this report to be very interesting. And actually, in the initial report, the author speculated that the reason for the less tau and less clinical decline in this woman was because she had less oligomers based on this Christchurch mutation. And so finally, just a little bit about the Phase II study. Dr. Solomon is going to tell you a lot more about this. It's 3 arms, it's 18 months. But I'll go to the next slide. One of the things we did to choose the doses for this study is we worked with a company called Certara. It is a really nice modeling work with our target engagement assay and without going into all the details on the slide here, they modeled all the potential doses that we could look at. And based on steady state peak and trough degree of target engagement, we felt like 35 mg per kg, really, even at trough, you're above 70% of target engagement. And so that's a very viable dose. And of course, at peak, it's better than that. And then we picked one higher dose, where we may have some plaque reduction, we may have some ARIA, we'll see in our Phase II study. But of course, with the higher dose, the 50 mg per kg, we have even greater degree of target engagement. So we feel like either one of those doses certainly has the potential to be efficacious based on the target engagement and it will be interesting then to see also how the safety compares between the 2 doses. And so with that, I thank you very much for your attention, and I'll turn it over to Dr. Solomon, who can tell you about the state of the field and in our Phase II study.

Well, hello, it's an honor privilege, I think, to follow these amazing, if I can use that word, preclinical research that's been done on this treatment. When you look at the current therapeutic options in AD, it's been a very good year. The past year has been an inspiring year for patients with Alzheimer's disease. And for those of us who treat these patients. And those who develop these treatments, and I think you're seeing very good melding of this -- in this today. The emergence of lecanemab also known as LEQEMBI and donanemab also known as Kisunla, coming to market as disease-modifying therapies have changed the course of Alzheimer's disease for patients that we have the privilege to follow. We've seen an enormous interest among our patients for not only the treatments that have now come to fruition and are available, but also for what's going on in clinical research. But I would say there have been also been some challenges, I think, that are worth briefly talking about. Some very good news is that Medicare will now pay for amyloid PET scans. So we're not guessing about pathology in the brain. The bad news is there can actually be some long delays in obtaining these scans. There is also other good news in that patients want to try these treatments. The difficult news is that it is difficult now to get access to either of the approved medications. And the reasons for that are difficult to come across. But patients now can wait 6 months for access to these approved medications. You just heard from Eric about the advent of fluid biomarkers with the identification of patients who can be eligible treatment and this is going to increase. It's been a rapid race to the top to see which ones are going to do the best. But I think we have a pretty good sense of which one it is, and you heard about it in the previous speaker. As you look at the slide, you can see that there is increasing demand for current treatments, and it's growing geometrically. And we wonder how we're going to accommodate all of these needs. We have very good treatment at this point, access to them has been challenging. And we hope that there are going to be things that will mitigate that. So next slide, please. So donanemab is a plaque-targeting treatment and lecanemab, which is now described as having a dual mechanism of action targeting both plaques and protofibrils. And that's interesting. And how does that line up with Acumen sabirnetug? Well, it's because that this sabirnetug falls under the amyloid beta umbrella, if you think about it that way. And it does so by targeting A-beta oligomers. So some of the things we're seeing, I think, are going to lead to a treatment that will be interesting and hopefully successful. My sense about all this is that the 2 approved treatments will provide a foundation for foreseeable future. And people will take these as a standard of care, and that's probably going to go on for some time. But I think when we're really going to get to see interesting things is when we have these treatments is the standard of care, and we're actually able to add other treatments initially in clinical trials and in clinical treatment down the road. We could talk about anti-tau therapies. There's now a lot of interest in anti-tau therapies. They would be one perhaps a way to do this kind of trial. And also, we are actually beginning to do trials with mRNA. And I think nothing would be more interesting than to see how that might work out in a trial with the standard of care. So to summarize, I think it's my sense that monotherapy is going to be the standard of care, but it's going to need some help to truly cure Alzheimer's disease. We think about other diseases, cancers. There was not a silver bullet, one thing that would cure it, but by adding together lots of treatment, several treatments, it's come under doing very well. Next slide. So I was asked to discuss a little bit how we decide what clinical trials we're going to do. I've been a clinical trial investigator for 34 years. My staff tells me that I have been the PI on 300 clinical trials over about a 34-year period. I don't know if they're right, but it's been a lot of trials. And we are approached with many more trials than we can accommodate. Our goal essentially is to have a group of trials that covers all interested patients from mild to moderate disease and it's an MMSE of 12 to 30 if that helps you characterize it. But what are we looking for in each trial. I'd like to work with sponsors who we know well, but I also recognize that there are some hidden gems out there. One of the most important characteristics in trial selection to me, though, is who's running the show. And so what I learned that this was Eric running the show, it wasn't a hard decision to participate. We decided to participate in the ALTITUDE-AD trial for a number of reasons. The protocol design, as you have seen today is very well thought out. The preclinical work on this that Eric did and so did Steve talked to you about, you can see has been just elegant. And the basic research, which you've heard about today as well is also elegant. This is not the characteristics that we often see in other trials that are trying to get into Phase II and Phase III trials. So a little bit more specifically, the protocol design is clearly well thought out. The 2 dose arms plus placebo is rare to see, but the reason that we like it is because the patients have a much higher chance of initially getting the IP and that's really important to patients. It's really important to us. Sadly, we don't see enough of that. There's an open label extension. So all patients are ultimately going to get treated. And this is quite interesting, patients up to 90 years old are eligible. And this is a rare event. And you might say, well, how many 90-year-old are there who want this treatment. And what I can tell you is that about every 2 weeks, we see a patient in our clinic who is 90 years old or even a little bit higher. At closing, I would say the pTau screener prior to PET scans has really been very helpful in reducing the -- in reducing studies negative amyloid scans, the need for amyloid scans by 50% compared to the Phase I trial as we're seeing. So it's a good example of using biomarkers to streamline clinical trials, and that's nothing but good. So from there, I guess, I'm going to turn over to the last speaker.

