Welcome to the Cantor Global Healthcare Conference. I'm Pete Stavropoulos, a biotech analyst with Cantor. With us, we have Acumen, a company we cover, and I'm pleased to introduce Dan O'Connell and Jim Doherty. Dan, CEO, and Jim Doherty, the Chief Development Officer. Welcome, and start off with a brief introduction of yourselves and a snapshot of the company, and touch on milestones that will shape the company over the next 6- 12 months. Thanks, Pete, and thanks to you and your colleagues at Cantor for inviting us to this year's conference. I'm Dan O'Connell. I'm the CEO of Acumen. I've been in the life sciences space for the majority of my career. I've been focused on working in building small neuroscience-focused companies. Acumen has been a core element of that effort, and excited to share more with you today on the story. Yep, good to see you, Pete. My name's Jim Doherty. I'm President and Chief Development Officer for Acumen. Neuroscientist by training. I've worked in CNS drug discovery, drug development for quite a long time now, both in large companies and in small companies. In terms of Acumen's profile and status, we are a publicly traded company working to advance better treatment options for patients impacted by early Alzheimer's disease. Our current pipeline includes sabirnetug, which is a monoclonal antibody that is highly selective for what we view as the most toxic species of A-beta, principally referred to as A-beta oligomers or amyloid beta oligomers, which have been shown over a couple of decades of research to be potent neurotoxins at the synaptic and neuronal level. And we think sabirnetug, based on its selectivity, has the ability to unlock greater efficacy and safety for early Alzheimer's patients. In addition to sabirnetug, which as I mentioned, will read out phase II clinical proof of concepts data late this year. We are advancing a couple of candidates in what we refer to as Enhanced Brain Delivery. This is using a receptor-mediated transport technology that we've sourced from a partner in Japan called JCR Pharmaceuticals that has a transferrin-directed moiety that allows for the binding of the transferrin receptor and the delivery of large molecules. They have programs in other disease indications, rare and otherwise. We are their only partner in Alzheimer's disease, and we're using the JCR carrier technology to deliver Acumen A-beta oligomer selective payloads, including sabirnetug and a sabirnetug-like molecule. That program is still finalizing the profiles on two candidates with the goal of filing an IND in mid 2027. Okay. When most hear amyloid beta antibody therapy for Alzheimer's, they think about plaque reducers like the approved drugs lecanemab and donanemab. However, like you just mentioned, the therapeutic hypothesis for sabirnetug is differentiated from the approved amyloid beta antibodies. Can you just give us a synopsis of the oligomer hypothesis and sabirnetug's mechanism of action? Thanks, Pete. Amyloid lowering is now the therapeutic space that broadly characterizes a variety of different species of A-beta in amyloid pathology. We're principally focused on neutralizing these small, soluble toxic aggregates of the A-beta-42- peptide that have been shown to bind to neurons at synapses and induce tau hyperphosphorylation, induce calcium influx, and basically be a prime instigator of Alzheimer's pathology and a persistent contributor to ongoing pathology. The current agents, one from Eli Lilly and Company, one from Eisai and Biogen, those are directed at other species, including amyloid plaques, which really represent the end stage of amyloid accumulation over 15- 25 years. It has been shown clinically, amyloid lowering strategies have been clinically validated. There are two approved agents. There's also now growing commercial traction for those agents. We're in the era of optimizing within the amyloid space, and we think sabirnetug and oligomer-directed approaches have a unique value proposition to patients and physicians based on that mechanism. Do you think that targeting oligomers could lead to earlier or more rapid cognitive benefit or protection? I think there's a possibility. I think that the primary mode of toxicity for these species is disruption of circuit function. Alzheimer's itself is a disease of loss of synapses. We do think that it's hard to predict in a large ongoing phase II study when effectively there will be a separation on clinical measures. But we're hopeful that, not only at 18 months, which is our primary outcome measure, but potentially sooner in the course of treatment, there's an observable effect on clinical measures in addition to biomarker effects. I think that's another point to make is that the field has progressed pretty dramatically over the last 10 years, whereby we have a much greater panoply of tools available to us to help