Good day, and welcome to the Acumen Pharmaceuticals Second Quarter 2025 Conference Call and Webcast. As a reminder, this call may be recorded. I would now like to turn the call over to Alex Braun, Head of Investor Relations. Please go ahead.

Thank you. Good morning, and welcome to the Acumen conference call to discuss our business update and financial results for the quarter ended June 30, 2025. With me today are Dan O'Connell, our Chief Executive Officer; Dr. Jim Doherty, our Chief Development Officer; and Matt Zuga, our CFO and Chief Business Officer. Dan and Matt have some prepared remarks, and then we'll open the call for questions. Joining for the Q&A session, we also have Dr. Eric Siemers, our Chief Medical 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 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 2 of our corporate 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 in the accompanying presentation as a result of new information or future results or developments. And with that, I'll turn the call over to Dan.

Great. Thanks, Alex. Good morning, everyone, and thanks for joining us today. I have a few remarks to make before handing the call over to Jim to provide some details about our recently announced enhanced brand delivery or EVD program. Then Matt will detail our quarterly financial results before we open the call for questions. The second quarter was a productive one for Acumen, marked by steady operational progress and an important strategic partnership to expand our portfolio. Following the rapid completion of enrollment in our Phase II AlTiTUAD study in the first quarter, we continue to make great progress with the study. At the recent AAIC conference in Toronto, we received positive feedback from site investigators about the study design, patient retention, and our team's engagement. Based on this strong execution, we continue to expect top-line results in late 2026 inclusive of the key efficacy and safety measures. Altitude is investigating Sebernatag, our monoclonal antibody with high selectivity for toxic oligomers. This selectivity is key to why we believe severity could unlock potentially greater clinical efficacy and improved safety relative to antibodies targeting amyloid plaques. At AAIC, we also presented data showing Sebernatag achieved the highest selectivity for abetaligamers over monomeric Abeta when compared to recaucanumab and aducanumab. The reason why this is important is that Abeta-monomer levels are approximately 7,000-fold higher than the low abundance toxic oligomer levels found in the Alzheimer's brain. So lower affinity for monomeric Abeta what Sebernatag demonstrates is going to increase functional selectivity because less of the antibody will be binding to monomer. I'd also like to mention that we are encouraged by the recent comments from commercial players in the space, highlighting the growth of the clinical infrastructure for diagnosing and treating people with Alzheimer's disease. Feedback from key opinion leaders and others in the field have also noted greater easing of clinical bottlenecks. Real-world long-term data from the currently marketed products reported at AAIC demonstrate the clinical benefit of these products growing over time, further supporting their adoption. In addition, the first blood-based biomarker has been approved by the FDA and others are being developed. We believe blood-based biomarkers will revolutionize the field by making an accurate and potentially earlier diagnosis much more efficient. We also believe they will help expand the demand for anti-amyloid treatments. It's terrific to see the field moving forward in the clinical infrastructure coming online as well as the increased blood-based diagnostic options for the benefit of patients and their families. This momentum, we believe, sets the stage for Sebernatag and potential next-generation EVD products in the future as there remains a very significant untreated patient population interested in receiving anti-amyloid therapy. We're excited about the potential of Sebernatag to provide a differentiated benefit-risk treatment option for patients and the future possibility of building on that with an EBD product or products. Moving to EBD. In July, we announced a strategic collaboration and license agreement with JCR Pharmaceuticals based in Japan. This collaboration is to develop an Alzheimer's disease product combining our Abeta oligomer selective antibody expertise with JCR's transferrin receptor targeting blood-brain barrier-penetrating technology. We chose to partner with JCR as they are an established leader in the BBB space. Importantly, the partnership extends our portfolio and builds on our confidence in the potential treatment benefit of targeting toxic Abeta oligomers. We've been working closely with JCR for more than a year, and I'm very excited at the potential to develop a differentiated next-generation treatment option for patients and shareholders alike. We expect to make a development decision for up to 2 product candidates in early 2026 based on nonclinical data. I'll now turn the call over to Jim to expand on our progress and our EVD strategy.

