Acumen Pharmaceuticals, Inc.

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 1 1 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 1 1 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 Seamers, 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 Investor section of the Acumen website to find a press release issued this morning and related slide presentation that we'll discuss today. Please note that during today's conference call, we may make forward-looking statements within the meeting 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 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 statement. 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 one intercept AD trial, evaluating AC193 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, AC193, 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, 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 for 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 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 three, 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 2-3 activities in anticipation of successful results from our phase 1 study. An end of phase 2 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 a phase 2 to a phase three 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 Leucanumab'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 the NANAMAB's Trailblazer 2 Phase 3 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 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.

Eric? Thanks, Dan, and good morning, everyone. We continue to work diligently as we near the finish line of our phase one 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, CSFPK, 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 olivar concentrations in CSF are generally reported to be less than two picomore, 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 one 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. 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 1 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 ADPD 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 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 pathogenesis, such as ACU193. Finally, the success of denatumab in the Trailblazer ALTS II study announced last week provides further scientific support for the amyloid beta hypothesis broadly. These results build on the success of licanumab 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. Denatumab targets deposited amyloid plaques and reduces plaque loads of every four weeks. Lacanumab targets A-beta protofibrils, but also reduces plaque load with every two-week dosing. The rate of ARIA-E with bananumab in Trailblazer ALTS2 was reported to be 24%, while for lacanumab, 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 REAE with equal or better efficacy compared to denanamab and licanamab. We applaud the well-run study results from Trailblazer ALTS2 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. 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 10Q 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 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. Operator?

Great. Thank you. At this time, we'll conduct the question and answer session. As a reminder, if you want to ask a question, please press star 11 on your telephone and then wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A roster.

Our first question.

I believe this is James on the phone for Seifel.

Hi, this is James here. Thanks for taking our question on for Paul Matisse. We were just wondering, how are you thinking about the different scenarios for what your phase two 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, at the interim and basing your decision to expand the trial? Any color there would be great. Thanks so much.

Thanks, James. And I'm going to invite Eric to comment on that question. Good question.

Yeah, sure. So, yeah, 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'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 two or to increase the size of the study and make it a phase three registration trial. So that interim analysis involves an algorithm that will look at a number of different things. So, of course, they'll look at things like the IDRIS, which will be actually our primary outcome, but also the CDR Summit boxes, the ADAS-COG, that sort of thing. Obviously, if you would have statistical significance on one of those clinical measures and an interim analysis, I think that would be a fairly clear signal to scale up to a phase three. 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 one 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 MLA 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. 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 three or do you just continue it out as a phase two study? So 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 Schrader 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. So, 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.

So, maybe I'll take that one, too. So, again, I always have to preface this. Another good question, but I always have to preface this by saying, you know, I'm a clinical trialist by nature, and so I take the real answers. ultimately have to come from the clinic. But as our poster illustrated at ADPD, there's a lot that we're still learning about what are the most toxic species. Thus far, it would appear that the species that AC193 targets are the ones that are relatively more toxic. I mean, the most toxic that we've been able to find. Or to put it the other way around, we don't see any evidence that AC193 binds to species that are not toxic. But 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, You know, the concentrations of oligomers in spinal fluid, as mentioned, are very low, you know, less than two picomolar. But no one knows really the concentration of oligomers in interstitial space in the brain. So 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. So, 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. And 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 abit antibodies on the market and any evolved thinking around including a comparator or a combination arm with another abit antibody in any subsequent trials, whether it's for a potential phase three or beyond that, and how could that affect 193'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 two or how you would deal with moving into the phase three 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. But, you know, in terms of comparators, that question has come up A lot, especially since the last week with the announcement. I think there's a pretty broad agreement that well, 1st 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. And 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. Uh, at the American Academy of neurology meeting couple weeks ago, they have what they call fireside chat and someone who is a, I think a lead investigator in the clarity style for was talking about all the things that you would have to do to use that in in your clinical practice. So these are practicing neurologist. And there was a lot of, um. 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 Denanamab actually will be even more complicated because they have this Tau requirement. So now you have to get maybe an amyloid PET scan and then a Tau PET scan. So 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 AC193, that infrastructure should be much more better developed. So, yes, stay tuned. But for right now, we do not expect there to be any requirement for a head-to-head trial. And so, 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 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 two, three clinical trial, then at some point we're gonna have to finance And even if we run a very large phase two clinical trial, to be determined, we would have to finance at some point after 2025. I hope that helps. 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 Ting An for Collins. Thanks for taking our question. So at ADPD, Dr. Selco 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 repalitated and led to the discovery of new species, which they call short-circuited So that somehow raises the question if the neurotoxicity and bioactivity previously observed with those soluble brain extracts are solely attributable to the oligmos. I think some of the first work was from the famous work from another HMS lab. What's your thought over this finding? And we're just wondering, like out of curiosity, besides solubility, how differentiated are these soluble fibrous fibril species from protofibrils or oligomers, for example. Thank you.

