Good morning, and welcome to the UBS Biopharma conference. I'm Colin Bristow, one of the Biotech Analysts. My pleasure to have Acumen Pharmaceuticals with us here today. On behalf of, on behalf of the company, we have Dan O'Connell, President and CEO. Dan, thanks for being with us today. Thanks, Colin. So, you know, it's great to have you here sort of right after CTAD and some really interesting developments in the overall Alzheimer's space. You know, obviously, you guys had a presence at CTAD, some interesting updates. Before we sort of dig into 193, just what were some of the sort of most interesting takeaways for the field that you walked away with? Sure. Thanks, Colin. Yeah, CTAD was an exciting event this year, just generally for the field. There were interesting updates and data to suggest the field is really moving forward, and that advancements in terms of patient treatment and options are, you know, on the horizon. So in terms of the key elements, I mean, it was interesting to see both Eisai Biogen and Lilly really highlight the fact that early treatment is advantageous. That basically people with less pathology do better on these A-beta treatments. And so I think that paradigm will continue to evolve, and I think the pursuit of identifying patients that have early signs of pathology and intervening earlier is ultimately gonna be kind of the future of therapy in this space. The other development that was of interest was the subcutaneous administration of Leqembi, which I think resolved the question about whether ARIA was mediated based on Cmax versus AUC. And it's really, at least in the data from the Clarity AD OLE cohort, it's really an AUC-driven event. So exposure drives ARIA, it also drives plaque reduction if that's your intended objective. So it removes sort of the prospect that SubQ is a safer mode of A-beta treatment. It certainly advances, you know, on the basis of equivalence in terms of overall safety and efficacy, at least plaque clearance, if that's your definition of efficacy, and then, you know, I think, I mean, those were the big findings. I mean, for us, we had a late breaker symposium on Friday morning with three talks. One around the dosing strategy for the 201 study, the 2/3 study, which we can talk about in greater detail. And then, further analysis and interrogation on the plaque clearance or the plaque reduction, I should say, that was observed in the higher dose cohorts in the INTERCEPT-AD study. And then lastly, Dr. Stephen Salloway from Brown highlighted the... reviewed the five cases of ARIA that we had in that Phase 1 study and talked a little bit about the individual case series, as well as noted the absence of any ARIA in the E4 homozygote population, which is of, you know, small n, but kind of an interesting- Mm. observation, given that even, like Leqembi, has a 30% rate of ARIA-E in the homozygote population. Going back to the sort of updates we had around SubQ administration, how does that... You know, as you look forward to 193 being on the market and commercialized, and you're obviously thinking about SubQ now as well, but, you know, what is your latest? Did that data set make you more or less enthused about the potential of a SubQ modality? So I think it kind of we have maintained an equipoise about SubQ, to be honest. And now we have established a partnership with Halozyme, which does give us a route to a potential SubQ formulation for 193. But I think it really, you know, we're in the early stages of the infrastructure build. This is an, you know, in Alzheimer's treatment. And, you know, we heard a little bit of that earlier this week from Eisai and Biogen in terms of the rollout. And I think it's happening. I think there's a tremendous demand on the part of patients and families to access an intervention for this, you know, devastating disease. I think as we foresee the future for 193, you know, in, you know, years out when we are nearing launch, you know, you're sort of in a mode where people are accustomed to going either IV or SubQ. We think these will exist, you know, in some balance, and that will serve as choices for patients. Having that infrastructure in place gives us sort of a distinct advantage, you know, if in fact we can demonstrate the unique value proposition of 193 in terms of its overall safety and efficacy. Last question before we sort of really dig into some of the 193 specifics. But, you know, on your point about Eisai, Biogen and, you know, I guess for want of a better sort of term, but you know, a somewhat underwhelming launch initially, despite Biogen, I think, and Eisai telegraphing, it would be... You know, your comments around it, there's just a ton of demand. What are you hearing as to why that's not translating right now? Is it just infrastructure right now is not there? Yeah, my perception is it's infrastructure. Yeah. That there is a backlog of demand and interest. The lines of communication, the patient sort of funnel is, you know, not in an efficient or directed kind of configuration. And I think it will take time, and I think that's, you know, good in some respects for us as a, you know, fast follower, if you will. But it will take time, and I think, you know, this, these products will be successful. They'll be large. There are, you know, so many patients, you know, interested in doing something about the disease. You know, we think, I don't think that, you know, this is not a, an existing brand line extension. This is truly, you know, first-in-class products for a modality that hasn't had this type of option available. So I don't think we should be underwhelmed, disappointed with the launch. I think we should be a bit patient about getting the system, and