Thanks, Dan, and good morning, everyone. Thanks for joining us today. I'd first like to build on Dan's comments about AAIC and the positive sentiment surrounding current Alzheimer's disease therapies and the potential for next-generation treatments. A number of KOLs have recently commented to us that if a patient is appropriate for one of the available monoclonal antibodies and makes the decision to begin treatment, compliance with the IV infusions and MR monitoring is very high. When used in clinical practice, the safety profile of amyloid-targeting antibodies appears similar to what's been reported from placebo-controlled clinical trials. That said, additional improvements in the modest efficacy and reduced need for safety monitoring with the current drugs would be welcomed. One of the major challenges for treating neurological disorders like Alzheimer's disease is the restriction of many therapeutic agents from entering the brain in high enough concentrations to provide therapeutic efficacy. The blood-brain barrier, or BBB, is a system of epithelial cells that line blood vessels in the brain that very effectively limit entry into the brain from many therapeutic agents. Selectively leveraging a process called receptor-mediated transcytosis has become an exciting technology to improve delivery of therapeutic macromolecules from the bloodstream into the brain. Receptor-mediated transcytosis takes advantage of natural systems that selectively transport specific proteins into the brain, thereby delivering substantially higher amounts of enzymes or antibodies to where they need to be. We have recognized for some time that this approach could benefit our program at Acumen by delivering oligomer-targeted therapeutics to the brain in a safe and effective manner. Although a number of receptors have been identified that can serve as access points for RMT technology, we have chosen the transferrin receptor as the appropriate carrier for our program based on clinical experience and the potential to mitigate the risk of ARIA associated with amyloid-targeting therapeutic approaches. We conducted an extensive search and evaluation process to assess many technologies, and we're drawn to JCR because they are an established leader in the blood-brain barrier space with an approved therapy in Japan using their technology that is associated with low rates of anemia. JCR's cargo technology is a proprietary JCR drug delivery system that efficiently delivers drugs to target tissues, including the central nervous system through receptor-mediated transcytosis. It's applicable to various modalities, including antibodies, enzymes, oligonucleotides, lipid nanoparticles, gene and cell therapy, peptide, and decor receptors. The first drug developed based on this technology is approved in Japan for the treatment of lysosomal storage disorder and exhibits an established safety profile. We have worked with JCR for more than a year on feasibility studies. And in July, we announced a collaboration license and option agreement to investigate the combination of our oligomer-targeted antibodies with their transferrin-targeted blood-brain barrier technology. As you heard Dan discuss, we believe selectivity for toxic Abeta oligomers is a key opportunity for both safe and effective next-generation disease-modifying antibody therapy. Pairing this differentiated cargo with JCR's validated carrier technology may offer an attractive next-generation product candidate for Alzheimer's patients. We are investigating both Sebernatag and other oligo-selective antibodies from our library and exploring both single-chain and variable heavy domain antibody constructs with JCR, which we consider cutting-edge approaches in the blood-brain barrier space. A nonclinical candidate data package inclusive of a nonhuman primate study is expected in early 2026, at which point Acumen has an exclusive right to exercise our options to deliver up to 2 development candidates. And now I'll hand the call over to Matt.

