The day of the Citi Biopharma Back to School Conference. I'm Geoff Meacham. I'm thrilled today to have Acumen, so welcome, guys. There's been a lot of discussion in the Alzheimer's space from a commercial perspective. Maybe, Dan, do you want to give a background to where we are in the life cycle? Then we can obviously talk in great detail about the phase IIb data coming up. Sure. Yeah, sure. Thanks, Geoff. Thanks to you and your colleagues for including us in this year's meeting. We're glad to be here. Yeah, it's an exciting time for us in the Alzheimer's space, principally as the market continues to develop and reflect the broad and large unmet need of the growing Alzheimer's population. We at Acumen have a pipeline that includes phase II assets, sabirnetug, that will read out later this year. We'll talk more in detail on that in a minute. As well as a preclinical, nonclinical program working towards an IND in 2027 that involves some transferrin-directed transport to the brain. So very excited about our portfolio and pipeline to position new and better treatment options for people impacted by Alzheimer's disease. I think it is important to recognize we are still in the early innings from a commercial market development standpoint. We have two approved agents that have been shown in studies to slow the disease, its progression relative to placebo. Those two agents have now achieved annual sales run rates exceeding $1 billion and are expected to be north of $2 billion by 2028 and $3 billion-$4 billion in 2030. So, it's a growing market in demand of better treatment options, and that's really where Acumen is positioned. We're now at a point where I think there's clinical commercial regulatory validation of amyloid targeting strategies as a cornerstone to disease modification. We at Acumen have a unique riff or scientific hypothesis associated with a species of amyloid or A-beta that is potently toxic, and one that we think by neutralizing A-beta oligomers we have the ability to potentially unlock greater efficacy and safety for patients in this population. Maybe just talk about the science behind the idea of oligomers being the more toxic species. You guys have some clinical data, phase I, prior data, phase II, that underpins that. But maybe just for the audience here, just to give us a bit of more background or context. Of course. Just because I am joined here by my colleague, Jim Doherty, our Chief Development Officer and President, I invite Jim to comment. Yes As the neuroscientist in the room and someone that has been tracking this field for a couple of decades. Yeah, happy to do so, Dan, and good morning, Geoff. Yeah. It is a really good question. As Dan said, A-beta amyloid is now a validated target for the treatment of Alzheimer's disease, and that is a huge step forward in any endeavor to find new therapies. Really, when you look at the biology of amyloid beta, the protein has a normal function, and it normally exists as monomer single units. Something happens, and it is not entirely clear yet what that core thing is, but it leads to misfolding and misaggregation of that protein. So now instead of doing its normal job, it is coming up the works. I say it that way intentionally because there is all the things known about the larger things like amyloid plaques. Really, the best evidence for true toxicity causing damage to synapses, causing damage to cells, preventing plasticity in the brain, and ultimately progressing, interfering with cognitive function, is really associated with the small soluble oligomers, at least when it comes to the in vitro and preclinical settings. So a lot of evidence that these small aggregates of amyloid protein are actually interfering with key synaptic functions, so messing up signaling. It is an early element in disease. We all know that Alzheimer's is a progressive disorder, and so this dysfunction associated with oligomers occurs early in the course of disease, and it is persistent. So that is a really interesting place to go from a neurobiological point of view. Given that targeting of soluble oligomers with sabirnetug, we are really excited to be testing the oligomer hypothesis really for the first time by getting cognitive data in the ALTITUDE trial. Yeah. There's really Oh, go ahead. Okay. Oh, I was just going to say that, yeah, as Jim was suggesting, there's a couple of decades of evidence in support of these A-beta oligomers as being a primary toxin. Of course, the origins of our lead program, sabirnetug. Sabirnetug was designed to neutralize and selectively target these species. So it has a high selectivity for oligomers versus monomer and versus plaques. Based on that mechanism and based on some successful phase I data, we do think sabirnetug is positioned for success and differentiation through this robust 542-patient phase II study that reads out later this year. Great. Yeah. Let's get into the study. Data is expected later this year-end. Could you walk us through maybe the trial design and what