given the safety monitoring and all of that, I mean, this is, it's a pretty significant lift, you know, for the field. ... So you're obviously gonna be the beneficiaries of sort of others' work to build the infrastructure, so it's yeah, it's a good thing for 193. And as we think about 193 now and positioning and differentiation, I mean, we have Leqembi, and you know, it feels like donanemab is gonna be on the market with some reasonable certainty. You just talk about positioning and differentiation of 193. Sure. So we think there's a path to differentiation, both in terms of safety and ultimately on efficacy. And I think the INTERCEPT-AD, the Phase 1 study, has given us kind of the building blocks for that path in terms of, you know, we had a low overall rate of, well, a good safety profile overall. I think we have reported these 5 cases of ARIA in the totality of 48 subjects exposed to 193, 3 cases at the higher dose level. So all of that has kinda shaped our thinking in the 201 study and, guided us towards the dosing strategy. And, ultimately, what we really wanna do is show not only an improved safety profile, but more significant efficacy. And the ACU193 is differentiated based on its selectivity for Aβ oligomers, right? Which are different than amyloid plaque, and that are acknowledged to be potent toxins to neurons through their propensity to bind the neurons and induce tau phosphorylation. And so we think by overweighting or directing your treatment towards these toxic species, such as we do with ACU193, there is a path to a safer and more efficacious product. On that note, 193 is 85-fold selectivity for oligomers over fibrillar forms of amyloid beta. Did you suspect that the dose levels being tested in Phase 1 would also bind and remove plaque to the extent we saw? You know, Colin, we didn't know, which is why we ran the experiment and why we included the PET scans on a post-last dose basis. I think we at the company acknowledged we were a little surprised and taken aback at the level of and rate of plaque or amyloid reduction in those high dose cohorts. The mechanism around that, I think, is still, you know, TBD in some respects. I think there are two sort of simple explanations to that, whether it's essentially at the elevated dose level, you have exposure, interaction with plaque in a direct fashion. So, there's sort of that direct ACU193 hitting plaque in a directed fashion, or on the other end, and these are not mutually exclusive, there's more of an equilibrium shift. At the elevated dose levels, we know we're getting very robust target engagement. You know, we are the, I think we have, one of the first that we delivered on in this INTERCEPT-AD study was using this, CSF, A-beta oligomer, 193 complex assay. So we actually have direct target engagement and showed a dose response to the signal of, of that complex, in the study. So at the elevated dose levels, we have very robust, oligomer target engagement, and we are also seeing a corresponding effect on, reduction of amyloid PET. So these are, it, you know, I think we would probably view, and I think others, you know, so Leqembi as a protofibril targeting antibody. They have, Eisai and BioArctic have sort of called that an equilibrium shift, even on their plaque clearance, which is kinda interesting here. So I think it's likely more towards the equilibrium shift, and less towards direct plaque interaction. But it's an exciting pharmacodynamic effect. I mean, the drug is having, you know, it's seeking its target. It's having an effect on some of these imaging biomarkers. We'll be reporting on fluid biomarkers in the near term, and it'll be interesting to see how, you know, any of this holds together in terms of other downstream effects as a consequence of dosing with 193. Based on some of the updates we've seen recently, do you, has your opinion shifted in terms of how critical it is for an anti-amyloid, you know, antibody to bind and remove plaque? Yeah, I mean, it, that remains a controversial subject, even internally to Acumen. I mean, you know, the genesis of the company, the fundamental science at Acumen was all predicated on neutralizing the toxicity of Aβ oligomers, these soluble aggregates that are distinct from plaques. And I think there's, you know, decades of research in support of oligomer pathology and toxicity, and, you know, there's not as much evidence to support that plaques are directly neurotoxic. They're clearly, you know, the pathological hallmark of the disease, and it's, you know, the primary mode of diagnosis. So I think we are still very much in pursuit of the optimal target. The field is anchored on plaque clearance, and I think that's a consequence of the convenience of amyloid PET and the corresponding clinical slowing that's been observed in a couple of these studies. But I think the field, you know, continues to push ahead, and we have more to learn, undoubtedly. Okay. And so with regards to your CTAD presentation specifically, what are the sort of 2-3 main points that you'd want us and investors to take away from that? Yeah, so I think the robustness of the INTERCEPT-AD dataset is first and foremost. Like, we got really interesting dosing information. We confirmed the safety profile and the target engagement and plaque reduction. Those are kind of, you know, first in the field, sort of outcomes for an antibody at that early stage of testing. But I think that's the sort of takeaway from the primary talk. The other element is that all of these results have, you know, informed our PK/PD model and our dosing strategy for the 201 study. So we are moving forward with-... Two doses, two active doses and placebo, and we'll dose at 50 mgs per kg every 