Good day, and thank you for standing by. Welcome to the Acumen Pharma Q1 2023 Conference Call and Webcast. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to Alex Braun, Head of Investor Relations. Thanks, Jill. Good morning, and welcome to the Acumen Conference Call to discuss our business update and financial results for the quarter ended March 31st, 2023. With me today are Dan O'Connell, our Chief Executive Officer, Dr. Eric Siemers, our Chief Medical Officer, and Matt Zuga, our Chief Financial Officer and Chief Business Officer. Before we begin, we encourage listeners to go to the Investors section of the Acumen website to find our press release issued this morning and a related slide presentation that we'll discuss today. Please note that during today's conference call, we may make forward-looking statements within the meaning of the Federal Securities laws, including statements concerning our financial outlook and expected business plans. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. Please see slide two of the accompanying presentation, our press release issued this morning, and our most recent annual and quarterly reports filed with the SEC for important risk factors that could cause our actual results to differ materially from those expressed or implied in the forward-looking statements. We undertake no obligation to update or revise the information provided on this call or any accompanying presentation as a result of new information or future results or developments. After our prepared remarks, we'll open the call for Q&A. I'll turn the call over to Dan. Thanks, Alex. Good morning. Thank you everyone for joining us today. The Q1 of 2023 marked the completion of enrollment in our phase I INTERCEPT-AD trial evaluating ACU193 in early Alzheimer's patients. The study is near completion with top-line results expected in the Q3. For those of you who may be new to Acumen, our product candidate ACU193 is differentiated from other monoclonal antibodies studied in Alzheimer's disease based on its high selectivity for A-beta oligomers. Scientific consensus asserts that oligomers are the most toxic form of A-beta. Once they bind to neurons, they inhibit synaptic function and induce neurodegeneration. We are pleased that our top-line results are positioned to provide important clinical proof of mechanism data to a monoclonal antibody developed to selectively target toxic A-beta oligomers in the effort to develop a next-generation therapeutic for Alzheimer's patients. INTERCEPT-AD will provide valuable information required to finalize the design for the program, including dose selection. At present, we have growing confidence that every four-week dosing is a viable scenario for ACU193. In addition, as previously disclosed, preliminary CSF PK data from cohort three, our 25 mg per kg single ascending dose cohort, showed ACU193 concentrations substantially above reported levels of A-beta oligomers, indicating this may be a dosing option to include in our next study. We continue to prepare for phase II/III activities in anticipation of successful results from our phase I study. An end of phase II meeting with the FDA to discuss the design of the next trial is anticipated to be held in the Q4. As previously disclosed, the study design incorporates an interim decision to expand the size of the study from a phase II to a phase III study, which is the most expeditious route to a BLA registration. We, along with the rest of the field, are encouraged by the positive momentum in the evolving Alzheimer's landscape. We are keen to see upcoming outcomes for lecanemab's advisory committee meeting, PDUFA date, and any shift in CMS coverage decision, which would increase access and uptake for this therapeutic option for patients. We are also highly interested in digesting the full data set from donanemab's TRAILBLAZER-ALZ 2 phase III study announced last week. We recognize that robust plaque clearance has shown clinical benefit, albeit modest and with safety caveats. We believe there is potential better options for patients that involve selective targeting of toxic species more closely related to disease pathology, and that ACU193 embodies that product profile. We look forward to sharing our INTERCEPT-AD top-line data with you in the Q3 of this year, a data set that will be informative from a safety, target engagement, and dose ranging perspective. With that, I'll hand the call over to Dr. Siemers. Eric? Thanks, Dan. Good morning, everyone. We continue to work diligently as we near the finish line of our phase I trial. As Dan highlighted, the totality of the data from INTERCEPT-AD will be important for choosing doses for subsequent studies of ACU193. This includes data on safety, CSF PK, and CSF target engagement. As I mentioned on our last call at the end of March, the assay for our target engagement is designed to measure the complex