Thanks, Dr. Solomon. I'm going to take us through a few milestones and some future growth possibilities. So we entered into a partnership with Halozyme in November 2023 to develop a subcutaneous version of sabirnetug that has the potential to have a competitive target product profile within the broader anti-A-beta field. We believe a potential subcutaneous formulation of sabirnetug alongside an IV formulation will create optionality for patients, which will vary based on patient caregiver and provider preference. Greater convenience via subcutaneous administration may be more important and advantageous in some cases, whereas more touch points with providers via IV infusion may be more preferred by others. Next slide. In July, we announced the first subjects had been dosed in our Phase I subcutaneous study of sabirnetug. The study will compare the pharmacokinetics between intravenous and subcutaneous administration of sabirnetug in healthy volunteers. As you can see here in the study design, the purpose here is to understand the pharmacokinetics and bioavailability of subcutaneous dose segment. This information is necessary to determine what next steps in study design plans will be appropriate for next steps of development for this particular format. Top line results were the Phase I are anticipated for the first quarter of 2025. Next slide, please. So operationally, we've made significant progress with the clinical development of sabirnetug in 2024, initiating both our Phase II trial and our Phase I subcutaneous trial. In 2025, we anticipate good progress in both with the subcutaneous results expected in the first quarter and the completion of enrollment in our Phase II ALTITUDE-AD trail in the first half of 2025. And importantly, we continue to believe our cash on hand will fund us into the first half of 2027. Next slide. In summary, with the potential clinical safety benefits confirmed by its A-beta oligomers selectivity, sabirnetug has an opportunity as a next-generation treatment of choice for this significant and growing early AD population. The potential for sabirnetug to offer best-in-class efficacy and safety is underpinned by positive Phase I data. And as you heard today, we are laser-focused on the next stage of development and executing against our plans in a thoughtfully designed clinical development program for sabirnetug. Before we move to questions, I want to quickly thank Dr. Salloway, Dr. Solomon from participating this morning and the entire Acumen team, past and present, for their hard work and dedication. I also want to acknowledge the study participants in INTERCEPT-AD and ALTITUDE-AD as well as the investigators and study personnel, who are helping us to advance the science and opening up new possibilities in Alzheimer disease.