inform development decisions and pharmacodynamic effects. We think that's going to be an important. It's contributed to the conduct of the phase II study and will help in terms of the translatability of sabirnetug outcomes to inform our strategy for the Enhanced Brain Delivery program. Yeah. Sorry, go ahead. Thinking about the amyloid hypothesis and the soluble oligomer hypothesis, part of the reason why it's such an exciting time in Alzheimer's disease right now is that we have been able to translate a finding that's been known for a long time, that this amyloid protein is one of the core pathophysiologies in AD. To now, for the very first time, that we've been able as a field to demonstrate that you can alter clinical course by sequestering that protein. Which is fantastic. But it's also still complex biology. Amyloid encompasses a lot of different types of protein. It's all one protein, but the different forms of the protein are highly relevant. There's actually quite a lot of evidence to support that the small soluble oligomers, as Dan was saying, are acutely neurotoxic and cytotoxic and synaptotoxic. That is, I think, the core part of the soluble oligomer hypothesis that we're trying to test, is that we'd like to expand the thinking around how amyloid can best be addressed as a treatment for Alzheimer's disease. Okay. Can you just go into some of sabirnetug's properties in terms of affinity and selectivity for different species of amyloid and some of the preclinical data that sort of increases your confidence in the mechanism? How it can potentially translate to a differentiated efficacy profile. Yeah. We can give you some real quick metrics on the non-clinical piece, but I think that the phase I data are really what underpin our confidence in phase II. Sabirnetug was raised against oligomers. It has 10,000 fold selectivity for oligomers versus monomer. It has over 100 fold selectivity for oligomers versus fibrils or other species. We know it's oligomer selective. I think what builds on that sort of preclinical or non-clinical profile is the data we generated in phase I. We took sabirnetug into an exclusively Alzheimer's population in phase I, both for single ascending dose evaluations as well as multiple ascending dose evaluations. There we saw, not only were we able to establish target engagement of oligomers using a novel mechanism developed by our team and a dose response associated with that target engagement, but a safety profile consistent and competitive on the basis of our mechanism. Essentially low rate of ARIA observed in this small short duration phase I study, then moving both imaging and fluid biomarkers in the right direction. That is really, when we think about three doses of sabirnetug in the multiple ascending dose cohorts, moving the PET imaging in addition to cerebrospinal fluid, p-tau181, A-beta 42:40 ratio, as well as synaptic markers like neurogranin and VAMP2. These are the things that, taken together, give us a lot of confidence in why the phase II is positioned for success. Just stepping back on the phase I data, the overall study design. You did do it in Alzheimer's patients, but you had the SAD and the MAD part and just describe the MAD, how far dosing went. Sure. The MAD had three active doses, 10 mg per kg dosing every four weeks, 25 mg per kg dosing every two weeks, and 60 mg per kg dosing every four weeks. Effectively three active doses over roughly three months of time. That, of course, is a fairly wide range of dosing in an MAD phase Ib type study, which was really important to us to, in patients, establish a safety threshold and a window at which we could dose sabirnetug safely and reliably. Then we hadn't really anticipated seeing the magnitude and the consistency of the biomarker effects across both imaging and fluid. That really helped inform the dosing strategy for phase II, in that we have taken forward an active dose of 50 mg per kg every four weeks and 35 mg per kg every four weeks as our active doses versus placebo in the phase II study. Right. You've done extensive biomarker analysis. Mentioned a little bit of it now. What are some of the observations that you find most intriguing or Eric finds most intriguing? For me, Jim should really comment, the synaptic piece is really intriguing to me. I think if we are protecting synapses from oligomer toxicity and it's a downstream effect that's observed, these synaptic markers are not Alzheimer's markers per se. They're neuronal synaptic health. Preservation of synapses in this population would be, I think, a really interesting mechanism to validate in this large ongoing phase II study that would really usher in, I think, a greater awareness of how we optimize within the amyloid space and why oligomers are such a compelling therapeutic target. A lot of valuable data has come out of the INTERCEPT study and