we could expect later this year from ALTITUDE-AD? Yes. So ALTITUDE-AD is a double-blind, placebo-controlled study, 18-month double-blind period followed by a 12-month open label extension. There are three arms in the study, two active arms at 35 and 50 milligrams per kilogram IV, once monthly IV administration, relative to a placebo arm. Primary endpoint is the iADRS scale, which is a combined scale of ADAS-Cog, which is a cognitive function scale, as well as another scale for activities of daily living. So it really is that combination of cognitive impairment as well as impact that has on daily living. We have a number of other cognitive scales also in the study, including CDR Sum of Boxes and a variety of others. As I was just saying, we see the critical test for the oligomer hypothesis, and given that, we really want to, as closely as we can, be measuring cognitive performance. In addition to that, we're also looking at a number of different biomarkers, and I think that's a really interesting area to be talking about these days for Alzheimer's therapies. We are certainly well-represented when it comes to biomarker analysis. That includes imaging biomarkers like PET scans. We'll be doing amyloid PET as well as a small tau PET sub-study. MR imaging from a safety perspective, and a number of biochemical plasma-based biomarkers. That's the overall design, 542 subjects enrolled in the study, about 180 per arm then. We are rapidly approaching the conclusion of the study, so we're very excited. Just to follow up on that, if you think about the differentiation, is it reasonable to assume that the efficacy could be directionally maybe better than the current-- if oligomers are the toxic species, could you see numerically better? On a, obviously, cross-trial comparisons considerations. Then also talk a little bit about ARIA and the drug and the differentiation from that perspective. Absolutely. Yeah. We do think that there are opportunities to differentiate from existing therapies when it comes to either efficacy and/or safety. I think different arguments for both, as you rightly point out. From an efficacy point of view, it's our hope that given the mechanism we've been talking about, we do have that additional benefit by directly targeting oligomers. We're expecting to see significant benefit. We're also going to be looking at timing to see if perhaps we see effects at a different time course than what's been demonstrated so far. But our target for what we'd like to see in the study is what we've been saying is about a 30% slowing in cognitive decline. If you look at the studies that have been conducted to date, the range is somewhere between 27%-32% slowing, depending on the study, depending on the endpoint. We feel that anything 30% or better is a really good outcome for sabirnetug. Of course, we're hopeful to see even more than that, but that's why you run the study, so we'll wait and see what the numbers look like. But timing is also a relevant thing that we're going to be looking at, the rate of any potential improvement. On the safety side, as you point out, ARIA is a key risk with the class of molecules, something to pay close attention to. We've, of course, been looking at safety even in our phase I studies. What we saw there was an overall ARIA rate at about 10%, which is, at least numerically, a little bit of an improvement on what's been seen in much larger studies to date. I always talk about the numbers from the phase I study with the appropriate caveats. It's a small study, but those are the data we have. What we see there is a total of five cases out of about 50, so about a 10% ARIA rate. Four out of five of those events were non-symptomatic, so we had one that was mildly symptomatic. Three of those five were at 60mg / kg which is a dose that we have not taken forward into the phase II study. So, we're hopeful to see an attractive profile when it comes to risk-benefit, both on the efficacy side as well as on the safety side. I guess, could we talk a little bit about how discussions are going with regulators as you are approaching later stage development and readouts? Yeah. So we have interacted with U.S. Regulatory, with the FDA, at the end of the INTERCEPT study, a so-called end of phase II meeting. So, a very good interaction. There's obviously a lot of activity in the Alzheimer's space, and so there's a lot of good feedback from the agency. One of the critical pieces of that was the understanding that with a well-controlled and a robust ALTITUDE-AD study, the one we're running now, that coupled with a single confirmatory phase III study could support a regulatory submission. So that is the strategy that we've been following, is that we would conduct the ALTITUDE-AD study, and if successful, conduct a single confirmatory phase III study to provide a package to support an approval in the early Alzheimer's space. I wonder if I could visit a little bit on the phase I data, just while we're talking about ALTITUDE-AD and probability of