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spk16: Thank you for standing by. Welcome to Acumen Pharmaceuticals' full-year 2022 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 11 again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Alex Braun, Head of Investor Relations. Please go ahead.
spk12: Thank you, Michelle. Good morning, and welcome to the Acumen Conference Call to discuss our business update and financial results for the year ended December 31st 2022. With me today are Dan O'Connell, our Chief Executive Officer, Dr. Eric Siemers, our Chief Medical Officer, and Matt Duga, our Chief Financial Officer and Chief Business Officer. Before we begin, we encourage listeners to go to the Investors section of the Acumen website to find our press release issue 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 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 will open the call for Q&A. Now, I'll turn the call over to Dan.
spk08: Thank you, Alex. Good morning, and thank you, everyone, for joining us today. 2022 was a pivotal year for Acumen, marked by significant progress advancing the critical development of ACU193, the first monoclonal antibody tested in Alzheimer's patients that was discovered and developed to selectively target soluble amyloid beta oligomers. Over the course of the year, we received fast-track designation from the FDA, added experienced and talented members to our team to guide our development plan, and completed important CMC work to scale production in anticipation of upcoming Phase II study. In February of this year, we announced the completion of enrollment in our Phase I Intercept AD trial, which sets us up to report top-line results in the third quarter. The Intercept AD results are anticipated to provide important proof-of-mechanism information for AC193, including safety, pharmacokinetic, and target engagement data that Eric will speak to in greater detail shortly. Thus far, we are encouraged by preliminary PK and blinded safety data observed to date. which supports our thesis that at appropriate dose levels, an antibody selected for A-beta oligomers, such as AC193, may provide a differentiated product profile in the fight against Alzheimer's disease. I want to briefly comment on the protocol that we disclosed in early February, just prior to completion of enrollment. Based on the preliminary CSF PK data observed that indicated that AC193 antibody concentrations were in excess of reported A-beta oligomer concentrations, And considering the blinded case of RAE observed in the cohort four at the time, we opted to amend the trial's protocol to reduce the dose level in cohort seven, our last cohort, to 25 mg milligrams per kilogram every two weeks. We believe the 25 mg per kilogram dose every two weeks in cohort seven will provide us with more meaningful dose ranging, safety, and target engagement information in support of establishing clinical proof of mechanism for ACU193 in this study. Looking ahead, we're actively preparing for Phase 2-3 activities in anticipation of successful results from our Phase 1 study in the third quarter. We will request an end of Phase 2 meeting with the FDA to be held in the fourth quarter to discuss the design of our Phase 2-3 study, a design that incorporates an interim decision to expand the study from a Phase 2 size to a Phase 3 study. On the CMC front, we remain well positioned to scale manufacturing to have sufficient drug supply to meet requirements of our current development plan. In addition, we have made meaningful progress in assessing various options for potential development of a subcutaneous formulation as part of our AC193 product development plans. We intend to continue to explore such options based on data generated in our phase one study. On a final note, I would like to acknowledge the significant change in the overall treatment landscape for Alzheimer's disease over the past year. The positive clarity AD results for licanumab in the fall of 2022 meaningfully advanced the field. Because it is a proto-fibril targeting antibody, licanumab has driven renewed interest in the role that soluble aggregated A-beta species, such as A-beta oligomers and A-beta proto-fibrils, may play in the pathology of Alzheimer's. and how targeting these species can contribute to safe and beneficial treatment options for patients. Furthermore, the negative graduate study results for gantanarumab, a plaque-targeting antibody, support the hypothesis that for plaque-targeting antibodies, clinical efficacy can only be achieved with a near-complete removal of amyloid plaque. Most recently, the negative A4 results for selenazumab and A-beta monomer-targeting antibody reinforce the evidence that targeting monomers may not be a viable means to produce clinical benefit, even when intervening at the earliest stages of disease. Aside from these clinical data sets, the field is also seeing advancement with both fluid and imaging biomarkers, which continue to develop rapidly and could offer a diverse set of future alternatives that are predictive of effects in AD beyond amyloid PET imaging. Given the size of the disease burden, we are encouraged by the additional clarity of these data have provided to the field, and look forward to additional upcoming data from many companies with differing approaches. At Acumen, we recognize the importance of these advances and strive to use the learnings to inform our approach to developing AC-193 as a potential disease-modifying therapy in early Alzheimer's patient population. To this end, we look forward to sharing our Intercept-AD top-line data with you in the third quarter, a data set we believe will be informative from a safety target engagement and dose-ranging perspective. With that, I'll hand the call over to Dr. Siemers. Eric?