4 weeks, and then at 35 mgs per kg every 4 weeks. At those dose levels, have you done any modeling work in terms of how you think the level of the sort of level of plaque clearance will be versus Leqembi at 10 mgs per kg? Well, not on a comparative basis. I think what we've done is really, I mean, I think what you see in the INTERCEPT-AD data set, and what we've presented is at the, you know, Clarity AD, the Leqembi Phase 3 study had a 3-month PET scan. So we're in our high dose cohorts in the INTERCEPT-AD study at 60 and 71 days, both the cohort 6 and 7 all approximated the level and rate of plaque clearance observed with Leqembi. So we're pretty confident that we will replicate those results in the next study. I think what we've done from a PK/PD modeling standpoint is to really leverage the target engagement evidence to suggest that not only, you know, to try to make sure that we have near maximal target engagement at both dose levels, you know, both in terms of peak and trough, and that, you know, with an accumulation of drug over time, we'll continue to extend and expand on that target engagement. So that's really how we ended up at the 50 and 35 mg per kg. I think that either of those, you know, could have plaque clearance. Presumably, more will do more. But we have not compared it on a model basis with Leqembi. And what levels of CSF oligomer target engagement are you expecting at those doses? Yeah, so on average, there's variability even in the, in the Phase 1 data set, and that will continue in Phase 2, but we're in the 85%-90%+ range on a snapshot basis. And we think that with, you know, with chronic dosing, you continue to sort of pick up and mop up the native oligomers. So we think that will be sufficient to drive an efficacy signal in, you know, at a minimum, the Phase 2 portion of the study. In terms of your expectations around the incidence of ARIA for these two doses, and looking at the high dose, we've seen data from the 25 milligrams per kg Q2 weekly, and from 60 milligrams per kg Q4 weekly. Is either which one of these would you consider to be more predictive of the 50 mg per kg at Q4 weekly, or is this, you know, purely a sort of modeling triangulation exercise? Yeah, I think it's probably premature to try to predict. I think that we've 60 struck us as more than we needed to do, and going a little bit lower, based on the model, suggests that we'll have a lower rate of ARIA than we would at 60. And I think we know this from other, you know, programs, just the more drug exposure, the more likely you are to have ARIA. I think that the... It was interesting, you know, in our Phase 1 study, there were three cases of ARIA at 60 mg per kg dosed every four weeks, and the 25 mg per kg dose cohort was at every two weeks, and we only had one case. So the Cmax AUC question, at least in our experience, would suggest that, you know, the Cmax might be driving ARIA, but I think that's now less likely the case given what we've observed with Leqembi. We're almost halfway into 4Q, which is unbelievable. But, have you? Can you confirm if you've had your FDA meeting yet? So I can confirm that we're gonna update on our FDA status on our earnings call on Monday. And I think, you know, time is limited in the quarter, and one might presume that we've had that meeting, but perhaps haven't had all the finality of minutes and the rest of it. But I think Monday will be an instructive point in time to sort of give some color on where things stand with the FDA. Okay, very helpful. And of course, I mean, the key elements of that, you know, we had guided to an end of Phase 2 meeting with the FDA to explore the possibility of running the next study as a potential Phase 2/3 pivotal study. You know, we also explored, you know, primary endpoints, dosing, all of that. But I think it'll be interesting to see if there is alignment with the agency on the prospect of running the 201 as a seamless 2/3 study. Great. And then we're also expecting some more biomarker data from you. Can you give any granularity, sort of one, on timing, and two, what we're gonna get from you? Sure, Colin. And the biomarker stuff, you know, for reasons that have to do with accessing kits and turnaround times with vendors, I mean, it's just taken some time to get samples run and analyzed and so forth. So we are, you know, we have both CSF and plasma biomarkers under review. I think we will be providing an incremental update, Monday, as to the precisely where we are with those assays. I think we're gonna be really interested to see what happens on, you know, the Aβ42/Aβ40 ratio, the phospho-tau 181, maybe phospho-tau 217, GFAP, neurogranin. These are all kind of analytes of interest, and both, whether they be in CSF or plasma, we'll have those. We'll definitely have them by the end of the year, and certainly we'll have an update, I think, on some aspects of that come Monday. Fantastic. Just getting back to CTAD, so we saw some data on Roche's trontinemab. Just any thoughts there in terms of, you know, the sort of index of concern from a competitive perspective for 193? Yeah, I mean, so it was a really interesting talk. I think, you know, the expectations for that talk were modest. Actually, I don't think I think they were modest. I don't know that they were all over the map. I think no one knew what the reveal would be, and I think it was a really interesting talk from Roche. I think the fact that they have this very dramatic plaque reduction with gantenerumab at, you know, a very relatively low dose, 1.8 mg per kg, is kind of interesting. So it's an early, you know, study. They'll have more data. There does appear to be some element of a safety signal on anemia, and it's a different