Good day, and welcome to the Acumen Pharmaceuticals Second Quarter 2025 Conference Call and Webcast. [Operator Instructions] 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. 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 Sebernatype, our monoclonal antibody with high selectivity for toxic amalgam. 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 disease, Alzheimer's brain. So lower affinity for monomeric Abeta what Severity 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 and space, highlighting the growth of the clinical infrastructure for diagnosing and treating people with Alzheimer's disease. Feedback from KOLs and others…

Thanks, Dan, and good morning, everyone. Thanks for joining us today. I'd first like to build on Dan's comments about AIC 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 1 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 macro molecules 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…

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, 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 first quarter, apologies 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 2D 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. Operator?

[Operator Instructions] Our first question comes from Jason Zemansky with Bank of America.

Congrats on the progress. wanted to talk to you a little bit about AAIC. Specifically, if you look at Roche's similar sort of brain shuttling technology, the [indiscernible] initial results there and how to benchmark a potential brain shuttling technology around Subernatug? And then, I guess, secondarily, given the overall plaque reduction seen in those patients, what does that mean for your epitope, given kind of the focus on the oligomers.

Thanks, Jason. Great question. I guess I'd like to direct that to Jim initially and Eric, you may have some comments as well.

Yes, absolutely. So yes, thanks, Jason. We've obviously been paying close attention to this entire space, including ROSE 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 trentinimab, 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 in concentrations. And I think we see the same kind of opportunity with [indiscernible] where, of course, their difference is in the fundamental targeting of the molecules. So -- we believe very much that these toxic naptha -- toxic oligomers are directly toxic within the brain during the pression 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 -- we all refer to amyloid as the target, and it certainly is. Amylybiology is pretty complex. And so there are ligamers 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 Subarnatag to really effectively access silicas and we think that, that 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 with 542 patients that will read out at the end of next year. And so -- 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 Algidstudy.

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 kind of what you guys are hearing about the PTL 27 testing used in the screen 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 AIC 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 algos study, and it overkill 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 sands 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 lumber countries for spinal fluid, so it worked very, very well when we're studying. 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 podcast, 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 chest business screening procedure -- and that even includes primary care physicians and we're starting to see now. So certainly, the specialists that we don't talk to 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 on for Paul. Yes, just again, just thinking about comparisons of CR technology to what Roche has shown. Just curious how you think you guys could potentially be differentiated particularly even on the safety side, if you have any commentary on that? And then just on the same topic, just wondering what you think -- I know it's early, but what the Phase II development could potentially look like and then sort of separately, just a broader question. There's been a lot of attention in the investor community on the early Alzheimer's studies, presymptomatic studies being conducted by Lilly and Novo. I'm just curious what you guys think of these trials? And if you have any commentary there. I'm sorry, Lilly and Eisai is what I meant there.

Thanks, Jon. Yes. So I think I'll lead out, maybe, Jim, you want to comment a little bit more on the safety differentiation. And then Eric, you can comment on what we sort of talk thinking about from a clinical development standpoint. I think as we envision the JCR collaboration, there are 2 points of differentiation. It's principally both on the carrier element and the way the JCR transferrin binding carrier technology may lead to better safety relative to other transferring mediated delivery modalities that actually induce a level of anemia, so I think that's one area of interest to us to exploit and potentially validate. The other is -- and Jim mentioned this in his prior comments around the cargo. And the preference of alignum-or-directed antibodies to avert even further reduce ARIA or other safety elements. So those are kind of the 2 primary modes of differentiation we see based on the synergistic partnership we've established with JCR. Jim, I don't know if you have more comments to make. And I think we probably should talk a little bit about reference kind of the potential future clinical design for an EVD directed product.