spk02: Thanks, Dan, and good morning, everyone, from Gutenberg, Sweden, where I arrived today to attend the ADP meeting that's happening this week. We are delighted to have completed enrollment of our Phase 1 Intercept AD trial as we announced in February. This is a true testament to the hard work and dedication shown by our team and by the investigators the site personnel, our CRO, and most importantly, the patients, families, and their study partners. I would like to thank them for their ongoing support in advancing our understanding of the potential of ACU193. With top-line results now expected in the third quarter, I'd like to take a few minutes to provide some context around our expectations for those results. Our phase one study is a randomized placebo-controlled first in humans sad, mad study with 65 patients enrolled with early Alzheimer's disease. The objectives of the trial are to evaluate safety and tolerability, evaluate PK and establish target engagement for ACU193 administered intravenously. The primary trial endpoints are focused on safety and PK. As far as safety, And in support of our protocol amendment disclosure in February, we announced that we had seen two cases of asymptomatic ARIA-E as of January 31st in this blinded trial. Based on the preclinical data, we had expected less ARIA than that seen with some other monoclonal antibodies at their highest doses. And the preliminary blinded cases we observed in the first quarter were aligned with that expectation. We remain encouraged that the safety profile of ACU193 to date will support targeting soluble amyloid beta oligomers. We also note that ARIA-E cases do provide evidence of central pharmacology, that ACU193 crosses the blood-brain barrier in sufficient quality to have a central effect. Keep in mind as well that cohort 6 is ongoing at a dose of 60 milligrams per kilogram every four hours, which is considerably higher than doses pursued by several other antibodies, including aducanumab, lacanumab, and dinanumab. The preliminary PK data we disclosed support this line of thinking. We know that preliminary CSF PK data from our 25 milligram per kilogram cohort showed ACU193 levels that were substantially above the levels reported for oligomers. Oligomer concentrations in CSF are generally reported to be less than two picomolar, which is a very low concentration compared to other soluble species such as A-beta monomers. If this is the case, a dose of 25 milligrams per kilogram every four weeks could be a viable dose to test in the next phase of our program for ACU193. Turning to target engagement, as many of you know, the assay for our target engagement is designed to measure the complex of A-beta oligomers bound to ACU193 in CSF, simply detecting the complex after administration will satisfy the target engagement threshold. In non-clinical studies, Merck was able to measure these complexes in brains from transgenic mice after ACU193 administration using an immunoassay. Acumen is developing a conceptually similar methodology for the Intercept-AD trial to look at CSF using proprietary materials that increase the assay's specificity for both ACU193 and A-beta oligomers, and thus specificity for the ACU193 oligomer complex. Importantly, we will be performing test runs of this assay prior to our database block to ensure the sensitivity is optimized. Exploratory measures that are built into our Phase I study include computerized cognitive testing for signs of early effects and arterial spin labeling with MRI scans to understand if cerebral blood flow has increased. While these analyses are exploratory and are unlikely to result in a statistically significant signal in this small study with a short treatment duration, the detection of a potential signal would suggest important central pharmacodynamic effects. Depending on our Phase I results, these measures may be employed in subsequent clinical trials using ACU193. Turning toward our upcoming Phase II-III clinical study, the team has been working diligently to develop an algorithm that would include evaluations by the Data Monitoring Committee of clinical measures computerized cognitive testing, and biomarkers to enable a go-no-go decision to scale a phase two study to a phase three study. We are confident that the algorithm we finalize will provide a rigorous method to allow a go-no-go decision to expand from phase two to phase three. And with that, I'll turn the call over to Matt.
spk20: Thank you, Eric. Good morning, everyone. Our complete year-end 2022 financial results are available in the press release we issued this morning and in our 10-K that will be filed later this afternoon. We ended 2022 with approximately $193 million in cash and marketable securities on the balance sheet, and we continue to expect that cash runway to last through 2025. R&D expenses were approximately $32.4 million in 2022. The increase over the prior year was primarily due to the increased activity in the ongoing Intercept-AD trial. G&A expenses were $12.9 million in 2022, and the increase over the prior year primarily the result of increased headcount. This led to a loss from operations of $45.2 million in 2022. Regarding our exposure to Silicon Valley Bank, we had approximately $1.7 million in cash in our operating accounts there as of March 10th, 2023, all of which has been moved to another institution. In conclusion, we remain well resourced to execute against our strategic priorities over the next few years. We look forward to reporting top line data for Intercept AD in the third quarter of 2023, and we'll 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?
spk16: As a reminder, to ask a question, please press star 11 on your telephone and 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.
spk01: First question comes from Paul Matisse with Stifel.
spk16: Your line is now open.
spk11: Hey, thanks so much.
spk13: On the interim analysis that you're planning, how is this similar or different to just your typical interim? where a blinded group looks at the data, recommends sample size adjustments, or can stop the study. And then I have one follow-up. Thank you.