success and what we saw in phase I and how that translate into phase II. We used a novel target engagement assay in phase I that confirmed sabirnetug's ability to bind to and essentially sequester oligomers in a dose-dependent fashion, which was First in use novel, but really robust. What we saw there was really as we pushed the dose a little bit higher, plateauing of the target engagement signal, which said in the context of 60 mg/kg, having three cases of ARIA, we do not need to go that high in phase II. With phase II, we have the two doses that Jim mentioned, 35 mgs / kg and 50 mgs / kg. What we did see in addition to target engagement in phase I, were biomarker effects both on imaging as well as fluid and CSF and plasma. With a short duration phase I with three doses of sabirnetug, we are moving multiple biomarkers, imaging and fluid in the right direction. Our expectation, our hope is that chronic dosing over an 18-month placebo-controlled period, we are going to replicate and expand on those biomarker effects and as a consequence, really deliver an efficacy signal on a cognitive functional scale that is meaningful to patients and regulators. I think that we have a lot of ways to win in ALTITUDE with the two doses we have in that study and the way we have enrolled and conducted the study as a registration quality study. Jim or Dan, when you think about the baseline of the ALTITUDE study, how would you say you can compare with either the Eli Lilly or the Biogen and Eisai? Those are more contemporary kind of trials. I think we have learned a lot over the years on how to run an Alzheimer's study in terms of who we exclude. Maybe do a compare and contrast with those two. Yes. It is a really good question, and you are absolutely right. That has been a robust learning in the space, right? As we have talked about, it is a progressive disorder, finding those patients who are most likely to benefit is a critical issue. I would say first up, and this was a key learning from earlier trials, we put a lot of emphasis on really confirming amyloid positivity. That meant that what we were able to do is use a p-tau217 pre-screen. At the time when we were launching the ALTITUDE study, it was sort of early days, Eric and the team did a great job of recognizing the potential there. What turned out to be true was that we could significantly reduce the number of failures of amyloid positivity by doing a rapid, relatively inexpensive plasma-based screen to select patients for ultimate confirmation, either by amyloid PET or by CSF lumbar puncture. It really led to a more efficient entry criteria design and really getting what we think are the right patients. The other thing that's critically important is aligning entry criteria to get patients in the right phase of disease to really maximize your chances to see beneficial effects. This is where we've sort of taken our cue from those trials that you had mentioned. We're targeting what's conventionally called the early Alzheimer's population, so that's MCI as well as mild dementia. Within that, if you use those two donanemab and lecanemab programs as a bit of a benchmark, they're not exactly the same. By design, the Eli Lilly program used a tau entry criterion as well, and that resulted in a slightly more severe patient population relative to the lecanemab trials, which was an active choice. In our case, we are not using a tau requirement, and so our study population is probably closest to the lecanemab population when you really come down to it. In fact, when we were publishing our entry criteria, they're going to look pretty similar to what people have seen previously with the lecanemab studies. A truly early Alzheimer's population, really with a lot of MCI in that sort of balance between MCI and early dementia. Even if it's less severe population over the 18-month endpoint, though, you'll have more than enough time to see progression. I think that's the biggest risk, right? That's the balance point, right? Yeah. Because consistently, studies have been showing that the earlier you intervene, the larger the benefit to patients. That is, of course, kind of a population argument. At the same time, you do not want to go so early that you have not had enough time to see a decline in your placebo group or your untreated group. It is a balance between early enough to really maximize benefit to patient, but late enough so that you can run a reasonably sized and reasonably powered 18-month trial. We think we have hit that balance point, but that is really the approach. Yeah. Great. Could we talk a little bit about some of the KOL feedback you have been receiving around the trial design and maybe the potential usage of sabirnetug in the future? I guess also with the endpoints you have mentioned, you have more functional endpoints along with biomarkers. What are the KOLs looking for here? I think we have had great reception from the KOL community on the program. The program, we had first reception on INTERCEPT data, phase