of A-beta oligomers bound to ACU193 in CSF. We have since run preliminary assay tests using CSF from patients, which have increased our confidence that the assay is performing as intended. Recall that oligomer concentrations in CSF are generally reported to be less than two picomolar, which means that our target engagement assay must be very sensitive. We also anticipate announcing exploratory data with our top-line results from our phase I study, including Cogstate computerized cognitive testing, as well as arterial spin labeling pulse sequences on MRI, which will determine if cerebral blood flow is increased after treatment with ACU193. These analyses are exploratory and may not result in a clear signal in this small study with a short duration of treatment, these techniques may be employed in the subsequent larger clinical trial using ACU193. We have included typical clinical measures like the CDR-SB and the ADAS-Cog in our phase I study. Because this is a small, short study, it is unlikely that those measures will show a drug effect. During the Q1, our team also presented a poster at AD/PD in Sweden that demonstrated the utility of a human in vitro model of induced pluripotent stem cell-derived excitatory neurons for a better understanding of which forms of A-beta oligomers contribute to the pathogenesis of AD in the human brain. This study found that soluble A-beta size may influence synaptic binding. Low molecular weight soluble A-beta species such as monomers, dimers, and trimers demonstrated the lowest levels of detectable synaptic binding compared to those of mid and high molecular weight, defined as greater than 150 kDa. We believe that these research efforts can contribute to the development of next-generation therapies with higher selectivity for toxic soluble amyloid species that are the most relevant to Alzheimer's pathogenesis, such as ACU193. The success of donanemab in the TRAILBLAZER-ALZ 2 study announced last week provides further scientific support for the amyloid-beta hypothesis broadly. These results build on the success of lecanemab reported in the phase III Clarity AD trial. Broadly speaking, these antibodies are both related to the amyloid hypothesis, there are important differences between them. Donanemab targets deposited amyloid plaques and reduces plaque load substantially with dosing every four weeks. Lecanemab targets A-beta protofibrils, but also reduces plaque load with every two-week dosing. The rate of ARIA-E with donanemab in TRAILBLAZER-ALZ 2 was reported to be 24%, while for lecanemab, the rate of ARIA-E was reported to be 12.6%. For both antibodies, about 20% to 25% of ARIA-E cases were symptomatic. We believe that ACU193 targeting oligomers has the potential to have lower rates of ARIA-E with equal or better efficacy compared to donanemab and lecanemab. We applaud the well-run study results from TRAILBLAZER-ALZ 2 and Clarity that solidify forward momentum in the field. While these treatments are a good first-generation start, ACU193 may further improve the benefit-risk profile of a disease-modifying treatment for patients and families navigating Alzheimer's disease. With that, I'll turn the call over to Matt. Thank you, Eric. Good morning, everyone. As a reminder, our Q1 2023 financial results are available in the press release we issued this morning and in our ten Q that will be filed later today. As of March 31st, we had approximately $184 million in cash and marketable securities on the balance sheet and continue to expect that cash to last through 2025. R&D expenses were approximately $8.7 million in the Q1. The increase over the prior year was primarily due to the increased activity in the ongoing INTERCEPT-AD trial. G&A expenses were $4.4 million in the quarter, with the increase over the prior year primarily the result of increased headcount as we built the company to support INTERCEPT-AD. This led to a loss from operations of $13.1 million in the quarter. We are encouraged to report top-line data for INTERCEPT-AD in the Q3 and will remain financially disciplined as we use our capital to advance our clinical program for ACU193 and deliver value to patients and shareholders. With that, we can open the call for Q&A. Operator? Great. Thank you. At this time, we'll conduct a question-and-answer session. As a reminder, if you want to ask a question, please press star one one on your telephone and then wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. Our first question. I believe this is James on the phone for Stifel. Hi, this is James here. Thanks for taking our question on for Paul Matteis. We were just wondering, how are you thinking about the different scenarios for what your phase II could look like and what exactly you'll be able to test? You know, for example, if, say, 193 were to have a similar effect size as the A-beta antibodies, you know, would this study be powered