modality. I mean, it's exciting to think that the field has, you know, continues to pursue these other ways of driving, you know, patient benefit. So, you know, I don't know that we worry about it as a from a direct competitive piece, but certainly it reinforces the, you know, some of these mechanisms in different modalities. And it's great to see that Roche is gonna, you know, stay in the room and be in the hunt and be an active participant in this field. I mean, they've kinda had to live through a couple of, you know, sort of epic, you know, Phase 3 disappointments. Right. You know, their staying power, I think, is important, you know, just in terms of you have options and capital and expertise in pursuit of better choices for patients. That's great. So you also announced this week your collaboration with Halozyme for their ENHANZE technology for subcutaneous ACU193. Can you give us a bit more details around the plan here, timelines, you know, any broad considerations for dosing? Sure, Colin. Yeah, so we're really excited about the collaboration with Halozyme. You know, they are the leader in, you know, with their ENHANZE product for SubQ co-administration. We're excited. You know, this is a non-exclusive deal, so it was, you know, sort of within our budget and allowed us to get, you know, sort of market-leading technology and expertise and know-how. So we're really excited about the collaboration, as I believe they are. You know, the first step here, I mean, this. The good news with ENHANZE is it's from a regulatory and, you know, clinical standpoint, there's a lot of history and experience. So the first step will, for us, likely involve a Phase 1 PK study in healthy volunteers to establish the bioavailability of the ACU193 and ENHANZE co-administration. That's a study that we think will, you know, you know, initiate in the middle part of next year and would read out, you know, you know, you know, this is not a chronic study, it's really a safety study. But that would then read out and help inform precisely what a patient-based study would look like. So I think it's, it's too early for us to, to guide on precisely, you know, let's call it a biomarker or an efficacy-type study. But I think in the near term, our, our work plan is, is pretty, well-constructed and, and laid out for us. Have you had any discussions with FDA on this yet, or? We have not- Okay. -actually. What would be a reasonable timeframe, just ballpark, in terms of when we could see some data from, you know, that SubQ healthy volunteer population? Would it be, you know, end of 2024? You know, I don't. I think that's, well, you'd have to sort of look at what other people have done in this space. I think- Sure. You know, these are not long studies. I, you know, I would hope that that timeframe would apply in our circumstance, but don't want to be too specific about that. Sure. And will the development plan for the SubQ formulation in any way interact or affect the IV 193 timeline? Yeah, we don't think so. I mean, IV, we think, is going to be an established route of treatment, and we have a very clear design for the Phase 2, 201 study. And so that is very much, you know, kind of our primary goal is advancing that as expeditiously as possible. I think where we bring the SubQ into the development program and whether that's a standalone, you know, 1B 2A-type study for the SubQ or whether, as others have done, adding it into an OLE, you know, protocol amendment, those are things that are, you know, ahead of us. We have more to learn before we commit to one path or another, but IV is very much our top priority. And then as we, you know, thinking about the evolution of the treatment of Alzheimer's, there's a lot of discussion around sort of combination therapies. Any early thoughts about mechanisms that would be, you know, obvious to pair 193 with? Yeah, so I think, you know, even just coming out of CTAD, I think, you know, the, this sort of dynamic between amyloid and tau, and amyloid driving tau, and so I think there's probably the, the first order of combination, and I don't know which precise tau mechanism or modality to choose, but something in and around tau with, you know, ideally an oligomer-selective agent, such as 193, could be, you know, a really attractive way to elevate the efficacy of, you know, for, for patients. You know, other immune-modulating elements to reduce inflammation might be complementary, if not synergistic, so those are also kind of on the horizon. Maybe just to summarize, because we're right at the end of time, what would be the, you know, as we look at the next 6-12 months, what are the key updates that you would advise us and investors to pay attention to? Sure. So I think, stay tuned to the INTERCEPT-AD dataset. It continues to perform and reveal more of the, confirm the activity and safety of the antibody, and so that fundamentally de-risks the next stage of development, and it fundamentally informs our dosing strategy for the 201. I think understanding, so the data piece is important. The regulatory piece, I think, is also instructive as to kind of what the option is for getting, you know, quickly to a BLA. And then, you know, SubQ, let's see how that progresses, whether, you know, Eisai gets approved and whether they have, you know, ultimately clinical benefit observed with that modality, and it's still a question there, how the payers will react. And then, you know, we'll presumably will be in the clinic with the SubQ, you know, you know, certainly by this time next year. Well, I think we're firmly at the end of time. Dan, thank you for your time, and really congrats on all the progress. Thanks, Colin. Really enjoyed the talk. Thank you.