Great. So I think we can open up the line for questions, Lisa.

[Operator Instructions] And our first question today is coming from Paul Matteis of Stifel.

This is Mark on for Paul. We had 2. So for one, if you could provide any more details on the interim analysis in the Phase II? And then our second question was some potential options you potentially have with the subcutaneous dose when you see that data?

Yes. So just to clarify, there are no anticipated public interim analyses in the ALTITUDE-AD study at present. And sorry, the subcutaneous will just -- and that's principally to give us information in terms of the bioavailability of subcutaneous sabirnetug versus IV administration of sabirnetug. That information, as I mentioned, is expected for the first quarter of '25.

And our next question is coming from Tom Shrader of BTIG.

Thank you for the event. Maybe the most fun R&D event ever. I have a couple of sort of remedial questions or just kind of consensus questions. What's the consensus on which species are in equilibrium? And then correspondingly, what's the consensus on why donanemab works given that it's broadly considered a plaque binding antibody, but we've just had this review on the A-beta hypothesis?

Thanks, Tom. I'm going to direct that one to Eric as the initial discussion others may have -- other information to share as well.

Well, yes, thanks. And actually, I look forward to Dr. Salloway and Solomon to potentially have some opinions on this, too. But in terms of the different species of beta, they are in equilibrium with each other. But as Jim walk you through, the concentrations are very different. So the concentrations of oligomers are much less than the concentrations of monomers. Now in some respects, that's a good thing because, because it's easier to stay an antibody excess if your target is it the low concentration. And again, Jim walked you through the specificity for the oligomers, which is, I think, really quite remarkable actually. So -- and then to get to your point about donanemab, it is interesting. I think our premise all along has been that the plaques themselves are not toxic. If there are a reservoir for the toxic species, the soluble toxic specie. And so our thinking has always been, if you're going to target the reservoir, you really have to get rid of it. You can't take a basketball and shrink it down the size of the soccer ball and expect anything to really come to that. And what studies have shown, not just with donanemab but with other antibodies, you have to get below like 24 centiloids if you're going to have clinical efficacy. So that's basically removing the plaque. And so that's held up if you want to go after the reservoir, you have to really drain the reservoir, partly lowering it isn't really going to help. So that would be my 2 points on that, but certainly, I open up for our colleagues here. They've probably got some other ideas, too.

Well, what patients want to know is does this work? And what is the evidence for it working. And we can see that in the data. We can see it in the patients. There are a large group of patients that have just done very well on this treatment. We follow them now for 5 years, going on to 6 years. And we see patients that just haven't changed very much in that period of time. Is it everybody? Of course, not. But there is enough there to really be enthusiastic about this. And although we care about mechanisms of action and all these other things, patients don't care about that. They want to know are the plaques getting out of there, and I haven't changed in 3 years. That's good enough for them. The rest of it is less than interesting for them. So when we see a patient that we followed for 3, 4, 5 years, and we just haven't seen much change. That's a remarkable thing. And it's been interesting and fun to do this after for me, a lot of failures.

I think the correct answer to that is we don't know. I think Eric was getting at that, that so far, the data, I agree with Eric is holding up, that you have to lower amyloid plaque burden to a certain degree to get a clinical benefit. But then there's still a limited clinical benefit. And so there are other species both of amyloid and other pathogens that can be targeted. And so that's why this experiment with sabirnetug is important to see if we can target oligomers, and certainly, it could be combined. There's no reason this couldn't be a combination treatment as well as a monotherapy. We just have to prove that it works and it's safe. But we don't know for sure yet.

Okay. A quick follow-up for Eric, although the answer may also be detailed, but your data look much better for Tau181 than for 217. Is that just asking too much at this early data? Or does that make sense, I think these are also an area where I think there's -- it's not crystal clear to all of us, what the difference between these 2 markets is? And maybe can you give us the current thought? And does it make sense based on what you think your antibody is doing?