spk08: Hey, thanks, Paul. Yeah, I was going to invite Eric to comment on that. I mean, there's a simple explanation, I think.
spk02: Right, yeah. So, well, of course, you're right. A lot of times interim analyses are done to adjust sample sizes. And usually that's based on purely a statistical look at the data. One thing I should just emphasize is that it's not a futility analysis, and so everyone should be clear about that. But the interim analysis itself is actually quite a bit more complex than the sort of thing that's done just to adjust sample size. In other words, we, and as I discussed, we're developing the algorithm But we'll look at the clinical measures. I mean, we have things like the CDR cell boxes in the trial. And so in a little study like this, it would be surprising to see a drug effect there. But we'll look at those things. We'll look at the ADOS-COG. And again, we'll look at our computerized cognitive testing, some of the MRI results, and also some biomarkers. And we will develop this algorithm to give to the DMV. And the DMV, if the algorithm is successful, so to speak, then the study will be scaled up to the size of phase three study. If it doesn't fulfill the algorithm, then it will be completed as a phase two study. So at a minimum, we'll complete the next study as a phase two study.
spk13: Okay, thanks. And then you've talked a little bit more about enthusiasm. I'm sorry, Dan, go ahead.
spk08: Well, I was just going to say, and Paul, of course, the 2-3 design is really intended to be the fastest path to a potential, you know, registration for the product, you know, hypothetically. So if that's not obvious, I just want to make that comment.
spk13: No, that's clear. Thank you. And then you've talked more about confidence in this 25-megapartic dose. Is that based on anything you're seeing? I guess what if you don't see a clear dose response on a target engagement assay, Does that mean you might take forward a lower dose? Like, how are you guys thinking about these scenarios in the second half of this year? Thank you.
spk08: Yeah, thanks, Paul. So, I mean, I'll just comment. I think we really made the protocol amendment in February based on some observations in the study, including the PK and the RA case. So, I don't think we're not in a position to continue to roll out information until the third quarter. I do think that when we made the decision to modify the cohort seven dose level, it became sort of obvious to us at the time, given that might be a viable dose in terms of just the overall drug required to dose at 25 megs versus 60 every couple of weeks, which was the original concept for cohort seven. So I think we're really encouraged that, you know, sort of the overall thesis for the AC-193 is very much intact and are confident that the modification for cohort seven in particular gives us more information Kind of with a mid-dose level between the 10 mg per kg and the 60 mg per kg that's ongoing in cohort six. Thank you. Yeah.
spk16: Please stand by.
spk01: Please stand by for our next question.
spk16: Next question comes from Tom Schrader with BTIG. Your line is now open.
spk04: Thanks. If you had more to say, it's almost the same question anyway. I have a little bit of a question about the world of plaque removal. There's still some controversy about how important it is. I think we might call it confusion, but what's your sense about where the FDA is on that issue and how important that would be in an interim look. Are they going to be okay with a trial that is ignoring plaque removal or is that kind of all your own business? But given that it's kind of unknown how important it is, how much do you have to think about it going into a trial with an interim look? Thanks.
spk02: So maybe I can... So, from an FDA standpoint in the plaque reduction, that was for an accelerated approval. In other words, FDA considered plaque reduction to be, quote, reasonably likely to predict a clinical effect. And that led then to the accelerated approval. Now, one of the things that I think has become even more clear, I think it was clear before, but as Dan mentioned, If you're going to target plaque, you have to essentially get rid of all of it to have any clinical efficacy. And I think that, again, Neuromab graduate studies demonstrated that very well. And in our case, this interim analysis that we're doing is not really in anticipation of an accelerated approval or any sort of a regulatory approval. It's for our internal decision-making in terms of phase two study and then scaling it up to a phase three study. So, there really isn't a regulatory piece to the interim analysis as we're doing it. All right, great.
spk03: Thank you.
spk08: And I think, and Tom, just to, you know, we are doing amyloid PET in the current study and would anticipate doing it, again, not that we would expect to see it move dramatically, but just as a kind of the convention standard practice.
spk03: Okay, great. Thanks for the answer.
spk16: Please stand by for our next question. Our next question comes from Collin Bristow with UBS. Your line is now open.
spk14: Morning, everyone. This is for Collin. Thanks for taking our question. So, we have two questions and a follow-up, if we may do. The first question is for patients in the cohort six in MAD. In our last correspondence, you noted they have not yet received MRI scans. Just wondering if they have received by now, and if so, could you provide any safety updates? And then second question is more general. Do you think there's a general correlation to dose A oligomode-targeted antibody more frequently than those core plaque targeted ones, given the faster turnover kinetics here? Thank you.
