Day of Bank of America's Annual Healthcare Conference in a very, very warm Las Vegas. My name is Jason Zemansky. I'm one of the midcap analysts here at Bank of America, and I'm very pleased to have join me on stage, Acumen, Daniel O'Connell, Chief Executive Officer. Daniel, thanks so much for joining us. Thanks, Jason, thanks to you and your colleagues for having us to the meeting. Well, perfect. Just to start at a higher level for those less familiar with the story, can you briefly describe sabirnetug and its mechanism of action? Sure. Just to introduce Acumen real briefly, Acumen is a clinical stage company that is committed to advancing better treatment options for people living with Alzheimer's disease. sabirnetug is our lead program. It's a humanized monoclonal antibody that has high selectivity for soluble toxic Aβ oligomers, and that mechanism and for sabirnetug is one of the ways we think it has the potential to really differentiate on safety and efficacy measures for patients. That program is in phase II study that will read out late this year. We can go into more of the details on that, but it's a very exciting time in the field and for Acumen. A second program that we've described in the last 12 months involves using enhanced brain delivery, taking some of our therapeutic cargos, sabirnetug and sabirnetug-like antibodies, and using receptor-mediated transcytosis to deliver more of that payload into the brain and interstitial space. That is slated to go to hit an IND milestone mid 2027, really excited about that part of the portfolio as well. Maybe if we could go a little bit deeper on the rationale for targeting specifically the oligomers versus other subspecies, like the monomers, the protofibrils, and soluble plaque. Sure, Jason. You know, as our chief medical officer is accustomed saying, "Amyloid is not monolithic." It comes in a variety of shapes, forms, and aggregated states. A-beta monomer is a normal physiological peptide that's produced with high rates in the body. It accumulating aggregated A-beta has had a pathological consequence. It's really sort of the hallmark of Alzheimer's disease. In terms of therapeutic strategies, we think, because these soluble aggregates or oligomers have over a couple decades been shown to be potent toxins to synapses and neurons, that they represent a distinct and attractive therapeutic target for slowing down disease progression in Alzheimer's disease. The hallmarks of oligomer toxicity involve more circuit disruption, synaptic loss, tau hyperphosphorylation, and induction of calcium into cells, and essentially initiating and propagating the neurodegenerative processes in Alzheimer's disease, which is distinct from monomer, which is really not toxic and shown to, you know, really strategies that have interacted with or targeted monomer have been ineffective, safe, but ineffective, for the most part. There's obviously a lot of emphasis right now in the field on, you know, plaque reduction as a mode of getting to a clinical benefit. We think sabirnetug and oligomer-directed approaches really offer a different approach that could yield improved efficacy and safety relative to those plaque-directed approaches that are kind of the current class, if you will, today. Excellent. It goes without saying, a recent Cochrane review raised questions about the efficacy of the class. you know, when you look at the results, how would you what are your takeaways there? Again, kinda thinking about the evidence behind sabirnetug, you know, what's your rebuttal? Thanks, Jason Zemansky. For those of you that might not be familiar, the Cochrane report was a meta-analysis looking at over a decade of A-beta-directed strategies towards clinical benefit for Alzheimer's patients. That meta-analysis included a number of agents that had been shown to be failed and essentially shifts the conclusion towards those other programs, you know, which didn't yield the results that at least the first two approved agents in well-designed, controlled phase III studies have shown clinical benefit of between 25% and 32% slowing on clinical measures and also, you know, other biomarker effects. I think the report itself, the methodology, has been called out by many experts in the field. You know, the Alzheimer's Association has sort of highlighted some of the flaws in the approach and the underlying conclusions that the report asserts. We do think that, you know, it's been my own experience to sort of observe how the field has cumulatively learned what, you know, not to do in terms of more monomer targeting strategies and other things, and has really found a path towards designing studies with the right population and now with agents that are really more prone and designed to target the pathological species. Maybe this is a good time to pivot to your INTERCEPT results, can you briefly summarize what those were and then, you know, looking ahead, what gave you confidence to move into the ALTITUDE phase II? Sure. Our INTERCEPT-AD study was the first-in-human study, a phase I single ascending dose and multiple