Well, yes. So I come back, I think the answer to that is probably we don't know. But just to give you a little bit better answer. Just to remind you, we have 8 people in each cohort on drug. So the clinical sizes are really small. When -- and again, they only got 3 administrations of drug. To try to compare what you want in 217, I think in these small sample sizes, it's a little hard to tell, to be honest. 217 is kind of everybody's favorite right now, but we'll see going forward. But when we get to Phase II study, so the Phase II study, with a total of 540 people, then you can maybe start to look at some head-to-head comparisons between pTau217 and pTau181 and other things.

The -- I'm not sure if everybody is aware of this, but Medicare will now pay for an amyloid PET scan. And that's really changed things in terms of diagnosis. And we think they're going to be willing to provide more than one PET scan. That seems to be in the narrative. We're not sure about that. But this is really change diagnosis and important.

And our next question will be coming from Jason Zemansky of Bank of America.

I appreciate the updates. A couple of questions, if I may. We've only been looking at ARIA, I think, is a side effect to be avoided. And I'm curious, it looks like it may just be an on-target effect and something that needs to be mitigated. Curious to hear your thoughts on this and where the field is headed. And then a follow-up, if I may, please.

Well, I could start with that. Thank you. Well, I think the ARIA, and our understanding of the mechanism underlying ARIA is basically antibodies that target plaque binding to amyloid and the arterial wall, small blood vessels in the brain, dislodging them and causing some leakiness. And along with that, there can be an inflammatory component, which can be either small or large. And so the edema can be very mild and transient, or it can be more serious and severe. And some patients, we don't have a good marker for this yet. So I don't think that it is -- and partly true what you said, it's related to the target binding, but I don't think it's... [Technical Difficulty] Can you hear me now? Sorry about that. I don't think it's the plaque binding that's causing the ARIA. I think it's really the binding to vascular amyloid. So there may be ways to deliver these type of amyloid lowering treatments without that same degree of vascular -- binding to vascular amyloid and having a lower rate of ARIA and less serious ARIA. So that's one option. People looking at this through shuttle mechanisms where we can get drug in at higher concentrations into the brain, maybe binding in a different way. And there may be ways to mitigate also that vascular amyloid binding as well. Now the question I thought people were going to ask, maybe this is your next question, I don't know, why is this drug? Why is sabirnetug causing ARIA? It doesn't bind the plaque very much. How come we're getting that ARIA? Well, the answer, at least, there may be people at Acumen that know, but I don't think we know yet. But it could be that the drug is inducing some -- in a small percentage of patients. This was only seen in a handful of people, an inflammatory response or a microglial activation that could be causing ARIA. Certainly, we saw this with the TREMs trends, at least one of TREM2 antibodies doesn't target plaque directly, but can cause significant ARIA.

So from a clinical perspective, I think that we see ARIA as a manageable side effect, 95% of people don't have any symptoms from it. Nevertheless, they're taken off IP until the ARIA resolves. And for the other 5%, probably not a good idea to continue. And so that's how we have treated this over the past, I guess, now at 6 or 7 years, seems to work out okay, but it would be good to know what's causing it and to be able to prevent it for sure.

Yes. And maybe I can comment just on the sabirnetug itself is that, as Steve mentioned, they're currently an inflammatory response. Sabirnetug is an IgG2, so it has less effector function, but it's not 0, and it doesn't bind the plaque very much, but nothing is 100%. So one possibility for the reason why we see plaque reduction in ARIA cases is that you've got some binding of sabirnetug to plaque and enough effector function to reduce the plaque and then get some ARIA along with it. The other possibility that actually, I think might be more likely is all these species exist in equilibrium. And as Jim walked you through around the plaque is the halo of the soluble species. Because they all exist in equilibrium, you could have binding of sabirnetug to the oligomers around the plaque that the equilibrium or at the actual neuritic plaque that you would see on PET scan becomes less and then you can also have some ARIA associated with it. So -- and those 2 things are not mutually exclusive. So you could have some direct binding of plaque. You can also have the equilibrium shifts. I think the bottom line is that we'll get this out of the Phase II study is what's the net result and what's the frequency of ARIA.