Yeah, so thanks. Dr. Silico, 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. So one of the things we've talked about before is that AC193, of course, targets oligomers licanumab was designed to target protofibrils. Now, partly this gets into definitions, and Dr. Sulco in the past, and I think currently actually, would sort of define anything that's soluble as an oligomer. So a protofibril is actually one type of oligomer if you want to use that definition. But he recently presented, and I think this was part of the ADP presentation, that how you define soluble can vary. So in other words, what happens is you centrifuge things and whatever ends up in the pellet is not soluble and whatever ends up in the supernatant is soluble. But if you centrifuge it faster and harder, you can change what is in the pellet and what's in the supernatant. So all of 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. So they're not exactly the same thing. We think of those as cousins. So 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, there's no other antibody that targets what we target that's currently in the clinic. So 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. So you mentioned we'll use IDRIS for the FIT2 as a primary endpoint. In DMAPs TBRs to top line, there seems to be some disconnection on IDRIS benefit for the HITEL group versus CDR-SB, where we see CDR-SB benefit was more consistent across the TEL subgroups. So what's your thought on the DMAP data and as well as what were some of your primary reasons to use IGRIS instead of CDR-SB for the FIT2S primary endpoint? Thank you much.

Yeah, right. So, one of the things, just to remind everybody, is that we only have a press release from Lilly on the Denatomab data. So, there's, they included quite a bit in their press release, which was great, but they didn't include everything. So, questions like that, how did the IGRIS, perform compared to whatever else, the CDR sum of boxes and the high tau group versus the intermediate tau group. Those are things I think we just have to wait for the presentation at AIC to really better evaluate. But our decision, and again, you know, things can change depending on new data, but our decision to use the IDRIS is really based on everything's up until this point in time. It actually appears to be a very good scale. And as you know, you know, that's what Lilly has used as their primary outcome. So we'll be looking forward to seeing more of those data from Trailblazer Alts, too. And, you know, we will always further refine our choices depending on new data.

Okay, thank you, Eric. If we may, maybe one last, like, question from our side. Will there be additional PKPD or safety updates ahead of the 3Q update? Thank you.

No, we don't anticipate.

Yeah, we don't anticipate any new disclosures prior to our top line results in the third quarter. And the study was going, well, you know, I mean, if there were some new safety information or something, obviously, we'd have to say something about that. But at this point, in any study, even though we're all blinded, we're feeling pretty comfortable about the safety profile. And so, 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. And now looks to be our last question. And this is from Charlie Yang with B of A. Go ahead with your question.

Hi, thanks for taking this question. This is Charlie Yang with Jeff Mitchell. Can you talk about, you know, just given like donor data, you know, potentially to kind of include one of the A beta drugs in your kind of phase two, phase three trials?

I'm sorry, I'm not sure I quite understood the question. Would we include other A-beta drugs in our Phase 2-3?

Right, as a potential combination therapy, you know, given the reason.