spk08: Hi, Teng. Thanks for your question. I think on the first one, as I mentioned, and as Eric mentioned, we disclosed the ARIA cases back in February in conjunction with the protocol amendment. And Eric just noted that Cohort 6 continues to proceed per protocol. So we haven't provided any other information in terms of ARIA cases and so forth. I think maybe I would turn it to Eric in terms of the dosing frequency question with respect to an oligomer antibody. I mean, I think, yeah, Eric, maybe you would care to comment on that aspect of Ting's question.
spk02: Yeah, so it's a really interesting question. And I think what you're really asking is that for an antibody that targets plaque, the antibody binds to the plaque. It actually starts an inflammatory response with microglia. And so it's not necessarily so dependent on the PK that you would see even in spinal fluid at any given time, since once it's bound to plaque, it's obviously not going to show up in spinal fluid. In our case, it may be a little bit more straightforward in that we do want to show that we're in antibody excess. In other words, that you have more antibody there than you have oligomers. And that was one of the reasons why the preliminary data, CSFPK data in cohort three, which is 25 mgs per keg, really was so exciting for us is that we were in antibody excess. And so, The situation is a little bit different, you're right, but I think in our case, again, I think the important thing is to show that we're in antibody excess.
spk14: Thank you much. Sorry. Yeah. Yeah. Sorry. Thank you for providing all the colors. Really helpful. We have a follow-up question, which kind of like echoing Tom's earlier question, also what Dan has mentioned in the prepared remark on A4. So we understood solonizumab is primarily, sorry, primarily monomer targeting, but it has some capacity to oligomers, though it does not touch any plugs. So there were some concerns following solanizumab's complete failure that maybe some level of plaque clearance are still needed for the best treatment efficacy. We are curious to hear your thoughts. And if you could provide any colors to us, it would be greatly appreciated. Thank you so much.
spk02: Well, Dan, you want me to go ahead and take that since I have a bit of familiarity with solanizumab. First of all, for the A4 result, of course, there's really just been press releases and we'll need to see all the data. What for me was a bit surprising and interesting is that actually even though there were no statistical differences, the trends actually favored placebo over drug. And that was at a dose of 1,600 milligrams every four weeks. Well, when solanizumab was given to people with mild Alzheimer's disease at 400 milligrams every four weeks, the trends were very consistent in terms of favoring drug. So why you didn't see that with the higher dose of solanizumab is a bit of a mystery, and I think we'll have to see all the data to understand that. You know, again, our thesis has always been that if you want to target plaque, you really have to get rid of it. And, you know, certainly Gantanirumab and also going all the way back to Bapinoizumab has taught the field that a little bit of plaque reduction doesn't really get you anywhere. So I don't think that you could approach this as saying, well, let's target monomers, and then we need a little bit of plaque reduction. I think that probably would not end up being successful.
spk08: And Eric, to your note, just to clarify, are you aware of any oligomer binding properties for psilocybin? I mean, it's almost a pure monomer targeting antibody, is my understanding.
spk02: Well, and that's always been mine. Now, you know, you can always find publications where somebody shows a little binding to this or to that, and typically those are in, you know, in vitro studies, and so they're kind of artificial conditions. But all the data that I'm aware of has really been quite consistent that actually solanazumab is remarkably specific for monomers.
spk08: Really, 193 has been developed to principally target oligomers and not have much interactions with monomer.
spk15: Understood. Thank you so much.
spk16: Please stand by for our next question.
spk01: Next question comes from Judah Firmer with Credit Suisse.
spk16: Your line is now open.
spk18: Yeah. Hi. Good morning, guys. Thanks for taking the question.
spk19: Just getting back to the protocol amendment and probably the key question we got around that, you know, how are you thinking about potential impact to a commercial profile and I guess a reimbursement profile for 193? does this change the story in some way in that, you know, you might need MRI monitoring when you thought you might not have needed that prior? And, you know, have you had any preliminary discussions with payers on sort of, you know, acceptable levels of RER, how that might compare to Lucanumab or anything else that comes between now and then?
spk08: Yeah, thanks, Judah. Good question. So, I think, you know, in terms of A lot wrapped into that. I think in terms of the safety profile, we continue to believe that oligomer targeting antibodies such as 193 may offer an attractive safety profile relative to plaque targeting antibodies. And Leukemia does have a rate of RAE in 12.5%. So that's sort of a safety benchmark that we use internally. in terms of the dropping the 25 megs per kg uh you know that becomes a dose level but that may be more amenable to a subcutaneous formulation so that was actually part of the consideration in early february as we contemplated what to do really with cohort seven like what made the most sense from a programmatic standpoint so that was um you know and we'll see we've as i mentioned earlier on the call we've looked at a couple of different options as to moving 193 at some point into a subcutaneous format. And that modified dose for cohort seven does provide important PK information that will help inform the prospects of that. We haven't had any payer interactions per se. I do think that as we've envision the next study, we've always anticipated, you know, routine MRI scans for safety and other, you know, for general development purposes. I think that study is much more likely to be instructive as to what would be required commercially. So we just won't have enough, you know, chronic exposure in this, in the intercept AD study to definitively say what's required from a safety and really what's required from the overall, you know, this is a phase one study in terms of the Thank you.