ascending dose study in early Alzheimer's patients. We deliberately included patients in both the SAD and the MAD cohorts in order to assess key attributes of sabirnetug, including its safety profile, the ability to engage oligomeric target, and to assess any impact on both imaging and fluid biomarkers. In the study, the results of the study, it was a short duration study, so the, you know, the single ascending dose had four dose levels escalating over time, single administration of the drug, IV, I should mention. Then, the three MAD dose cohorts had three different dose levels. You know, again, Excuse me. There were only three doses administered in that MAD portion of the study. What we found in the study was robust target engagement and sort of dose proportional elements of engaging oligomeric target as measured by a novel assay assessing that complex of sabirnetug bound to oligomers in the cerebros spinal fluid of patients. Corresponding with the target engagement, we also observed effects on imaging biomarkers, so the amyloid PET in particular at the high dose levels, which moved the PET signal consistent with what's been shown for agents like lecanemab at a three-month time point. In addition to the imaging biomarkers, we had assessment of CSF and plasma biomarkers, and there, though we hadn't had sort of overzealous expectations to see effects with such a short duration study, we actually moved kind of the standard fluid biomarkers of the Abeta 42/40 ratio, elements of phospho-tau, so p-tau181, as well as p-tau217 in plasma. Intriguingly, we did actually see also on synaptic markers, neurogranin and VAMP2, again, achieving nominal statistical significance at some of the higher dose levels. Those are, the totality of those results in phase I gave us confidence to move into phase II and kinda underpin our optimism for a successful result later this year in ALTITUDE-AD. Obviously a very exciting year. We'll see the results of ALTITUDE-AD at the end of this year. Can you help us frame expectations going in? What would you like to see on the primary endpoint, the ADAS-Cog? Sure. In terms of ALTITUDE-AD, it's a robust phase II study. We have two active doses versus placebo. The two dose levels are 35 mg/ kg and 50 mg/ kg, and this is Q4W dosing IV. There we have designed that with 180 subjects per cohort, so in as short as 10 months, we enrolled 542 patients in that study across five countries, and with fewer than 80 sites. There was robust enrollment in the study, and I think it was attributed to the phase I results, I think enthusiasm for our mechanism advancing the field in terms of oligomer-directed approaches. The study is an 18-month placebo control period, and the primary outcome is the iADRS, which is a composite score that includes aspects of the ADAS-Cog, as well as the ADCS ADL measure, so both cognition and function. You know, what we would You know, a clear win for us on the primary would be something in the, you know, 30% slowing over 18 months in this particular early Alzheimer's population. You know, it's, it is We'll also be looking at the Clinical Dementia Rating Sum of Boxes. We also have both imaging and fluid biomarkers. The totality of the results are gonna inform the next step for sabirnetug. We the study conduct has been great. You know, the early terminations have been consistent with our forecast and expectations. Last November, we had the first patient enrolled into an open-label extension, and that open-label extension has attracted high rates of conversion from the placebo into OLE in the, you know, upper 90 percentile in terms of people willing to stay in the study and know that they will be on sabirnetug for the open-label portion of the study. Excellent. Well, I did wanna pivot to your developmental, more developmental portfolio. Can you tell us a little bit about the Enhanced Brain Delivery System? What made you partner with? JCR JCR? You know, what the potential sort of added benefit is there? Yeah, sure. The field of receptor-mediated transport of larger molecules into the brain is something that's been evolving over the last couple decades. Again, where different targets on the blood-brain barrier have the ability to transport larger molecules, payloads, or cargos are the terminology that we use. JCR Pharmaceuticals is a Japanese company that's been a pioneer in the field. They have an approved product using a transferrin-directed enzyme replacement therapy for Hunter syndrome. You know, we, about two years ago, as the proof of principle data were coming out on a program that Roche has in phase III now, became apparent that these delivery modalities afford the potential sort of supercharge or enhance a product profile. Potentially greater efficacy, lower dose requirements, potentially improve safety and convenience. Those fundamentals were what kind of got our attention about sort of what should our strategy be. Engaging with JCR, we found that their clinically validated approach, for instance, their IZCARGO product has not shown any anemia either in development or clinically. We think