Right, gotcha. Now, 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 with a different complementary mechanism rather than, you know, another one that's related to abate or amylate in one way or another. In terms of our Phase 2-3 study, Um, we, we don't have any, uh, safety data from animal studies based on combinations. They have, like, an amount with AC one ninety three. And so I don't think it would make a lot of sense for our phase two, three 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 clinical uptake is going to be pretty slow, actually, for both licanumab and dinanumab. And so I think, you know, for us to run a placebo-controlled trial for our phase 2, 3 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 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, 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. Thank you. you Thank you. Thank you. 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 11 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 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 Seamers, 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 investor 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 meeting 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 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 statement. 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 one intercept AD trial, evaluating AC193 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, AC193, 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, 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 for 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 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 three, 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 2-3 activities in anticipation of successful results from our phase 1 study. An end of phase 2 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 a phase 2 to a phase three 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 Leucanumab's advisory committee meeting to do for 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 Denanumab's Trailblazer 2 Phase 3 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 AC193 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.

Eric? Thanks, Dan, and good morning, everyone. We continue to work diligently as we near the finish line of our phase one 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, CSFPK, 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 all of our concentrations in CSF are generally reported to be less than two picomoles, 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 1 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. 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 1 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 ADPD 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 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 pathogenesis, such as ACU193. Finally, the success of denatumab in the Trailblazer ALTS II study announced last week provides further scientific support for the amyloid beta hypothesis broadly. These results build on the success of licanumab 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. Denatumab targets deposited amyloid plaques and reduces plaque weeks. Lecanumab targets A-beta protofibrils, but also reduces plaque load with every two-week dosing. The rate of ARIA-E with Bananamab in Trailblazer ALTS2 was reported to be 24%, while for Lecanumab, 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 REAE with equal or better efficacy compared to denatumab and licanumab. We applaud the well-run study results from Trailblazer ALTS2 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. 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 10Q 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 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. Operator?

Great. Thank you. At this time, we'll conduct the question and answer session. As a reminder, if you want to ask a question, please press star 11 on your telephone and then wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A roster.

Our first question.

I believe this is James on the phone for SIFL.

Hi, this is James here. Thanks for taking our question on for Paul and Matisse. We were just wondering, how are you thinking about the different scenarios for what your phase two 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, at the interim and basing your decision to expand the trial? Any color there would be great. Thanks so much. Thanks, James.

And I'm going to invite Eric to comment on that question. Good question.

Yeah, sure. So, yeah, 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'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 two or to increase the size of the study and make it a phase three registration trial. So that interim analysis involves an algorithm that will look at a number of different things. So, of course, they'll look at things like the IDRIS, which will be actually our primary outcome, but also the CDR Summit boxes, the ADAS-COG, that sort of thing. Obviously, if you would have statistical significance on one of those clinical measures and an interim analysis, I think that would be a fairly clear signal to scale up to a phase three. 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 one 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 MLA 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. 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 three or do you just continue it out as a phase two study? So 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 Schrader 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. So, 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.

So, maybe I'll take that one, too. So, again, I always have to preface this. Another good question, but I always have to preface this by saying, you know, I'm a clinical trialist by nature, and so I take the real answers. ultimately have to come from the clinic. But as our poster illustrated at ADPD, there's a lot that we're still learning about what are the most toxic species. Thus far, it would appear that the species that AC193 targets are the ones that are relatively more toxic. I mean, the most toxic that we've been able to find. Or to put it the other way around, we don't see any evidence that ACE193 binds to species that are not toxic. But 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. But no one knows really the concentration of oligomers in interstitial space in the brain. So 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. So, 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. And 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 ABID antibodies on the market and any evolved thinking around including a comparator or a combination arm with another ABID antibody in any subsequent trials, whether it's for a potential phase three or beyond that, and how could that affect 193'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 two or how you would deal with moving into the phase three 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. But, you know, in terms of comparators, that question has come up A lot, especially since the last week with the announcement. I think there's a pretty broad agreement that well, 1st 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. And 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. at the American Academy of Neurology meeting a couple weeks ago. They have what they call a fireside chat, and someone who is, I think, a lead investigator in the clarity style for Leucanumab was talking about all the things that you would have to do to use that in your clinical practice. So these are practicing neurologists, and 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 the Nanomab actually will be even more complicated because they have this Tau requirement. So now you have to get maybe an amyloid PET scan and then a Tau PET scan. So 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 AC193, that infrastructure should be much more better developed. So, yes, stay tuned, but for right now, we do not expect there to be any requirement for a head-to-head trial. And so, 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 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 two, three clinical trial, then at some point we're gonna have to finance And even if we run a very large phase two clinical trial, to be determined, we would have to finance at some point after 2025. I hope that helps. 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 Ting An for Collins. Thanks for taking our question. So at ADPD, Dr. Selco 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 repelitated and led to the discovery of new species, which they call short cyborgs. So that somehow raises the question if the neurotoxicity and bioactivity previously observed with those soluble brain extracts are solely attributable to the oligmos. I think some of the first work was from the famous work from another HMS lab, which is not over this finding. And we're just wondering, like out of curiosity, besides solubility, how differentiated are these soluble fibroids fibril species from protofibrils or oligomers, for example. Thank you.

