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. 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, Joe. Good morning, and welcome to the Acumen conference call to discuss our business update and the financial results for the quarter ended March 31, 2023. With me today are Daniel 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 a 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 in the 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, and thank you, everyone, for joining us today. The first quarter 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 third quarter. 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 the high selectivity for A-beta oligomers. Scientific consensus asserts that oligomers are the most toxic form of A-Beta. And 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 our 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 of our next phase 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 3, our 25-milligram per kilogram 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 fourth quarter. As previously disclosed, the study design incorporates an interim decision to expand the size of the study from 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 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 a potential better option 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 third quarter of this year, a dataset that will be informative from a safety, target engagement, and dose-ranging perspective. With that, I'll hand the call over to Dr. Siemers.

Thanks, Dan, and 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, and 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 2 pM, which means that our target engagement assay must be very sensitive. We also anticipate announcing exploratory data with our topline results from our Phase I study, including Cogstate computerized cognitive testing as well as arterial spin labeling pull sequences on MRI, which will determine if cerebral blood flow has increased after treatment with ACU193. While 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. As a reminder, we have included typical clinical measures like the CDR sum of boxes and the ADAS-Cog in our Phase I study. However, because this is a small, short study, it is unlikely that those measures will show a drug effect. During the first quarter, 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 5-way 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 kilodaltons. 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 type of genesis such as ACU193. Finally, the success of donanemab in the TRAILBLAZER II 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 trial. While 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 in 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. And with that, I'll turn the call over to Matt.

Thank you, Eric. Good morning, everyone. As a reminder, our first quarter 2023 financial results are available in the press release we issued this morning and in our 10-Q that will be filed later today. As of March 31, 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 first quarter; 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 third quarter and will remain financially disciplined as we use our capital to advance our clinical program for ACU193 and deliver value to patients and shareholders. And with that, we can open the call for Q&A.

Our first question comes from James on the phone for Stifel.

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? For example, if ACU193 were to have a similar effect size as the A-beta antibodies, would this study be powered for stats on these clinical scales? Or would you be looking at something else at the interim and basing your decision to expand the trial? Any color there would be great. Thanks so much.

Let's exchange. I'm going to invite Eric to comment on that question. Good question.

Yes, sure. Thanks. Great question. So 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 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. So that interim analysis involves an algorithm that we'll look at a number of different things. Of course, we'll look at things like the IDRs, which will be actually our primary outcome, but also the CDR sum of boxes, 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. But 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. And 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. So in other words, if your drug affects a mild of COGS, or in our case, A-beta oligomers, if you see a change in phosph-tau, that really gives you a sign that you're having an effect on the underlying disease process. So 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? So hopefully, that addresses the question that you brought up.

Yes, very helpful. Thank you.

Our next question comes from Tom Shrader with BTIG. Go ahead with your question.

Good morning. Thank you for taking my question. You're doing impressive work addressing one of the biggest questions in the field: which oligomers are truly significant? Is this altering your perspective on target engagement? I assume you prefer antibody levels that specifically target the relevant particles. Are you discovering that 2 pM might be an overestimate? Or do you believe it's necessary to capture most of the particles for safety? Or is that something that needs to be evaluated through clinical data? Thank you.

I can address that question. As I mentioned before, while my responses come from a clinical trial perspective, the true insights will emerge from clinical outcomes. As we demonstrated at AD/PD, there's still much to discover regarding the most toxic species. Currently, it seems that the species targeted by ACU193 are among the more toxic ones we've identified. We haven't found any evidence that ACU193 binds to non-toxic species, but again, clinical evidence is crucial. Additionally, it's worth noting that while oligomer concentrations in cerebrospinal fluid are very low, under 2 picomolar, the concentrations in the brain's interstitial space are unknown. Our antibody ACU193 needs to leave the arterial system and enter that space, where oligomer concentrations might be higher. So far, we've had positive outcomes with our target engagement assay, which appears to be functioning well, and we're eager to see the results in conjunction with others from INTERCEPT-AD.

Great. Thank you.

And now we have Judah Frommer with Credit Suisse. Go ahead with your call.

Yes. Good morning. Thanks for taking the questions. First, just as we think about potentially having two A-beta antibodies on the market, 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 us 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.

Yes. Let me address your first question and then pass it to Matt for the second. Regarding comparators, this topic has been frequently discussed, especially with the recent announcement about Donanemab. There's general consensus that conducting a head-to-head trial with such drugs is quite challenging. One has to perform a non-inferiority study, which requires significantly large trials. From conversations I've had, it seems that nobody expects regulatory agencies to demand this kind of head-to-head comparison at this time. Another key point of interest is how quickly these treatments will be integrated into clinical practice. At a recent American Academy of Neurology meeting, a lead investigator for the Clarity trial on lecanemab discussed the complexities involved in implementing it in clinical settings. Many practicing neurologists expressed concerns about the complications since the necessary infrastructure for PET scans and MRIs is not yet fully established. Donanemab's requirements will add further complexity because it necessitates both an amyloid PET scan and a top head scan. Consequently, I believe the market adoption will take time. However, this creates a potential advantage for us; by the time we launch ACU193, the required infrastructure should be significantly more developed. So, while we’ll keep monitoring the situation, we do not anticipate a need for a head-to-head trial at this moment. Now, I’ll turn it over to Matt.