Thank you, Jim. As a reminder, our second quarter 2025 financial results are available in the press release we issued this morning and in our 10-Q, which we will file later today. As of June 30, we had $166.2 million in cash and marketable securities on our balance sheet, which is expected to support our current clinical and operational activities into early 2027. R&D expenses were $37.1 million in the second quarter. The increase over the prior year was primarily due to an increase from manufacturing and materials for the Altitude AD clinical trial as well as an increase in clinical expenses now that we are fully enrolled. G&A expenses were $4.6 million in the quarter, roughly flat to the same period in the prior year. This led to a loss from operations of $41.7 million and a net loss of $41 million in the quarter. Finally, I would like to note that our collaboration with JCR Pharmaceuticals is a highly capital-efficient way to expand our portfolio of oligomer-targeted candidates. Under the terms of the agreement we announced in July, in addition to an upfront payment that JCR received if Acumen exercises our exclusive option to develop up to 2 development candidates, JCR will receive an additional option payment of $9.25 million. JCR will also be eligible to receive future milestone payments of up to $40 million related to development and up to $515 million related to sales for a total of up to $555 million, as well as single-digit percentage royalties on sales of any products that emerge from the collaboration. We are excited for the optionality and potential value this deal provides and await preclinical candidate data in early 2026. We are also confident in our strong execution about the EVD and look forward to sharing top-line results, which are expected in late 2026. We remain dedicated to delivering potential next-generation treatment options for the benefit of patients, caregivers, and shareholders. And with that, we can open the call for Q&A.

Our first question comes from Jason Zemansky with Bank of America.

Congratulations on the progress. I wanted to discuss AAIC, particularly in relation to Roche's similar brain shuttling technology and the initial results there. How can we benchmark a potential brain shuttling technology against Sebernatag? Additionally, considering the overall plaque reduction observed in those patients, what implications does that have for your epitope, especially with the emphasis on the oligomers?

Yes, absolutely. So yes, thanks, Jason. We've obviously been paying close attention to this entire space, including Roche's program. And I think where I'd start is where we see the opportunity for this technology is significantly enhance the ability to deliver your therapeutic target to the targeted areas in the brain. And you see that certainly with the transtuzumab, they see a significant change in the overall profile of the molecule from the days of delivering it directly at gantenerumab to what they're seeing now when combined with a shuttle to allow them to increase the concentrations. And I think we see the same kind of opportunity with the current safety profile. We believe very much that these toxic oligomers are directly toxic within the brain during the progression of Alzheimer's disease. And so being able to robustly target that, we think is a mechanism that's going to lead to improvement for patients. Of course, we also see some effect on plaques, and there's a complex biology there. The amyloid biology, although we all refer to amyloid as the target, and it certainly is. Amyloid biology is pretty complex. And so there are ligomers associated with plaques, and that's a much longer discussion. But I think where it really lands is that we see technology as enhancing the ability of Sebernatag to effectively access silica, and we think that this is going to be a mechanism that will be beneficial to patients. Eric, I don't know if you want to add anything to that?

Yes. The only thing I might add to that is just in terms of where we are in development, I mean, Roche has done a great job in terms of their Phase I study, and they're obviously starting 2 Phase III studies which will take a lot to read out. On the other hand, we're really looking forward to our Altitude AD study with over well over 542 patients that will read out at the end of next year. But they're doing a great job with their development plan, but it's early. They're in Phase I right now, and we're looking forward to the results of our Phase II study.

Our next question comes from Geoffrey Meacham with Citi.

It's Ross on for Jeff. I guess I just wanted to understand a little bit more about what you guys are hearing about the PTL 27 testing used in the screening process. Just kind of what you're hearing or any feedback or color on that from physicians in the practicing end?

Thanks, Ross. You want to handle that maybe mention the AAIC poster and some of the traction that we were getting from how we use that assay in Altitude. Yes, sure. Thanks. A great question. I really appreciate that. We, as you probably know, use that as part of the screening process in our Phase II study, and it worked very well, I think. We actually in our Phase I study when that wasn't available, over 60% of the PET scans that we obtained as part of the screening process were negative for amyloid. But when we use the screening process and got a T2017 level first and then allowed people to go on the PET, 17% of the scans were negative. So we didn't really want to have 0% negative because then you were too conservative in your set point. But in the poster that we had, we actually showed that as part of the screening process that actually reduced the cost by about 40%. And I think equally important, it reduces the burden for patients and their families because now you have our new patients going on to unnecessary PET forms and lumbar punctures for spinal fluid, so it worked very, very well when we studied. We're pleased with those results. But more broadly kind of in your question, we're hearing a lot of positive comments from clinicians in terms of the utility of this process, and there will be probably other blood tests that will become available, but this is the first one to potentially get FDA approval. So in the future, I think you'll see a lot of clinicians applying these blood tests in the screening procedures, and that even includes primary care physicians, and we're starting to see that now. So certainly, the specialists that we talked to and KOLs, they will use this, but I believe the utility of this method will become much more broad, which will get more people into the pipeline to get to these disease-modifying therapies. I'll leave it at that.