Yeah, so thanks. Dr. Silico, 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. So one of the things we've talked about before is that AC193, of course, targets oligomers licanumab was designed to target protofibrils. Now, partly this gets into definitions, and Dr. Sulco in the past, and I think currently actually, would sort of define anything that's soluble as an oligomer. So a protofibril is actually one type of oligomer if you want to use that definition. But he recently presented, and I think this was part of the ADP presentation, that how you define soluble can vary. So in other words, what happens is you centrifuge things and whatever ends up in the pellet is not soluble and whatever ends up in the supernatant is soluble. But if you centrifuge it faster and harder, you can change what is in the pellet and what's in the supernatant. So all of 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. So they're not exactly the same thing. We think of those as cousins. So 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, there's no other antibody that targets what we target that's currently in the clinic. So 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. So you mentioned we'll use IDRIS for the FIT2 as a primary endpoint. In DMAPS TBRs to top line, there seems to be some disconnection on IDRIS benefit for the HITEL group versus CDR-SB, where we see CDR-SB benefit was more consistent across the TEL subgroups. So what's your thought on the DMAPS data and as well as what were some of your primary reasons to use IGRESS instead of CDR-SB for the FIT2S primary endpoint? Thank you much.

Yeah, right. So one of the things, just to remind everybody, is that we only have a press release from Lilly on the Denatomab data. So there's, they included quite a bit in their press release, which was great, but they didn't include everything. So questions like that, how did the IGRESS perform compared to whatever else, the CDR sum of boxes and the high tau group versus the intermediate tau group. Those are things I think we just have to wait for the presentation at AIC to really better evaluate. But our decision, and again, you know, things can change depending on new data, but our decision to use the IGRS is really based on everything's up until this point in time. It actually appears to be a very good scale. And as you know, you know, that's what Lilly has used as their primary outcome. So we'll be looking forward to seeing more of those data from Trailblazer Alts, too. And, you know, we will always further refine our choices depending on new data.

Okay, thank you, Eric. If we may, maybe one last, like, side chat question from our side. Will there be additional PKPD or safety updates ahead of the 3Q update? Thank you.

No, we don't anticipate.

Yeah, we don't anticipate any new disclosures prior to our top line results in the third quarter. And the study was going, well, you know, I mean, if there were some new safety information or something, obviously we'd have to say something about that. But at this point in any study, even though we're all blinded, we're feeling pretty comfortable about the safety profile. And so 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. And now looks to be our last question. And this is from Charlie Yang with B of A. Go ahead with your question.

Hi, thanks for taking this question. This is Charlie Yang with Jeff Mitchell. Can you talk about, you know, just given like donor data, you know, potentially to kind of include one of the A beta drugs in your kind of phase two, phase three trials?

I'm sorry, I'm not sure I quite understood the question. Would we include other A-beta drugs in our Phase 2-3?

Right, as a potential combination therapy, you know, given the reason.

Right, gotcha. Now, 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 with a different complementary mechanism rather than, you know, another one that's related to avate or amylate in one way or another. In terms of our Phase 2-3 study, We don't have any safety data from animal studies based on combinations, say, of licanumab or denanumab with ACU193. And so I don't think it would make a lot of sense for our Phase 2-3 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 lacanumab and dinanumab. And so I think, you know, for us to run a placebo-controlled trial for our phase 2, 3 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 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, 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.