Got it. That's helpful. And I appreciate the color. That certainly was where I was going with this. So let me just conclude with another quick question on the enrollment of ALTITUDE. I was curious, could you provide a little more color here and sort of the enthusiasm, maybe not to [ cascade ] on your competitors? But is there a sense from the demand that more or more effective treatments might be available than those that are commercially out there?

Thanks, Jason. Jim, do you want to comment on that?

Yes. Well, look, I think we're pleased with the pace of enrollment. And I do think, as you heard from Dr. Solomon and Dr. Salloway is that the protocol such that people are enthusiastic about participating in the trial. I do think that we've been talking about the data today, and I think there's a level of interest out there. But I also think that it's probably too early days to be attributing much to comparative thinking. I would defer to Dr. Salloway and Dr. Solomon to talk about that in a little bit more detail. But we're just very pleased to see the response to enrollment in the trial so far.

And our next question will be coming from Ananda Ghosh of H.C. Wainwright.

I have kind of 3 questions. Maybe the first question, it's probably related to Dr. Salloway. He mentioned during his prepared remarks about one particular case where he saw -- where the general observation is a 48% reduction in amyloid plaque following ARIA-edema. What's the significance of this observation when looking at the broader landscape of anti-A-beta immunotherapy?

Well, is the question the amyloid lowering in the cases with ARIA [indiscernible]?

Yes, right.

Yes. Well, we've seen that now with other antibodies that target, actually target plaque that when you have ARIA and actually in animal models as well, that in the area of ARIA, there usually is a lot of amyloid. And if you do a follow-up PET scan in that area, some -- there have been anecdotal cases where that there is significant lowering of amyloid that we saw here in a handful of cases in the Phase I trial. So I think what's happening there is that there is amyloid -- activation of amyloid, mobilization of amyloid from the parenchyma, from the vascular to getting leakiness but also leading to a reduction. So if you can survive ARIA, you may do very well, because you're going to end up -- and I have had anecdotal -- again, anecdotal cases, the people who have had serious ARIA, they have to go to the hospital, get steroids and so forth, do well, though, the resolve. And then some have actually had a follow-up PET scan, that amyloid scan, that shows the substantial lowering. One was a neurologist who wrote a book about it called A Tattoo On My Brain, if you want to read about what that was like, and he's very good at describing as a neurologist his own experience. And I had other people say, gee, I contacted a colleague who had the case of serious ARIA. I said how is your patient doing, she's better than normal after the ARIA event, which she had done well. So these are anecdotal stories, but they're interesting, because I think there are in some patients, especially there can -- there is a physiologic effect of having amyloid lowering coinciding with the ARIA.

That's very helpful. The second question, I thought the mention of Osaka and the Christchurch mutation, the patients are very interesting. My question is, are these imaging characteristics, what have been seen in Osaka and the Christchurch, the patients with those mutations? Is it very similar to early preclinical AD patients? And then in that case, what's the -- does that also mean that sabirnetug might be a better drug in terms of targeting the preclinical AD patients?

Yes. I guess by preclinical view, people use that work differently, but I think a lot of times what we mean now is that would be people who have plaques but don't have any cognitive decline yet. And so for that group of people, it's kind of interesting those 2 mutations, how they contract with each other. So for the Osaka mutation, they essentially never get plaques. And so there -- well, you're born with the mutation, so you have a preclinical period by definition before you develop your cognitive loss. So in that population, preclinical would be characterized a little differently. For the Christchurch mutation, that's more similar to kind of what we see in sporadic Alzheimer's disease in that, again, especially this case report, woman had a lot of plaques in her brain, but for cognitive loss, it eventually did happen, but it was much later than you would have expected and she didn't have the downstream tau and that sort of thing. So for people who -- well, and the Christchurch mutation, of course, is very rare, especially having 2 mutations, one presenilin and one Christchurch. But that person is preclinical -- more similar way to preclinical sporadic Alzheimer disease, because again, probably most people on the call know that plaques 15 or 20 years before you finally develop clinical symptoms from it. So that preclinical population is certainly something of interest to us.