starting with just target engagement, for example. Being able to measure the bound complex of soluble oligomer and sabirnetug coming out of CSF from patients. A, gives you some upfront target validation because you're actually sequestering oligomer from the brains of these patients. It also gives you a much better sense of what the dose response is likely to be and led directly to the choices of dose that Dan was talking about for the ongoing ALTITUDE study. At 35 and 50 mg per kg, we're actually hitting both at the lower dose, the steep part of the curve of sequestering oligomer, but then also at the high dose at the asymptote at the top. It really gives us a lot of confidence that we've got the dosing right for phase II. I think on the fluid biomarker data, of course, it's great to see some of these individual markers moving following sabirnetug treatment. I think what's most compelling to me is the pattern of change. We're seeing effects at multiple levels of integration. We're seeing the expected changes in A-beta 42: 40 ratios, which is much more closely associated with amyloid itself. When you think about the p-tau181, the p-tau217, and importantly, those synaptic markers, looking at neurogranin and VAMP2, you're seeing the same pattern of change, which to me is suggestive of having a network-level response, which is really what we're shooting for with this hypothesis. Have you gone back and looked at 243 by any chance? So we have not yet. I think one of the most exciting things that's happening in this field right now is the rapid pace of development of soluble biomarkers. The work that's been done around 243 is accelerating very recently. So it's a highly relevant question. I think this is something that we'll be looking at moving forward, but I don't think it's going to be the last one that we'll see. So I think for all of us, it's going to be an evolving process of adding some of these new biomarkers into our analysis. Yeah. I agree with what Dan said earlier, which is basically over the last 10 years or so, there's been sort of an explosion in terms of markers. But I think the past three, four years has just been exponential. Yeah. I think you're going to have a lot to choose from, hopefully when you go into a phase III. ARIA, which is a concern for the approved drugs, lecanemab, donanemab. It was observed in your study. Just curious to touch on those observations. Yeah. I think it's important for you to characterize it as observations. We had five total cases of ARIA across the 48 subjects exposed to sabirnetug. Three of those cases came at the high dose of 60 mg per kg. One each at the lower two doses in the lower dose cohorts. Of the three at the high dose, only one of the five was characterized as moderately symptomatic, and that really is some numbness in a limb that was self-reported by the patient. At those upper dose levels, it seems to be a dose response. These are small Ns. It will be interesting to see what's observed in ALTITUDE in terms of the overall rate of ARIA-E, as well as the rate of ARIA-E in E4 carriers, which of course are the genetically predisposed population that's at higher risk of ARIA with the plaque-directed approaches. Anecdotally, in phase I, we had six E4 homozygotes that were exposed to sabirnetug, none of which developed any ARIA-E. We will have all of that data coming out of ALTITUDE, and it should inform whether there's evidence in support of this more at-risk population being supported with a sabirnetug-like mechanism, being safer, potentially more efficacious. Okay. Switching gears to the phase II study that's underway. Data is going to read out in 4Q. Can you just talk about the design of the study, and how did INTERCEPT actually inform the design? Yep. The ALTITUDE study is a three-arm study placebo control, 18-month placebo control period. Primary endpoint is the iADRS scale, so a measure of cognitive performance. We also have a number of other cognitive scales, such as CDR Sum of Boxes included in the study. In addition to that, we will be looking at the same sort of imaging and fluid biomarkers that we talked about from the INTERCEPT study, as well as robust safety monitoring. That's the design of the study, 542 subjects enrolled in the study across the three arms. As we had already said, 35 and 50 mg per kg are the doses for the two active arms. What's the study powering and what are the key assumptions? Yeah. Study powering, we haven't talked about the details of powering. I think from the assumption that people can make that we're looking to make sure that this is a well-powered study to be able to detect effects. As I said, 542 overall subjects. It's a very well-powered study to detect changes in cognitive performance. Anything you can say about the assumptions in terms of dropout rate, things of that nature, or? Sure. I'll comment. We did