spk16: As a reminder, to ask a question, please press star 11 on your telephone. Stand by for our next question.
spk01: I show no further questions at this time.
spk16: I would now like to turn the conference back to Alex for closing remarks.
spk12: Thanks, Michelle. Thanks, everyone, for joining us today. As always, we're available for follow-ups if you have any additional questions, so please reach out to us at the company, and have a great Monday.
spk16: This concludes today's conference call. Thank you for participating.
spk01: You may now disconnect. Hey, guys. It looked like you Thank you. music music Thank you. Thank you for standing by.
spk16: Welcome to Acumen Pharmaceuticals' full year 2022 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 your speaker today, Alex Braun, Head of Investor Relations. Please go ahead.
spk12: Thank you, Michelle. Good morning, and welcome to the Acumen Conference Call to discuss our business update and financial results for the year ended December 31st 2022. With me today are Dan O'Connell, our Chief Executive Officer, Dr. Eric Siemers, our Chief Medical Officer, and Matt Duga, our Chief Financial Officer and Chief Business Officer. Before we begin, we encourage listeners to go to the Investors section of the Acumen website to find our press release issue 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 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 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 will open the call for q a now i'll turn the call over to dan thank you alex good morning and thank you everyone for joining us today 2022 was a pivotal year for acumen marked by
spk08: significant progress advancing the critical development of ACU193, the first monoclonal antibody tested in Alzheimer's patients that was discovered and developed to selectively target soluble amyloid beta oligomers. Over the course of the year, we received fast-track designation from the FDA, added experienced and talented members to our team to guide our development plan, and completed important CMC work to scale production in anticipation of upcoming Phase II study. In February of this year, we announced the completion of enrollment in our Phase I Intercept AD trial, which sets us up to report top-line results in the third quarter. The Intercept AD results are anticipated to provide important proof-of-mechanism information for AC193, including safety, pharmacokinetic, and target engagement data that Eric will speak to in greater detail shortly. Thus far, we are encouraged by preliminary PK and blinded safety data observed to date. which supports our thesis that at appropriate dose levels, an antibody selected for A-beta oligomers, such as AC193, may provide a differentiated product profile in the fight against Alzheimer's disease. I want to briefly comment on the protocol that we disclosed in early February, just prior to completion of enrollment. Based on the preliminary CSF PK data observed that indicated that AC193 antibody concentrations were in excess of reported A-beta oligomer concentrations, And considering the blinded case of RAE observed in the cohort four at the time, we opted to amend the trial's protocol to reduce the dose level in cohort seven, our last cohort, to 25 mg milligrams per kilogram every two weeks. We believe the 25 mg per kilogram dose every two weeks in cohort seven will provide us with more meaningful dose ranging, safety, and target engagement information in support of establishing clinical proof of mechanism for ACU193 in this study. Looking ahead, we are actively preparing for Phase 2-3 activities in anticipation of successful results from our Phase 1 study in the third quarter. We will request an end of Phase 2 meeting with the FDA to be held in the fourth quarter to discuss the design of our Phase 2-3 study, a design that incorporates an interim decision to expand the study from a Phase 2 size to a Phase 3 study. On the CMC front, we remain well positioned to scale manufacturing to have sufficient drug supply to meet requirements of our current development plan. In addition, we have made meaningful progress in assessing various options for potential development of a subcutaneous formulation as part of our AC193 product development plans. We intend to continue to explore such options based on data generated in our phase one study. On a final note, I would like to acknowledge the significant change in the overall treatment landscape for Alzheimer's disease over the past year. The positive clarity AD results for licanumab in the fall of 2022 meaningfully advanced the field. Because it is a proto-fibril targeting antibody, licanumab has driven renewed interest in the role that soluble aggregated A-beta species, such as A-beta oligomers and A-beta proto-fibrils, may play in the pathology of Alzheimer's. and how targeting these species can contribute to safe and beneficial treatment options for patients. Furthermore, the negative graduate study results for gantanarumab, a plaque-targeting antibody, support the hypothesis that for plaque-targeting antibodies, clinical efficacy can only be achieved with a near-complete removal of amyloid plaque. Most recently, the negative A4 results for selenazumab, an A-beta monomer-targeting antibody, reinforce the evidence that targeting monomers may not be a viable means to produce clinical benefit, even when intervening at the earliest stages of disease. Aside from these clinical data sets, the field is also seeing advancement with both fluid and imaging biomarkers, which continue to develop rapidly and could offer a diverse set of future alternatives that are predictive of effects in AD beyond amyloid PET imaging. Given the size of the disease burden, we are encouraged by the additional clarity of these data have provided to the field, and look forward to additional upcoming data from many companies with differing approaches. At Acumen, we recognize the importance of these advances and strive to use the learnings to inform our approach to developing AC-193 as a potential disease-modifying therapy in early Alzheimer's patient population. To this end, we look forward to sharing our Intercept-AD top-line data with you in the third quarter, a data set we believe will be informative from a safety target engagement and dose-ranging perspective. With that, I'll hand the call over to Dr. Siemers. Eric?