Our next question comes from Paul Mattis with Stifel.

This is Julian speaking on behalf of Paul. I'm interested in how your JCR technology compares to what Roche has presented, particularly in terms of safety. Do you have any insights on how you might differentiate yourselves in that area? Additionally, although it’s early, what do you envision the Phase II development might look like? On a related note, there has been significant attention from investors regarding the early Alzheimer's studies and presymptomatic trials being conducted by Lilly and Eisai. What are your thoughts on these trials?

Thanks, Jon. I think I'll start, and maybe Jim can provide more insights on the safety differentiation. Eric, you can then discuss our thoughts on the clinical development aspect. As we consider the JCR collaboration, we see two key points of differentiation. First, it's largely about the carrier element and how the JCR transferrin binding carrier technology may enhance safety compared to other transferrin-mediated delivery methods, which can cause anemia. That's a key focus for us to explore and potentially validate. The second point, as Jim mentioned earlier, relates to the cargo and the preference for oligomer-directed antibodies, which may help in minimizing ARIA and other safety concerns. These are the two main areas of differentiation we see stemming from our partnership with JCR. Jim, do you have any additional comments? Also, we should discuss the potential design for the future clinical trials of an EVD directed product.

Yes, absolutely, I'm happy to. There are several factors that could influence the safety profile, which is part of the reason we are optimistic about this approach. At a high level, we see a chance to significantly reduce the delivered dose since a higher percentage of the circulating dose will reach the brain if the technology functions as intended, which we view as a positive outcome. When considering safety profiles, it’s important to look at target-related aspects such as ARIA, which is a major concern for anyone working on an amyloid-based antibody method. We are generally satisfied with the profile we observe for Sebernatag in regard to ARIA rates, based on our Phase I study, which we have discussed frequently. It is noteworthy that research from the Roche Group shows much lower ARIA rates for their antibody when transitioning darius from standard to en—this is supported by a scientific hypothesis about the localization of transferrin receptors that may alter how the antibody penetrates the blood-brain barrier. This presents an intriguing hypothesis and the possibility to enhance what we already believe is a favorable profile concerning ARIA risk. Additionally, as Dan mentioned, there are transferrin-related risks associated with conditions like anemia, which have been reported in Roche's program and noted in other programs targeting the transferrin receptor. We have considered this extensively and partnered with JCR because their clinical evidence indicates low occurrences of anemia with their marketed products. There are various factors at play, such as the affinity ranges for the transferrin receptor. It is also important to note that different shuttles can target the transferrin receptor but may not all target the same epitope. We are gaining valuable insights into how this technology operates, and we see an opportunity to significantly improve the safety profile of Sebernatag, which we are already quite proud of. We believe there is potential here. Regarding the Phase II study design, it is still early, but I want to highlight that Eric and the team did an excellent job in designing a progressive study for Sebernatag during Phase I. We can leverage the approach that incorporated both fluid and imaging-based biomarkers in Alzheimer’s patients with an EBD product. Moving forward, we have a lot of work ahead of us before reaching that stage, but we are very proud of the achievements in Phase I and believe there are learnings we can apply to the next stage of the program. I'll let Eric address your question about the ongoing preclinical studies.