Thanks, Eric. Judah, with regard to the cash, until we meet with the FDA and know exactly which clinical trial we're going to 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. So 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 going to have to finance. And 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.

Yes. Thank you.

Next, we have Colin Bristow with UBS. Colin, go ahead with your question.

Hi, good morning. This is Tina on for Colin. Thanks for taking our question. So at AD/PD, Dr. Selkoe for HMI, he presented interesting findings from his lab that previously thought as soluble oligomers from Stipulated monogomers AB, they can actually be replicated and led to the discovery of new species which they call short fibrils. So 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 will found the same rework on another HMS lab. Would you stop over this finding, and we're just wondering like out of curiosity, besides solubility, how differentiated are this soluble fibril species from oligomers, for example? Thank you.

Dr. Selkoe is engaged in advanced research, and your question highlights the current forefront of the field. One thing we've discussed previously is that ACU193 targets oligomers, while lecanemab is designed to target protofibrils. This ties into definitions, as Dr. Selkoe has defined anything soluble as an oligomer, which means that protofibrils are actually a specific type of oligomer under that definition. He recently presented information indicating that the definition of soluble can vary. Essentially, when you centrifuge samples, what settles in the pellet is not considered soluble, while the liquid above it is. However, if you increase the centrifugation speed and force, you can alter what is classified as being in the pellet or the supernatant. This terminology and understanding is evolving. To clarify the distinction between protofibrils and what ACU193 targets, protofibrils are linear structures, whereas the targets of ACU193 are globular. This difference is visible with atomic force microscopy, indicating they are not the same. We consider them related but distinct; they are both soluble by usual standards and both toxic, yet they differ in structure. ACU193 is unique in that it targets a specific type of oligomer that no other antibody in clinical trials currently addresses. I hope that clarifies things, though it's complex.

Yes, that’s really helpful. Thanks so much, Eric. We have a follow-up question. So you mentioned we will use IDRs for that as a primary endpoint. In relation to top line, there seems to be some disconnection on IDRs benefit for the high-top group versus CDR FP; we see the CDR FP benefit was more consistent across the subgroups. So what's your thought on the demand data and as well as worse of your primary reasons to use IDRs instead of CRB for the fifth primary endpoint?

Yes, just to remind everyone, we only have a press release from Laurea regarding the donanemab data. They provided a lot of information in that release, which was helpful, but it did not include everything. Questions regarding how IDRs perform compared to other metrics, like the CDR sum of boxes in the high tow group versus the intermediate tow group, are aspects we will need to wait for the presentation at AIC to better assess. Our decision to utilize the IDRs is based on all the information available up to this point. It seems to be a good scale, and as you know, that is what Lilly has chosen as their primary outcome. We are looking forward to seeing more data from TRAILBLAZER ALZ and will continue to refine our choices based on new data.

Okay. Thank you, Eric. If we may maybe one last set of questions from our side. Will there be additional PK/PD or safety updates ahead of the 3Q update? Thank you.

No, we don't anticipate any new disclosures prior to our top-line results in the third quarter. The study is progressing well. If there were any new safety information, we would, of course, inform you. However, at this stage, even though we are all blinded, we feel quite comfortable about the safety profile. Therefore, I do not expect any new disclosures before our top-line results.

Thank you so much.

And now it looks to be our last question. And this is from Charlie Yang with BofA. Go ahead with your question.

Hi, thanks for taking for question. This is Charlie Yang on for Geoff Meacham. Can you talk about just given the level of data, potentially to kind of include one of the A-Beta drugs in your kind of Phase II, Phase III trial?

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, combination therapy given the recent…

Right. Got you. Well, so combination therapy is an important topic, and it's something that we at Acumen have certainly had some discussions about. Now our approach to that would probably be the combination would be a drug that has a different complementary mechanism rather than 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, donanemab with ACU193. And so 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. But 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. And so I think for us to run a placebo-controlled trial for our Phase II/III is certainly going to be feasible. But 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. So you would use something that's related to tau, something that is related to inflammation, something like that to combine with ACU193, to see whether you get additive or even synergistic effects.

Thank you.

I'd now like to turn the call back over to Dan O'Connell.

Thanks, and 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 third quarter, data that will be informative on ACU193, as a selective agent neutralizing toxic A-beta oligomers. So 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.