And my last question is, there has been a debate specifically at the last AAIC, whether anti-A-beta immunotherapy should be given in a chronic way or should be stopped after the -- once you have a complete removal of plaque? Where do you see sabirnetug in this kind of debate?

So I guess maybe I can take that one. So the data on lecanemab and donanemab, well, the studies are designed differently and that the data have been interpreted a little bit differently. But especially when you look at lecanemab, which I think is more similar to sabirnetug, when you go off drug in the, what they call a GAP study, your biomarkers start to look worse and your rate of progression seems to get greater. So our thesis is that you really need to maintain therapy with sabirnetug. Your brain is never going to stop making A-beta. And so it's never going to stop making oligomers. And so it's not like you clear out all the plaque and then you stop. So in our view, this would require chronic therapy.

Yes. I think it's unclear with the current therapies that are approved, as Eric said, they were designed differently. So 1 is ongoing treatment. The lecanemab and donanemab had a follow-up PET scan. And then when the threshold was lower than the amyloid, the medicine was stopped. And we don't really have a head-to-head study or an induction and a maintenance study, which makes the most sense. I think that's what Eric was talking about. I foresee that in the future, there will be an induction phase of amyloid lowering and a maintenance phase where we can suppress amyloid. And that certainly sabirnetug could fit into there in both aspects of that if they prove to be efficacious. And we're going to need more. We are going to need more than the current treatments we have. It's a good start, but there's a lot of room from -- so figuring out how to maximize efficacy is really important and having different targets.

Thank you. And there are no more questions in the queue. Please go ahead.

Great. Thanks, Lisa. We do have a few questions that came in on the chat. And I do think we have some time for them. One of the questions is focusing on the percentage of the AD population that are E4 homozygotes and how important that is for the potential for improved safety outcomes in this subpopulation? Maybe we can direct that to the thought leaders on the line just to talk about E4 and how important that would be, if sabirnetug were to differentiate there?

Well, the E4 homozygotes are a very important population. They are very high risk in developing Alzheimer's. They develop at a younger age. There's going to be more testing for APOE. It's not very common in the general population, only 2% are E4 homozygotes, however, in an Alzheimer population in clinical trials, it's above 15%. And so these are patients with a family history. They come in, they're aware of it, and they're very eager for treatment and early treatment. So they're a great group and they need care. They're also very high risk for ARIA and finding safe ways to deliver new treatments, immunotherapy or otherwise, is very important. I'm -- we'll have to wait and see. I reserve judgment about the finding in this trial about the 6 homozygous that didn't have an ARIA event. Let's see what happens when we treat people for longer and larger numbers and see. But there is a need to have safe treatments started early for this population. It's a very important clinical population. I'm sure Paul would agree with that.

Yes, especially the younger group.

Yes, absolutely. You can find these people early. If you just do genetic testing, whether you can do a cheek swab or a blood test, you can identify people at risk many years before the onset of symptoms and target, because the chance of them developing Alzheimer's is really quite high. And so...

The question is, what do you do about it? And that's just...

Yes. Well, I think this treatment has a lot of -- I mean, we got to prove that it works in the population we're studying it for right now, but certainly, this would have -- is very [indiscernible] for using a drug, an anti-oligomeric drug early on.

Yes. So Eric hurry up.

Give us some good news so we can try it in different ways.

We're game.

We're going faster than we thought. It's a good news, sorry.

There is another question in the chat actually, to that point, Dan, maybe you can just confirm. I think we moved through the enrollment completion date pretty quickly in the presentation. So there are a couple of people wondering about data, if you can confirm when we expect enrollment to be completed in the Phase II?

Yes, sure. Thanks, Alex. As I mentioned, the study is up and operational at both in North America and in Europe at roughly 70 sites, which we think are the necessary sites to complete enrollment. And we have guided that based on the ongoing rate of school and enrollment that we will complete enrollment in the first half of 2025. So we're super encouraged by the enthusiasm of the study. We have Dr. Solomon and Dr. Salloway mentioned the Phase I data and a protocol for Phase II that seems to be compelling to sites and participants.