prioritize the iADRS as the primary because it has been shown to be a bit more sensitive for early phase development in this population. We will also have the CDR Sum of Boxes as a secondary. That was an intentional decision on our part to prioritize iADRS. In terms of study conduct has been phenomenal. Jim mentions 542 patients, and those patients were roughly 180 per cohort, enrolled in roughly 10 months, which is to our view very competitive in terms of enrollment. I think that rapid enrollment was a combination of a function of the INTERCEPT phase I data, working with sophisticated investigators that recognized the value potential of sabirnetug, and a willingness on the part of patients to participate in research studies even in the presence of approved agents. Like, what could be better? What could I be doing? That is an important metric. From a retention standpoint, the retention in the study has been good. It has been probably better than we would have expected. Dropout rate is, like I said, better than expected. Another interesting aspect is we have an open-label extension. After the 18-month placebo period, patients are eligible to go into an open-label extension where everybody is eligible to go on drug. We have had a better than 95% rollover of those patients eligible to continue in the open-label extension. Which again, is, excuse me, a sign that the study is going well. People are enjoying their participation and want to extend their involvement in the study. Not an endorsement or an indication of efficacy, but it is encouraging as we think about the level of commitment and the execution that the team has carried out in the ALTITUDE study. Okay. In terms of dosing, the lower bracket, 35 mg per day, I believe. What are your expectations there for ARIA and plaque reduction? Yeah. I think we will see, right? We do think that, as we were talking about from a mechanistic point of view, there is the opportunity to see lower rates of ARIA. I think on the efficacy side of things, too, we are hopeful that given a direct targeting of the soluble oligomers, we are going to see a differentiated profile. I think what you see at which dose, a little harder to judge. As I said earlier, the point of the 35 mg per kg dose is you are targeting the soluble oligomers much more selectively. When you get to the higher dose, you start to have additional binding to other forms of amyloid. We will have to see what the results look like. But I think in either case, there is that opportunity for differentiation based on efficacy and on safety. Yeah, we really think of this as the risk-benefit profile. Which of these doses, potentially both, can differentiate on a risk-benefit profile relative to the approved agents? That profile really is a consequence of the magnitude of the efficacy in the context of the safety profile. We are very excited to see how the study will read out, and it is upon us. It is a Q4 event, and we have been building towards this moment, and now really excited about the execution and the promise of sabirnetug reading out and kind of recasting the whole amyloid lowering debate or discussion, however you want to characterize it. All right. So base case for the readout, efficacy within lecanemab, donanemab sort of. Yeah, we've basically said, as you know, Pete, there have been a variety of different studies. There are different populations in those studies. To benchmark against those agents, we think anything 30% slowing on the iADRS or better is a clear win for us in the context of a competitive safety profile. Okay. All right. Last several minutes. Let's touch on the blood-brain barrier crossing technology. Can you just tell us about the agreement that you have with JCR and their tech? Sure. We embarked on landscaping the enhanced brain delivery or otherwise referenced as the brain shuttle approach a couple of years back. It was clear that these receptor-mediated transport mechanisms were establishing a degree of technical feasibility and clinical validation. It was really at that point where we said, "This is kind of interesting technology. We want to be in the game." Started to look at various options available to us, both in terms of which receptors to target, which sources of technology or intellectual property would be most amenable or attractive to us. We landed in the right place. We ultimately entered into, through an MTA with JCR, arrived at a data set that said we want to execute an option agreement and a license and have announced that, I think, last year. That set us on track for filing the IND sometime mid 2027. I would characterize it as a very capital-efficient way to get into this space. JCR has been working on transferrin delivery for almost two decades. They have an approved product in Japan, which has demonstrated a very compelling safety profile, particularly in respect of