for stats on these clinical scales, or would you be looking at something else, you know, as at the interim and basing your decision to expand the trial? Any color there would be great. Thanks so much. Yeah. Thanks, James. I'm gonna invite Eric to comment on that question. Good question. Yeah, sure. Yeah, thanks. Great question. The team has been working hard on finalizing the design of that study. It's not completely finalized yet, but to get to the question that you've raised, we'll look at a number of different things in order to make the decision whether to continue the study as a phase II or to increase the size of the study and make it a phase III registration trial. That interim analysis involves an algorithm that will look at a number of different things. Of course, they'll look at things like the iADRS, which will be actually our primary outcome, but also the CDR-SB, the ADAS-Cog, that sort of thing. Obviously, if you would have statistical significance on one of those clinical measures at an interim analysis, I think that would be a fairly clear signal to scale up to a phase III. we'll look at a variety of other things, and those things may include things like the computerized cognitive testing that we're using in our phase I study, and also a variety of biomarkers. Just to give you one example of that, phosphorylated tau, both in blood and spinal fluid, seems to be a quite good biomarker for effects of drugs on downstream pathology in Alzheimer's disease. In other words, if your drug affects amyloid plaques, or in our case A-beta oligomers, if you see a change in phospho-tau, that really gives you a sign that you're having an effect on the underlying disease process. We have an algorithm put together, we'll look at several different things like that, and then that will trigger the decision of do you increase the size of the study to a phase III, or do you just continue it out as a phase II study. Hopefully that addresses to the question that you brought up. Yeah, very helpful. Thank you. Great. I will move the next question into queue. Hold on, please. Okay, our next question comes from Tom Shrader with BTIG. Go ahead with your question. Good morning. Thanks for taking the question. You're doing all this elegant work with, I think, one of the biggest questions in the field, which is which oligomers really matter. Is it changing your thoughts on target engagement? I assume you'd like to have antibody levels that only hit the relevant particles. Are you learning that two picomoles is an overestimate, or do you think you need to get most of the particles in order to be safe, or is that something you need to read out from clinical data? Thanks. Maybe I'll take that one, too. Again, I always have to preface this. Thanks, Tom. Another great question, but I always have to preface this by saying, you know, I'm a clinical trialist by nature, and so I think the real answers ultimately have to come from the clinic. As our poster illustrated at AD/PD, there's a lot that we're still learning about what are the most toxic species. We. Thus far, it would appear that the species that ACU193 targets are the ones that are relatively more toxic. I mean, the most toxic that we've been able to find. To put it the other way around, we don't see any evidence that ACU193 binds to species that are not toxic. Again, you know, the proof is always in the clinic. The one other point that's of some interest, and this is a little bit more hypothetical, but you know, the concentrations of oligomers in spinal fluid, as mentioned, are very low, you know, less than two picomolar. No one knows really the concentration of oligomers in interstitial space in the brain. Our antibody, ACU193, has to exit the arterial system and then enter the interstitial space, and there, the actual concentrations of oligomers may be more, may be higher. Again, we've had some positive results regarding our target engagement assay. We think that assay appears to be working well, and we're really looking forward to seeing those results, along with all the others in INTERCEPT-AD. Great. Thank you. Okay, great. I'll bring our next call up to the stage. Hold on, please. Now we have Judah Frommer with Credit Suisse. Go ahead with your call. Yeah. Hi, good morning. Thanks for taking the questions. First, just as we think about potentially having two A-beta antibodies on the market and any evolved thinking around including a comparator or a combination arm with another A-beta antibody in any subsequent trials, whether it's for a potential phase III or beyond that, and how could that affect ACU193's clinical profile? And then separately, can you just remind us or give some direction on cash runway and potential to get you through phase II, or how you would deal with moving into the phase III given the cash position? Thank you. Yeah. Let me maybe take your first question and then