Great. Thanks. We have 2 more questions. I think we have time for them. One is there's a question about the lecanemab AAIC data. And the need for chronic dosing, showing that soluble amyloid continues to build in the brain following treatment. Maybe the thought leaders can walk us through that and what your take on that was, what that means for the broader landscape and as well as for sabirnetug?

Well, the situation is that LEQEMBI is portrayed to patients is something that's going to have to be continued indefinitely. If they get to a situation where you can use needles instead of having to come in for infusions, that will make that a little bit easier. But when you start looking at auto injectors and these other things, it's not so simple. Lilly seems to think that they don't have to pay any attention to this at this point, monitoring patients and so on. And it's a different treatment and it's a different view. So we'll see.

Well, I wish we had the data to see. That's the problem. I wish there's a way to design a trial where we actually treat people feel amyloid is lower. And then randomized them, either to chronic treatment, spaced out treatment or stop treatment and see how they do. Because there -- I think there are different courses. People really vary with Alzheimer's disease than the natural history. And so some people are going to be reaccumulating, have oligomers and have other pathology, certainly tau doesn't go away appreciably, and they're going to need ongoing treatment. So my gut feeling is, in general, we're going to need an induction phase and a maintenance phase. So it's not clear to me that once you've lowered amyloid, if you use like lecanemab or donanemab below the cutoff being considered amyloid positive, I don't think you need to come in 2 weeks or even do it at home every 2 weeks. I think you could suppress that amyloid either with the same drug or with another drug like sabirnetug or TBD, that could be given less frequently. But it's -- we don't have data about that. Paul can give his opinion, I give and Eric can give his opinion, every clinician can weigh in, but we don't really have controlled data because the trials were designed so differently.

And the investigational product is different, too. So there's a lot of things that, from a trial point of view are difficult to deal with.

But it is attractive to be able to reduce the dosing frequency. And I'm very encouraged. I don't want to talk about competitors, but just to show up by encouraging data that with trontinemab data that was shared at AAIC using a brain shuttle. There's a possibility of just a few doses of drug and then going to a maintenance phase, that would be very attractive.

It would.

All right. Last question that we have time for. And this one is -- I'm just going to read it off I think maybe Jim or Eric could probably handle this one. Your preclinical study showed sabirnetug rescue synaptic plasticity, cellular mechanism of cognitive function acutely or chronically. Your Phase I also showed protection of synaptic loss revealed by fluid biomarkers. Have you checked the synaptic function or neuro connection improvement, which may be early signs to predict future therapeutic efficacy? Quite a mouthful.

Yes Alex, let me take this first, and then I'll ask Eric to weigh into. It's a very good question. And the way I would respond is, yes, based on the data and based on the hypothesis associated with the data, you might expect that some of those functional measures would show benefit in the same way we saw a benefit with the fluid biomarkers in the INTERCEPT study. I think it becomes more interesting as you start thinking about some of the earlier populations, the preclinical phase of Alzheimer's disease that all the clinicians have been talking about. And I think that is certainly something that we're aware of. It becomes a question of identifying the right kind of functional test that will be amenable for a clinical study format. But I do think that the concept is a good one and is consistent with what we might predict. Eric, I don't know if you want to add anything?

Yes. Well, just from a clinical trial standpoint, if we would have known that our synaptic biomarkers would have grown so much effect from sabirnetug, we might have built more into our Phase II study. But the way you could approach that is to do something like functional MRI, which is technically pretty challenging, actually, where you could even look at something like PDG PET, which is a little bit more straightforward. So now there's always more studies and more biomarkers to think about, and that's good.

Great. All right. Well, that's it. That's all the time we have. I thank everyone for taking the time to listen in. There will be a replay made available on the website. And if there are any questions left unanswered, we will get back to you. All right. Thank you, all.

Thanks, everyone.

Thank you, everyone.

Thank you.

Thank you all for joining today's conference call. You may now disconnect.