Yes. Thanks, Jim. I think, yes, definitely for shuttle technology, the Phase I will be in patients and take some learnings from Sebernatag. But to get to your question about the clinical studies, that's something that's under active discussion. I think based on our Phase I data, Sebernatag would be a good candidate for a preclinical trial given its relatively low rates in our Phase I study. And so we're having active discussions about how that might be done. I think you could take the approach that you could use a blood-based biomarker, and that's all you would need to get into a preclinical study. I'm not sure that might be just a little bit too aggressive, but sort of the things we've talked about. The other thing is rather than just going straight to a PET scan, you could do essentially what we did in the Altitude study where you use the screening test, a blood test first, and then depending on the apron, either spinal fluid or a PET scan. The other piece to this that is really evolving nicely, I think, is using maybe doing a Phase II study for preclinical patients and with biomarkers. So you look at things like PTG17 but also GFAP and a number of other measures, and before you get a very large and very long Phase III clinical study, you got some good evidence that your biomarkers are going the right direction, you're having the kind of effect that you need in a smaller Phase II study. And then based on that, make a decision to be a much larger Phase III study, which would be a registration trial. So it's something that's under active discussion and asking right now.

Thanks, Eric. And I'll just comment, Julian, that I think the rationale for oligomer-directed agents in that preclinical population is very strong given the sort of elevated levels of oligomers that present and persist in that early preclinical phase of disease progression. So we're excited about that future opportunity.

Our next question comes from Chang Wong with UBS.

Just following up on the asymptomatic question, and you touched upon the blood-based markers identifying this population. Just how do you see that being integrated into trying to find patients? And then just how do you see it being covered by payers? Is this something that you'll see covered readily along with PET scans?

Thanks. Eric, do you want to take a first cut at that?

Sure. Yes. So there's a lot actually baked into that question. It's a good one. When you think about payers, now you're talking first about something that's available commercially and how payers pace these things. What we're hearing anecdotally is that payers are reimbursing for this L17 blood test that is now FDA approved. And I would expect that that would continue to be the case once you have a drug that you know has a positive clinical effect in this preclinical population. In other words, you were to delay the onset of symptoms. So it is a different study design. It's not slowing the rate of decline because these people are impaired. It is about delaying the onset of cognitive decline. But I think from a payer standpoint, and this will require some discussion, but from a payer standpoint, is there benefit within the Medicare population let's say, but is there benefit to outweigh the onset of cognitive decline because that's where healthcare costs start going up. So I think there's a lot of potential for this to play out clinically. But the first step, obviously, is we've got to do the study to show you that this strategy actually works. But I think it's got a lot of potential.

Our next question comes from Pete Stavropoulos with Cantor Fitzgerald.

As you mentioned earlier, there has been considerable enthusiasm regarding biomarkers, some of which indicate changes that occur before symptoms manifest, as well as reflect underlying pathology involving various paused species. Do the updates, including the new biomarker data from AAIC, influence your strategy and assumptions regarding clinical studies? Are there specific ones that you find noteworthy, such as those related to the altitude studies you previously disclosed or integrated into a Phase III study? Additionally, are you observing ARIA rates from the Altitude study on a blinded basis, and if so, do you have any insights on that?

Thanks, Pete. A lot in that question. I'm going to direct it to Eric for a quick comment on biomarkers of the AAIC and future development opportunities.

Yes, sure. Let me just talk about the biomarker question first. I mean, as much as we all are impressed by PTG217, there's a lot of additional work going on with additional biomarkers that are getting a lot of attention right now. So we continue to just watch that field very, very closely. Again, the results that we've had with PTG217 were, I think, quite good. And we, as you know, in our Phase I study, we also looked at TTL 181, we looked at GFAP. We looked at the beta 42 over 40 ratio. We reviewed a whole series of these biomarkers that you can look at. And one of the strengths of doing that actually is when directionally they're all going in the direction you want them to move, I think that's good evidence that you're having the right effect on the biology of the disease. So to get to your question about ARIA, I mean we're obviously in the midst of an ongoing blinded Phase II study. But what I can tell you is that we've not seen any data that are inconsistent with what we reported for our Phase I study. So that's what I can tell you at this point.