turn it over to Matt for your second question. You know, in terms of comparators, that question has come up a lot, especially since last week with the donanemab announcement. I think there's a pretty broad agreement that, Well, first of all, a head-to-head trial with drugs like that is very difficult to do. You have to do what's called a non-inferiority study, which requires really huge studies. At least of all the people I've talked to, I don't think anyone really would expect certainly regulatory agencies to require that kind of head-to-head comparison at this point. The other thing that's really of interest is how quickly these things will be taken up in clinical medicine. There was actually a at the American Academy of Neurology meeting a couple weeks ago, they had what they call a fireside chat. Someone who is a, I think, a lead investigator in the clarity style for lecanemab was talking about all the things that you would have to do to use that in your clinical practice. These are practicing neurologists. There was a lot of a bit of angst, I might say, among the clinical neurologists that this is really complicated because the infrastructure for, you know, PET scans and MRIs and all that just isn't there yet. I think donanemab actually will be even more complicated because they have this tau requirement. Now you have to get maybe an amyloid PET scan and then a tau PET scan. The uptake in the marketplace, I think, is not going to be overnight. The infrastructure needs to be built. That actually, to some degree, works to our favor because, by the time we would launch with ACU193, that infrastructure should be much more better developed. Yes, stay tuned, but for right now, we do not expect there to be any requirement for a head-to-head trial. Matt, I'll turn it over to you. Thanks, Eric. Judah, with regard to the cash, until we meet with the FDA and know exactly which clinical trial we're gonna run next, it's hard for me to tell you exactly when the cash might run out. However, all the forecasting that we've done, gives us confidence that our current cash will last through 2025. With that said, as we've disclosed in our filings, any next trial that we do is likely to take us out past 2025, and how far out past 2025 we have to go just simply depends on our interactions with the FDA. We can get very far down the road, but if we're running a phase II/ III clinical trial, then at some point we're gonna have to finance. Even if we run a very large phase II clinical trial to be determined, we would have to finance at some point after 2025. I hope that helps. Got it. Yes. Yes. Thank you. Okay, great. I'll bring the next question up. Next, we have Colin Bristow with UBS. Colin, go ahead with your question. Hi, good morning. This is Ping on for Colin. Thanks for taking our question. At AD/PD, Dr. Selkoe from HMS, he presented some interesting findings from his lab that the previously thought as soluble oligomers from the supernatant of the homogenized AD brain, they can actually be repalletated and led to the discovery of new species, which they call short fibrils. That somehow raises the question if the neurotoxicity and bioactivity previously observed with those soluble brain extracts are solely attributable to the oligomers. I think some of the first work was from the famous work from another HMS lab. What's your thought over this finding? We're just wondering, like out of curiosity, besides solubility, how differentiated are these soluble fibril species from protofibrils or oligomers, for example? Thank you. Yeah. Thanks. Dr. Selkoe, you know, of course, does some really cutting-edge research, and I think your question is a good example of just where the cutting edge is in the field right now. One of the things we've talked about before is that ACU193, of course, targets oligomers. Lecanemab was designed to target protofibrils. Partly this gets into definitions and Dr. Selkoe in the past and I think currently actually would sort of define anything that's soluble as an oligomer. A protofibril is actually one type of oligomer if you wanna use that definition. He recently presented, and I think this was part of the AD/PD presentation, that how you define soluble can vary. In other words, what happens is you centrifuge things and whatever ends up in the, in the pellet is not soluble, and whatever ends up in the supernatant is soluble. If you centrifuge it faster and harder, you can change what is in the pellet and what's in the supernatant. All these things are kind of evolving including the terminology. Just to get back to the protofibril differentiation with what ACU193 targets. Protofibrils are linear structures. The structures that ACU193 targets are globular, so the appearance is different on atomic force microscopy. They're not exactly the same thing. We think of those as cousins. They're both soluble by usual definitions. They're