spk02: Thanks, Dan, and good morning, everyone, from Gutenberg, Sweden, where I arrived today to attend the ADP meeting that's happening this week. We are delighted to have completed enrollment of our Phase 1 Intercept AD trial as we announced in February. This is a true testament to the hard work and dedication shown by our team and by the investigators the site personnel, our CRO, and most importantly, the patients, families, and their study partners. I would like to thank them for their ongoing support in advancing our understanding of the potential of ACU193. With top-line results now expected in the third quarter, I'd like to take a few minutes to provide some context around our expectations for those results. Our phase one study is a randomized placebo-controlled first in humans, sad, mad study with 65 patients enrolled with early Alzheimer's disease. The objectives of the trial are to evaluate safety and tolerability, evaluate PK and establish target engagement for ACU193 administered intravenously. The primary trial endpoints are focused on safety and PK. As far as safety, And in support of our protocol amendment disclosure in February, we announced that we had seen two cases of asymptomatic ARIA-E as of January 31st in this blinded trial. Based on the preclinical data, we had expected less ARIA than that seen with some other monoclonal antibodies at their highest doses. And the preliminary blinded cases we observed in the first quarter were aligned with that expectation. We remain encouraged that the safety profile of ACU193 to date will support targeting soluble amyloid beta oligomers. We also note that ARIA-E cases do provide evidence of central pharmacology, that ACU193 crosses the blood-brain barrier in sufficient quality to have a central effect. Keep in mind as well that cohort six is ongoing at a dose of 60 milligrams per kilogram every four hours, which is considerably higher than doses pursued by several other antibodies, including aducanumab, lacanumab, and dinanumab. The preliminary PK data we disclosed support this line of thinking. We know that preliminary CSF PK data from our 25 milligram per kilogram cohort showed ACU193 levels that were substantially above the levels reported for oligomers. Oligomer concentrations in CSF are generally reported to be less than 2 picomolar, which is a very low concentration compared to other soluble species such as A-beta monomers. If this is the case, a dose of 25 milligrams per kilogram every four weeks could be a viable dose to test in the next phase of our program for ACU193. Turning to target engagement, as many of you know, the assay for our target engagement is designed to measure the complex of A-beta oligomers bound to ACU193 in CSF, simply detecting the complex after administration will satisfy the target engagement threshold. In non-clinical studies, Merck was able to measure these complexes in brains from transgenic mice after ACU193 administration using an immunoassay. Acumen is developing a conceptually similar methodology for the Intercept-AD trial to look at CSF using proprietary materials that increase the assay's specificity for both ACU193 and Aβ oligomers, and thus specificity for the ACU193 oligomer complex. Importantly, we will be performing test runs of this assay prior to our database block to ensure the sensitivity is optimized. Exploratory measures that are built into our Phase I study include computerized cognitive testing for signs of early effects and arterial spin labeling with MRI scans to understand if cerebral blood flow has increased. While these analyses are exploratory and are unlikely to result in a statistically significant signal in this small study with a short treatment duration, the detection of a potential signal would suggest important central pharmacodynamic effects. Depending on our Phase I results, these measures may be employed in subsequent clinical trials using ACU193. Turning toward our upcoming Phase II-III clinical study, the team has been working diligently to develop an algorithm that would include evaluations by the Data Monitoring Committee of clinical measures computerized cognitive testing, and biomarkers to enable a go-no-go decision to scale a Phase II study to a Phase III study. We are confident that the algorithm we finalize will provide a rigorous method to allow a go-no-go decision to expand from Phase II to Phase III. And with that, I'll turn the call over to Matt.