Maybe I can layer a little bit on the biomarkers, as Eric was saying. I think there are more and more biomarkers that are coming out. And at a fairly high level, what I see is improving resolution to be able to understand disease progression. We know that Alzheimer's disease is a progressive disorder; patients progress over time. And existing diagnostics can sort of help do that diagnosis, but it's a relatively low resolution. So as more and more markers are being studied, of course, they're all peaking at different points in the disease course. And over time, multiple groups' work is going to pull together, I believe, a much more high-resolution ability to understand where a given patient is in their progression of the disease. And hopefully, that leads to more differentiated treatment. But I think that's the long-term opportunity that I'm seeing in the blood-based biomarkers coming along. Of course, it goes without saying you've also got the benefits of convenience and cost savings and things that go along with that. But it is that ability to sort of understand disease progression at a much higher resolution that I think ultimately is going to be the biggest impact.

All right. Just one more question, if you don't mind, on the blood-brain barrier technology. Any commentary around optionality in terms of like the design to find an optimized candidate? Will you be grafting subunits or fragments onto JCR's Fc backbone, or will you grab the transferrin receptor binding domain onto your antibody? Any details would be helpful. And what were some of the nonclinical data from the feasibility studies that you sort of found encouraging and influenced the decision to enter the agreement?

Yes. Thanks, Dan. Absolutely. Yes, Pete, so I think the opportunity here that we see, and it's why we talk about it in terms of combining the cargo from the Acumen side of things with the carrier from the JCR side of things, and JCR's technology is somewhat flexible. So it allows us to investigate coupling different carrier molecules that are going to have different properties. And so we're looking at things like the overall PK profile that is generated, the rates at which the drug enters into the brain, things like that. And I think obviously you're always interested in understanding the safety profile. And then on the cargo side of things, Sebernatag is, of course, our flagship antibody, but we do also have other antibodies in the library that Sebernatag came from that all have their own properties that we've characterized over time. And so you can imagine at this stage in the collaboration, we're looking at what are the best components to put together. So we've talked about looking at single-chain variable fragments and we've talked about looking at VHHs, and I think combining numerous different flavors of carriers with a couple of different possible cargos is the exercise that we're going through. And it's a really very interesting exercise because it really offers lots of different optionality. So that will be the process we need to finish up to make some decisions about which if any molecules to take forward. And then from a little bit of color around the types of studies, we're obviously interested in ensuring that we haven't altered the properties of the cargo by coupling to the carrier. We also want to make sure that the carrier is giving us the right targeting when it comes to pharmacokinetics and brain penetration. So there are a number of studies that are ongoing in preclinical species that will include a primate study to really kind of give us the characterization of the different possible combinations to pick the best ones.

Our next question comes from Tom Shrader with BTIG.

This is Jenny on for Tom. And I want to ask a couple of questions on your trial. Will there be any data on the range of MMSEs in your trial? And how often are cognition tests given? Is it every 6 months, or is it more often than that? Eric, do you want me to go ahead and take that?

Yes. So yes, we will have MMSE as a secondary outcome. As you may know, our primary outcome is the state called the Iris, which combines a cognitive measure and a functional measure. And we'll also be looking at the CDR sum of boxes that's frequently used in trials, and we have a number of other secondary outcomes that affect things like quality of life and that sort of thing. Most of the main cognitive assessments are done every 3 months in the study. And then, of course, we'll also have a lot of biomarker data. The one thing I might mention in terms of our data readout at the end of next year, all the data don't become available at exactly the same time, especially some of the biomarker data, it takes a while to run those assays. And so our top-line results will include top-line efficacy and safety, but some of the other more detailed biomarker results may take a little more time to become available. So when we do have our top-line results, again, we'll have top-line efficacy and safety, but we'll also have some additional especially biomarker results that we'll be rolling out in the subsequent view. I hope that answers your question.

I'm showing no further questions at this time. I'd like to turn the call back over to Alex Braun for closing remarks.

Thanks, Michelle, and thanks to everyone for joining us today and taking the time to listen in. If you have any further questions, we are always available at the company. So please contact us. Have a great day.

Thank you for your participation. This does conclude the program. You may now disconnect.