both toxic, but they don't have exactly the same structure. One of the things that's really unique then about ACU193 is that we're targeting a type of oligomer that's unique. I mean, we there's no other antibody that targets what we target that's currently in the clinic. I hope that helps, but it's a complicated question. Yeah. That's really helpful. Thank you much, Eric. We have a follow-up question. You mentioned, we'll use iADRS for the phase II as a primary endpoint. In donanemab's TRAILBLAZER-ALZ 2 top line, there seems to be some disconnection on iADRS benefit for the high tau group versus CDR-SB, where we see CDR-SB benefit was more consistent across the tau subgroups. What's your thought on the dMAB data and, as well as, what were some of your primary reasons to use iADRS instead of CDR-SB for the phase II as primary endpoint? Thank you much. Right. One of the things, just to remind everybody, is that we only have a press release from Lilly on the donanemab data. They included quite a bit in their press release, which was great, but they didn't include everything. Questions like that, how did the iADRS perform compared to whatever else, the CR sum of boxes in the high tau group versus the intermediate tau group, those are things I think we just have to wait for the presentation at AAIC to really better evaluate. Our decision, and again, you know, things can change depending on new data, but our decision to use the iADRS is really based on everything up until this point in time. It actually appears to be a very good scale. As you know that's what Lilly has used as their primary outcome. We'll be looking forward to seeing more of those data from TRAILBLAZER-ALZ 2. You know, we will always further refine our choices depending on new data. Okay. Thank you, Eric. If we may, maybe one last, like, fact check question from our side. Will there be additional PK/PD or safety updates ahead of the 3Q updates? Thank you. No, we don't anticipate. Yeah, we don't, we don't anticipate any new disclosures prior to our top line results in the Q3. The study is going well. You know, I mean, if there were some new safety information or something, obviously we'd have to say something about that. At this point in any study, even though we're all blinded, we're feeling pretty comfortable about the safety profile. I wouldn't anticipate any new disclosures before our top line results. Cool. Thank you so much. Yeah, thank you so much, everyone. Okay, great. Now looks to be our last question. This is from Charlie Yang with BofA. Go ahead with your question. Hi, thanks for taking this question. This is Charlie Yang for Geoff Meacham. Can you talk about, just, you know, just given, like, donanemab data, you know, potentially to kind of include one of the A-beta drugs in your kind of phase II, phase III trial? Yeah. I'm sorry, I'm not sure I quite understood the question. Would we include other A-beta drugs in our phase II/ III? Right. Okay. Right. As a potential combination therapy, you know. Okay. Yeah. Given the recent. Right. Gotcha. Combination therapy is an important topic, and it's something that we at Acumen have certainly had some discussions about. Our approach to that would probably be the combination would be a drug with a different complementary mechanism, rather than, you know, another one that's related to A-beta or amyloid in one way or another. In terms of our phase II/ III study, we don't have any safety data from animal studies based on combinations, say, of lecanemab or donanemab with ACU193. I don't think it would make a lot of sense for our phase II/ III study to allow that kind of combination. Obviously, that would make it a lot more complicated study, too. As we've thought through this, as I mentioned previously, I think that the sort of clinical uptake is going to be pretty slow actually, for both lecanemab and donanemab. I think, you know, for us to run a placebo-controlled trial for our phase II/ III is certainly gonna be feasible. Looking down the road in terms of combination therapies, which is the future, I think we all agree for Alzheimer's disease, I think it would make more sense to use some complementary mechanisms. You would use something that's related to tau, something was related to inflammation, something like that, to combine with ACU193 to see whether you get additive or even synergistic effects. Thank you. Great. I'd now like to turn the call back over to Dan O'Connell. Thanks, Jill. Thank you everyone for joining this morning's call. We are very much looking forward to sharing the INTERCEPT-AD top line data in the Q3, data that will be informative on ACU193 as a selective agent neutralizing toxic A-beta oligomers. Thanks again for joining. We look forward to speaking with you again soon. Thank you all for your participation in today's call. This does conclude the program, and you may now disconnect.