spk20: Thank you, Eric. Good morning, everyone. Our complete year-end 2022 financial results are available in the press release we issued this morning and in our 10-K that will be filed later this afternoon. We ended 2022 with approximately $193 million in cash and marketable securities on the balance sheet, and we continue to expect that cash runway to last through 2025. R&D expenses were approximately $32.4 million in 2022. The increase over the prior year was primarily due to the increased activity in the ongoing Intercept-AD trial. G&A expenses were $12.9 million in 2022, and the increase over the prior year primarily the result of increased headcount. This led to a loss from operations of $45.2 million in 2022. Regarding our exposure to Silicon Valley Bank, we had approximately $1.7 million in cash in our operating accounts there as of March 10th, 2023, all of which has been moved to another institution. In conclusion, we remain well resourced to execute against our strategic priorities over the next few years. We look forward to reporting top line data for Intercept AD in the third quarter of 2023, and we'll 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?
spk16: As a reminder, to ask a question, please press star 11 on your telephone and 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.
spk01: First question comes from Paul Matisse with Stifel.
spk16: Your line is now open.
spk11: Hey, thanks so much.
spk13: On the interim analysis that you're planning, how is this similar or different to just your typical interim? where a blinded group looks at the data, recommends sample size adjustments, or can stop the study. And then I have one follow-up. Thank you.
spk08: Hey, thanks, Paul. Yeah, I was going to invite Eric to comment on that. I mean, there's a simple explanation, I think.
spk02: Right, yeah. So, well, of course, you're right. A lot of times, interim analyses are done to adjust sample sizes. And usually that's based on purely a statistical look at the data. One thing I should just emphasize is that it's not a futility analysis, and so everyone should be clear about that. But the interim analysis itself is actually quite a bit more complex than the sort of thing that's done just to adjust sample size. In other words, we, and as I discussed, we're developing the algorithm But we'll look at the clinical measures. I mean, we have things like the CDR cell boxes in the trial. And so in a little study like this, it would be surprising to see a drug effect there. But we'll look at those things. We'll look at the ADOS-COG. And again, we'll look at our computerized cognitive testing, some of the MRI results, and also some biomarkers. And we will develop this algorithm to give to the DMV. And the DMV, if the algorithm is successful, so to speak, then the study will be scaled up to the size of phase three study. If it doesn't fulfill the algorithm, then it will be completed as a phase two study. So at a minimum, we'll complete the next study as a phase two study.
spk13: Okay, thanks. And then you've talked a little bit more about enthusiasm. Oh, sorry, Dan, go ahead.
spk08: Well, I was just going to say, and Paul, of course, the 2-3 design is really intended to be the fastest path to a potential registration for the product, hypothetically. So if that's not obvious, I just want to make that comment.
spk13: No, that's clear. Thank you. And then you've talked more about confidence in this 25-megapartic dose. Is that based on anything you're seeing? I guess, what if you don't see a clear dose response on a target engagement assay? Does that mean you might take forward a lower dose? Like, how are you guys thinking about these scenarios in the second half of this year? Thank you.
spk08: Yeah, thanks, Paul. So, I mean, I'll just comment. I think we really made the protocol amendment in February based on some observations in the study, including the PK and the RA case. So, I don't think we're not in a position to continue to roll out information until the third quarter. I do think that when we made the decision to modify the cohort seven dose level, it became sort of obvious to us at the time, given that might be a viable dose in terms of just the overall drug required to dose at 25 megs versus 60 every couple of weeks, which was the original concept for cohort seven. So I think we're really encouraged that sort of the overall thesis for the AC-193 is very much intact and are confident that the modification for cohort seven in particular gives us more information Kind of with a mid-dose level between the 10 mg per kg and the 60 mg per kg that's ongoing in cohort six. Thank you.
spk01: Yeah.
spk16: Please stand by.
spk01: Please stand by for our next question.
spk16: Next question comes from Tom Schrader with BTIG. Your line is now open.
spk04: Thanks. If you had more to say, it's almost the same question anyways. I have a little bit of a question about the world of plaque removal. There's still some controversy about how important it is. I think we might call it confusion, but what's your sense about where the FDA is on that issue and how important that would be in an interim look. Are they going to be okay with a trial that is ignoring plaque removal or is that kind of all your own business? But given that it's kind of unknown how important it is, how much do you have to think about it going into a trial with an interim look? Thanks.
spk02: So maybe I can... So from an FDA standpoint in the plaque reduction, that was for an accelerated approval. In other words, FDA considered plaque reduction to be, quote, reasonably likely to predict a clinical effect. And that led then to the accelerated approval. Now, one of the things that I think has become even more clear, I think it was clear before, but as Dan mentioned, if you're going to target plaque, you have to essentially get rid of all of it to have any clinical efficacy. And I think that, again, Neuromab graduate studies demonstrated that very well. And in our case, this interim analysis that we're doing is not really in anticipation of an accelerated approval or any sort of a regulatory approval. It's for our internal decision-making in terms of phase two study and then scaling it up to a phase three study. So, there really isn't a regulatory piece to the interim analysis as we're doing it. All right, great. Thank you.