anything that is directed towards the transferrin receptor has a potential vulnerability to inducing reticulocyte count drop and anemia in patients, and that's, you know, some of that has been observed with some of the ongoing programs. We really like the, the validated clinical transferrin-directed approach from J-Brain, from JCR, and then we're delivering the, the payload of sabirnetug and another Acumen antibody called ACU-234, which has similar, potentially enhanced properties such as sabirnetug. It has a little bit higher selectivity for oligomers over monomer, even than sabirnetug. We think both each of these agents and payloads are part of the candidate portfolio that we are close to designating two candidates as our exercising our option under the JCR agreement and looking to have a single clinical candidate to file an IND the middle of next year. You know, if you look at your competitor data, I think a couple things that we saw, certainly better overall efficacy, but more intriguing, I think, greater brain penetration. Is the idea that sabirnetug, you know, is there a potential for a, an overall synergistic effect going much deeper into the brain? Is it, you know, a chance just to extend more, more linearly the efficacy? What's been shown with other agents, and we're doing work to sort of confirm this, we've already demonstrated in non-human primates that we get somewhere between 14 and 40-fold elevated levels of drug in the cortex relative to the unmodified antibody. There, you know, that's a pretty massive and very competitive enhanced exposure profile. I think, the other element is that it's understood that, you know, using this transfer and delivery modality, a lot of the transference and delivery is through small capillaries. You're actually. It's not just, you know, higher levels, but it's a more broadly distributed delivery of the payload or cargo. In our case, you know, oligomers, have, you know, it's kind of interesting to look where oligomers sort of present early in hippocampal and other areas. To the extent that we have not only enhanced, you know, broader exposure, but also, you know, within, you know, more diffuse and, harder to reach parts of the brain and anatomy, we think that could be very synergistic therapeutically. The only other, the another sort of mechanistic thing that I think is, is some, of some interest is, you know, there are, transferrin receptors on neurons, and there's also, been evidence that there's Intraneuronal, Abeta. Whether you could actually get an antibody or a payload into a neuron and address underlying A-beta pathology, oligomer pathology with one of these enhanced brain delivery approaches is of interest to us. That's great. We have about one minute left, so I'm gonna ask probably the most challenging question for you. You know, you've maintained that anti-amyloid antibodies are likely to be foundational in Alzheimer's, and obviously we had some news this morning on an anti-tau approach. Sure Just, you know, can you give us your overall sort of high level thoughts here? Yeah. We do subscribe to the belief that A-beta strategies are gonna be a cornerstone of treatment for Alzheimer's patients for the foreseeable future, and that that population of patients, not only the early AD population that we're working on right now in ALTITUDE-AD and would anticipate in phase III, but also the preclinical population. I think the, you know, the landscape or the opportunity is expanding, and it's being enabled by novel technologies, diagnostic technologies, plasma-based diagnostics. That we would anticipate as sort of a cornerstone strategy. That field will continue to adopt new agents with differentiated mechanisms and better, you know, enhanced profiles, if you will. We see that is really where sabirnetug and EBD play into that cornerstone approach. I don't think anybody believes that Alzheimer's is a disease that is gonna be most efficaciously treated with a monotherapy, that there will be combination strategies. The news this morning on the Biogen tau program sounds encouraging potentially, so we'll need to see more of the data. To think that Biogen would be declaring the willingness to move forward on, based on what they've seen, and I think they probably do have a high bar internally for why they would continue given the nature of sort of some of the things the company has experienced over the last a bit of time. I guess I'm optimistic that they're seeing something. We haven't had clinical validation of a tau strategy heretofore. If they really do have evidence that they are on the right path, I do think that's a positive development for the field and something that puts us one step closer towards this combination strategy that ultimately may be, you know, the greatest benefit to patients. Hopefully that was a tough question, but I'm optimistic that the future is still bright in this space and we at Acumen have an important contribution to make. It was a great answer. Really looking forward to the readout later this year. Daniel, thanks so much for joining us. Thanks, Jason.