the anemia rates or the absence of any anemia. We felt like that was a differentiating aspect of their technology relative to other approaches. Combined with an oligomer-directed payload, we think that's a really competitive program in what is now kind of an increasingly crowded shuttle EBD space. It's an exciting technology for any brain-directed therapy. Obviously, one of the key challenges, especially for biologics into the CNS, is crossing the blood-brain barrier. So, an active transport to get an agent into the CNS is beneficial almost irrespective of the target. But beyond that, part of the reason why I think it's so compelling for amyloid-directed therapies is I think it gives you a couple of additional benefits. When you think about the broad distribution of amyloid across the cortical mantle, the fact that you can get into the brain through the capillary network, which is where the TFR proteins are mostly localized, gives you a much broader distribution. So it's not just that you're getting more into the CNS, but you're getting a much broader distribution throughout the CNS. On top of that, because your effective concentration in the plasma can be lower since you're getting better transport into the brain, it offers the opportunity to keep the circulating dose lower, which could have knock-on benefits when it comes to things like ARIA risk because you're not achieving the same concentrations as at the CAA plaques. Then finally, you have potential benefit. Being able to deliver a much lower dose gives you a lot more flexibility in dosing format for things like subcutaneous delivery. So really, that one technology offers you multiple benefits when it comes to the profile of an amyloid-targeting antibody. All right. You do have two candidates, so 301 and 401. Just a brief description of what the differences are between these two and how do you think about which agent you're going to take into the clinic? Yeah. Any of these antibodies, of course, is a bispecific antibody. You have your TFR targeting component, and you have the delivered cargo. In our case, we have two candidates that we are progressing, ACU301 and ACU401. The delivery technology is comparable for the two. What is different is the cargo being delivered. In ACU301, the cargo to be delivered is sabirnetug. In the case of ACU401, the cargo to be delivered is a related antibody from our library, also an oligomer targeting, called ACU234. We think that offers us some optionality. They have slightly different profiles, and of course, we know quite a bit about the clinical profile of sabirnetug, as we have been talking about. At the moment, both of those antibodies are being progressed through IND-enabling development. We anticipate that we will select one as the lead candidate to take into phase I clinical studies, and we are targeting an IND in mid-2027. You nominate one, but you still retain complete rights to develop the second one as well? Yeah, correct. Okay. So let's say that ALTITUDE is positive in 4Q. How does that impact your decision to bring the sabirnetug base construct forward versus the second one, 401? Yeah. I think we're still generating data on both of them. Part of the value of optionality is you've got some choice in the matter. I think we see the outcome of ALTITUDE as potentially validating for the whole hypothesis, the soluble oligomer focused hypothesis. So that would be an opportunity for either antibody. And part of the reason for selecting ACU234 as the other cargo to be delivered is it has a similar overall profile to sabirnetug. The differences are things like there's even more monomer selectivity with 234 than there is to sabirnetug. I don't know that the outcome of ALTITUDE alone impacts the decision between 401 and 301 because I think it's validating for either. But as we continue to generate data, things like PK profile and things like that could be determining factors for which one is the best candidate to take forward. But as you say, we also will retain the rights for the other one, and I think as you build a portfolio, it's a valuable thing to have other assets that are farther back in the pipeline. How similar are the two molecules? Are they basically just a couple of amino acid differences? Yeah, it's fundamentally true. They're very close. Okay. All right, we're coming to an end right now. Last question is, if we're sitting here 12 months from now, what would you like to say is the key value-creating accomplishment over the past year? The validation of the oligomer hypothesis through a robust and successful outcome in ALTITUDE-AD and moving EBD candidate first patient dosed in second half of 2027. Awesome. Well, would like to thank you for joining us at the Cantor Healthcare Conference. It's always great seeing you, speaking to you, and I wish you the best of luck in 4Q. Thanks, Pete. Thanks, Pete.