I data, which was encouraging, and now people are sort of on the edge of their seats knowing we have got a big data readout later this year. I think the biomarker observations in phase I have been encouraging to KOLs. I think there is a recognition that having more treatment options is desirable in this space. Most of the KOLs that we have talked with are experienced with both agents that are approved today, and are finding those to be suitable for a certain number of their patients. Then I think there is a clear interest in more and better options. The study design has been very well received. I think that we can comment quickly on the overall conduct of the study has been very robust. We enrolled 542 patients in 10 months as a small biopharma, swimming with the big fish in the Alzheimer's space. Really proud of that execution on the part of the team and study partners. The overall metrics within the study have been robust. We have had retention in the study that has exceeded our expectations. We have not seen high dropout rates due to safety or other considerations that would have been problematic from a powering and statistical standpoint. We have an open-label extension. After the 18-month placebo control period, patients are eligible to roll into an open-label extension for 12 months. We have had better than 95% of people eligible to roll into the OLE take that next step. Of course, all of this is occurring in the presence of approved agents. It sort of gives you a sense that patients and participants in the study are eager to see other options available to them and have committed their time beyond that to be in ALTITUDE in a fairly encouraging way from where we sit. Yeah, maybe just to echo what Dan's saying. Obviously, testing a key hypothesis for the field is critically important. This is a key program for Acumen's future. But it's not just the science or the ideas, it's about execution. And we are very proud of the team, and it's been exciting to see some of the metrics that Dan was talking about. In addition to that, at the AAIC meeting a couple of months ago in London, we had the opportunity to sit down with a number of the PIs from the study. And in general, the feedback was very solid. People liked participating in the study. They enjoyed the study design, the protocol, and these things really do matter. So we're glad to see that kind of feedback from the KOLs associated with the study. I think of the other KOL feedback, the A-beta oligomer hypothesis has existed for 20-plus years. It's been out there. It's been a little bit elusive. I think there have been prior claims and attempts to sort of provide the clinical validation, and I think when clinicians and KOLs that are active in research in the space recognize that ALTITUDE really is an at-scale robust test of that hypothesis. We're hopeful for the result, and our confidence is predicated on the success in phase I. But it's an exciting time for us, which really, with a successful ALTITUDE, I think it ushers in a new discussion within the A-beta space as to what targets are priority and how best to deliver a better risk-benefit profile to patients. Definitely. You mentioned this, but could we talk a little bit more about the OLE ongoing, just how is it progressing, and maybe what could we learn from that trial? Yeah. As we mentioned earlier, the OLE is a 12-month open-label extension. It is all patients, regardless of what their original treatment arm was, go on to a 35 mg/kg open-label treatment with sabirnetug. As Dan was saying, we've had really great numbers as far as percentages of people rolling over into the OLE. In fact, a little bit better than we had even projected, so that's a great sign to see. What it means is we're going to get a lot of data, so that's an important element of the study. We were talking about the 18-month time point to be able to see deviation from the normal decline rate, and it is true, but there's no question that as a progressive disorder, you really like to have data from even later time points to really see the progression of the effect. We think that the open-label extension is a really important part of the study, and glad to see so many people rolling into it. Let me ask you just on the differentiation, although you have the 18-month time point, given the oligomer hypothesis, is it reasonable that you could separate maybe at a faster rate than, say, lecanemab and perhaps donanemab? I would certainly love to see that. Yeah. Is it possible? I think so. Based on the science behind it, yeah, I think you can make an argument that these small soluble oligomers, if they're truly as toxic as the data would suggest, you may be able to see evidence of that even at an earlier time. I think this one really is going to. We'll have to see the data to really know for sure, but I would say that theoretically, it's certainly possible and something that we'll be looking to see. Particularly in that early end of the spectrum of early AD. I think that MCI population where the oligomer toxicity is sort of central to early disease progression. So, if you are intervening at that earlier time point, presumably there is more substrate to sort of restore or maintain. And even with the other agents, you have seen the earlier patients seemingly do better with Kisunla or LEQEMBI. So, with our mechanism, we could really sort of expand on that in a more robust way. But we will need the data to support that Right. That claim. You may have patients that are on for 20 straight months if they go from active to open label. Yeah. I mean, 30 months, right? 