Yes, absolutely, happy to. And I think there are a number of elements that could impact a safety profile that we think -- and it's part of the reason we're excited about this approach. And I think at a high level. We see the opportunity to really lower the delivered dose because you're going to get a higher fraction of circulating dose into the brain if the technology works as it's intended, which I think is overall a good thing. I think when you think about safety profiles, you can look at it from the perspective of target associated things like ARIA. So that's obviously something that's top of mind for anyone developing an amyloid-based antibody approach. We're overall pleased with the profile we see for Siburnatag when it comes to REA rates, and that comes from our Phase I study, which we talked about a number of times. But it is interesting when you look at the work coming from the Roche Group that in their case, their antibody, the ARIA rates are much, much lower when you convert gasierimabto en -- and there's scientific hypothesis around that based on where the transferrin receptors are localized, which can change the entry points for where the antibody is getting across the blood brain barrier. So that's an interesting hypothesis and offers the opportunity to even further enhance what we think is an already attractive profile for the potential for RA risk but -- and then as Dan mentioned, there are the transferrin related risks associated with things like anemia and that's certainly an element that's been reported in the Roche program to date. It's also been seen in other programs targeting the transferrin receptor, something we've thought a lot about and obviously went into our evaluation process. And we've landed…

Yes. Thanks, Jim. I think, yes, definitely for shuttle technology, the Phase I even would be in patients and take some learnings from suburbatype. 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, severity would be a good candidate for a preclinical trial given it's 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 Altice study where you use the screening test, a blood test first and then depending on the apron to either spinal fluid or a pet scan. The other piece to this that is really evolving nicely, I think, is using -- maybe doing sort of a Phase II study for preclinical patients and win at 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 II clinical studies, you got some good evidence that your biomarkers are going the right direction, you're having the kind of effective work 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 Banregistraton trial. So it's something that's under active discussion are asking right now.

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

Congrats on the progress, guys.

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 pecans?

Thanks, Jon. 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 Worldpay's pace of these things. What we're hearing anecdotally is that payers are reimbursing for this L17 blood test that on this FDA approved now. And I would expect that, that would continue to be the 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 done start to have cots 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 it's the benefit to be way the onset of cognitive decline because that's where health care 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 were mentioning before, there was a lot of excitement around biomarkers, some of which show change in biomarkers start to appear for in advance of symptoms as well as some of the underlying pathology like various pause species out of these updates, including new biomarker data at AAIC, inform your approach and assumptions about clinical studies. Are there any that stand out to you? -- as ones you may look at with samples at altitude studies that you have in disclose before or incorporated into a Phase III study? And also curious to know if you're seeing RU rates from the Alphasestudy on a blinded basis. And if so, any commentary around that?

Thanks, Pete. A lot in that question. I'm going to direct it to Eric for a quick comment on biomarkers of the AIC 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 PCL217, there's a lot of additional work going on with additional is 1 of the ones that is 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 PT217 were, I think, quite good. And we, as you know, in our Phase I study, we also looked at TTL 181, we look at GFT. We looked at the beta 42 over 40 ratio. I retire a whole series of these biomarkers that you can look at. And 1 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 BioMark 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 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 1 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 FAB fragment onto JCR's Fc backbone -- or will the graph you grab the transferrin receptor binding domain onto your antibody. Any details would be helpful. And what were some of the nonclinical data from -- or data from the feasibility studies that you sort of found encouraging and influence the decision to enter the agreement.

Go ahead. I think that's for you, Jim.

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 Accuen 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 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 safety profile. And then on the pro side of things, subunit is, of course, our flagship antibody, but we do also have other antibodies in the library that Supernus 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. And so that -- we've talked about looking at single chain variable fragment. We've talked about looking at VHHs, -- and I think combining numerous different flavors of carriers with a couple of different possible cargoes 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 PK and to 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.

[Operator Instructions] 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.

Is 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 mainly cognitive assessments are done every 3 months in the study. And then, of course, we'll also have a lot of biomarker native just to take that out too. And so we're looking forward to really looking at a package data -- the 1 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.

That -- thank you very much.

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