30 months. If I can do the math. Yeah. Sorry. Yeah. Yeah. But is that ending there, or do you follow this Yeah. Our plan for the readout For another month? Yeah. Let's be clear on that. We've guided to top-line results late 2026, and it's a Q4 event. Yeah. I don't think it's a year-end event, just to be clear. We have also indicated we want that to be a robust, informative, actionable data set, so real numbers and real outcomes. I think we have the ability to do that. It'll be material information for the company, so we have an obligation to disclose. We'll do that, again, inclusive of the primary outcomes of safety, efficacy, and secondary outcomes, inclusive of biomarker effects. That will be focused on the placebo-controlled portion of the study. Okay. We don't anticipate a top-line informing on the current status of open label extensions sort of beyond the Okay. That data will continue to presumably accumulate over time into next year. But we'll focus the top-line results on the placebo Just on the 18-month. On ALTITUDE. Yeah, exactly. Yeah. Okay. Let me ask you too, on the You're going to give the full details, or is this going to be like, wait till CTAD? Yeah, no. We don't have the luxury of waiting. We've been waiting for these data for a long time. So, we will be disclosing in a fulsome way that, again, is interpretable and actionable in the moment, not previewing something and holding for a future conference. Okay. So yeah. No, that's our commitment to all the stakeholders, participants in the study, investigators, investors, others. So. Is it reasonable to assume, though, that let's say a patient was on placebo for 18 months, then they switch to active. That's a sort of a separate kind of question in terms of the OLE. Well, as Jim is suggesting, this is an important fact of the way we've been fortunate to have the capital and the resources to do something at scale in a robust way. This is a study Big Pharma would do typically, right? This is not kind of fly-by-night biotech sort of cutting corners and otherwise. This is a study that will continue to yield more data beyond the late 2026 readout into 2027 and so forth. Those data, the biomarker data, the switchover from placebo, once we unblind placebo to active, the longer duration of people that are on for 30 months. These are really important information that will also inform on differentiation in the future, right? Maybe not in the immediate moment, but over time, as we contemplate what to focus in on phase III, in 2027, all those data will be sort of informing the strategy going forward. Just as part of your end of phase II meeting, I can't remember if you formally have agreed whether this could be a pivotal if successful, then you just run one phase III, or have you had those discussions? Yeah. As Jim mentioned earlier, it's very clear from our perspective that the way we've conducted and designed ALTITUDE, it can serve as supportive evidence in conjunction with a single pivotal phase III. Right. Okay. Which is an important fact, which I think is easily diligenced for a partner or however, anybody that wants to participate or support a phase III for sabirnetug. You've got one study to do, and there's not a lot of complexity to what that study ought to look like. It's going to be a two-arm study, active versus placebo, presumably an 18-month primary outcome. But maybe we see an effect in ALTITUDE that suggests we could win with maybe more patients, but at a 12-month time point. So there's more information. The data will inform the phase III design, but we think it's just a bigger version of the 542-patient study that we are running to completion later this year. Great. I'd love to, just with the time that we have left, maybe just have some time to talk about the EBD program as well. You're planning on announcing a lead candidate from the program in mid-2027. Maybe could you just review the background of the program and potential applications of the technology? Yeah. We're also very excited about the EBD program. When you think about active transport of macromolecules into the brain, there's a lot of interest, and there are a lot of people working on this very exciting technology. When you think about the reasons for it's on one level, fairly straightforward, but it's also pretty profound. The brain's pretty good at keeping things out. That's of an evolutionary benefit. When you're trying to get therapeutics into the brain, you've got the blood-brain barrier that lines all of the blood vessels into the brain, preventing those macromolecules from getting into the brain. It's especially challenging for monoclonal antibodies and other large proteins. The sort of off-quoted number is about 0.1%. 0.1% of the circulating plasma dose is actually reaching your target in the brain. Anything you can do to materially improve that ratio, we would expect to have a pretty big impact on your treatments. I think for a couple of reasons, that's especially true when it comes to amyloid therapy for Alzheimer's disease. I can get back into that if you're interested in some of those things. When it comes to then, if you accept that this is a valuable approach, then it becomes what's the best way to execute that? We see this fundamentally as it's certainly a bispecific construct, but you're combining a carrier element, which allows you to sort of hitch a ride on the transferrin-based system to transport into the CNS, coupled with the cargo you're trying to deliver. As we've been talking about, we think that the siderophil ligand-targeting monoclonal antibodies is definitely a robust approach. Combining that with a transferrin-based way to substantially increase brain penetration, lots of benefits. We have partnered with JCR Pharma in Japan. JCR has spent many years working on this technology, and there are a number of groups that have been. We were particularly impressed with JCR for a couple of different reasons. One of the potential risks, generically, of the technology is that if you sort of co-opt the transferrin system too much, you can lead to anemia and depletion of reticulocytes. What JCR has been able to do is balance the risk for that, including in multiple of their development programs, but including in their marketed product for Hunter syndrome. They don't see a ton of anemia with their approach. We worked together and went through a whole list of constructs. As a scientist, I can tell you, we didn't just click two things together. You do a lot of work to figure out what's the best combination of approaches. We landed on two candidate molecules that we are currently moving through non-clinical development in anticipation of an IND in mid-2027. Those are called ACU301 and ACU401. The difference between the two, ACU301 is the easier one to explain because the cargo is sabirnetug, coupled to the carrier technology. ACU401 is similar carrier technology, but coupled to a molecule that we're calling ACU234, which is from the Acumen library and an analog of sabirnetug, but with slightly different properties. We think that gives us some differentiation, or probably better to call it choice, right? We've got slightly different profiles of the two oligomer-targeting antibodies. We know quite a lot about sabirnetug, and we're learning about ACU234. So at the moment, both molecules are moving through non-clinical development. We anticipate choosing one to take into an IND. My hope is that we sort of choose the more attractive overall combination of properties, but that the other molecule remains in the pipeline and in the library for down the road opportunities. We see opportunity for both molecules, but we are going to be moving forward in 2027 with one. Earlier this year, we had announced some of the non-human primate data for some of these candidates. As Jim's mentioning, we were seeing 20- 40-fold increases in cortical exposure of the drug relative to unmodified native antibodies. It is just a huge advantage from a delivery sort of payload ability. Presumably, that has the possibility of adjusting dosing requirements and/or potentially driving efficacy, in addition to safety profile. We think of the EBD as, sabirnetug may not necessarily need a shuttle per se or an EBD mechanism, but boy, if we have a good result with sabirnetug in ALTITUDE, it is an obvious thing for a future generation life cycle management to have an EBD version of that or the ACU234 candidate because it will be a supercharged profile for safety, efficacy, and convenience. That particular profile, my ambition would be to see that product really play into this pre-clinical Alzheimer's population, which I know you are familiar with, which is really the people that are amyloid positive and increasingly, the field is establishing means by way they can anticipate who will likely progress to symptomatic disease within a three to five- year timeframe. Those are people. I mean, you can think about Alzheimer's has been this challenging space for anybody to make headway. I think we have arrived at this moment where we have achieved success. We have learned what not to do. We have learned some of the things what to do, and we are going to see a bit of an inflection in terms of the expansion of options and an expanded population that may be amenable to early interventions that afford better quality of life and maybe avert the onset of symptoms. Jim, Dan, thank you very much. Thanks, Ash. Thanks, Ash.