spk08: And I think, and Tom, just to, you know, we are doing amyloid PET in the current study and would anticipate doing it, again, not that we would expect to see it move dramatically, but just as a kind of the convention standard practice.
spk03: Okay, great. Thanks for the answer.
spk16: Please stand by for our next question. Our next question comes from Collin Bristow with UBS. Your line is now open.
spk14: Morning, everyone. This is Ting Ong for Collin. Thanks for taking our question. So, we have two questions and a follow-up if we may do. The first question is for patients in the cohort six in MAD. In our last correspondence, you noted they have not yet received MRI scans. Just wondering if they have received by now, and if so, could you provide any safety updates? And then second question is more general. Do you think there's a general correlation to dose a oligomode-targeted antibody more frequently than those core plaque targeted ones, given the faster turnover kinetics here? Thank you.
spk08: Hi, Teng. Thanks for your question. I think on the first one, as I mentioned, and as Eric mentioned, we disclosed the ARIA cases back in February in conjunction with the protocol amendment. We, and Eric just noted, the Cohort 6 continues to proceed per protocol. So we haven't provided any other information in terms of ARIA cases and so forth. I think maybe I would turn it to Eric in terms of the dosing frequency question with respect to an oligomer antibody. I mean, I think, yeah, Eric, maybe you would care to comment on that aspect of Ting's question.
spk02: Yeah, so it's a really interesting question. And I think what you're really asking is that for an antibody that targets plaque, um, the antibody binds to the plaque. It actually starts an inflammatory response with microglia. Um, and so it's not necessarily so dependent on the PK that you would see even in spinal fluid at any given time, since once it's found a plaque, it's obviously not going to show up in spinal fluid. In our case, um, it may be a little bit more straightforward in that we do want to show that we're in antibody excess. In other words, that you have more antibody there than you have oligomers. And that was one of the reasons why the preliminary data, CSFPK data in cohort three, which is 25 mg per keg, really was so exciting for us is that we were in antibody excess. And so, The situation is a little bit different, you're right, but I think in our case, again, I think the important thing is to show that we're in antibody excess.
spk14: Thank you much. Sorry. Yeah. Yeah. Sorry. Thank you for providing all the colors. Really helpful. We have a follow-up question, which kind of like echoing Tom's earlier question, also what Dan has mentioned in the prepared remark on A4. So we understood solonizumab is primarily monomer targeting, but it has some capacity to oligomers, though it does not touch any plugs. So there were some concerns following solanizumab's complete failure that maybe some level of plaque clearance are still needed for the best treatment efficacy. We are curious to hear your thoughts, and if you could provide any colors to us, it would be greatly appreciated. Thank you so much.
spk02: Well, Dan, you want me to go ahead and take that since I have a bit of familiarity with solanizumab? First of all, for the A4 result, of course, there's really just been press releases and we'll need to see all the data. What for me was a bit surprising and interesting is that actually, even though there were no statistical differences, the trends actually favored placebo over drug. And that was at a dose of 1,600 milligrams every four weeks. Well, when solanazumab was given to people with mild Alzheimer's disease at 400 milligrams every four weeks, the trends were very consistent in terms of favoring drug. So why you didn't see that with the higher dose of solanazumab is a bit of a mystery, and I think we'll have to see all the data to understand that. You know, again, our thesis has always been that if you want to target plaque, you really have to get rid of it. And, you know, certainly getting Neuromab and also going all the way back to Bapenoizumab has taught the field that a little bit of plaque reduction doesn't really get you anywhere. So I don't think that you could approach this as saying, well, let's target monomers, and then we need a little bit of plaque reduction. I think that probably would not end up being successful.
spk08: And Eric, to your note, just to clarify, are you aware of any oligomer binding properties for psilocybin? I mean, it's almost a pure monomer targeting antibodies, my understanding.
spk02: Well, and that's always been my, now, you know, you can always find publications where somebody shows a little binding to this or to that, and typically those are in, you know, in vitro studies, and so they're kind of artificial conditions. But all the data that I'm aware of has really been quite consistent that actually solanazumab is remarkably specific for monomers.
spk08: Really, 193 has been developed to principally target oligomers and not have much interactions with monomer.
spk15: Understood. Thank you so much.
spk01: Please stand by for our next question.
spk19: next question comes from judah firmer with credit suisse your line is now open yeah hi good morning guys thanks for for taking the question um just just getting back to the the protocol amendment and and probably the key question we got around that you know how are you thinking about potential impact to a commercial profile and and i guess a reimbursement profile um for 193 Does this change the story in some way in that, you know, you might need MRI monitoring when you thought you might not have needed that prior? And, you know, have you had any preliminary discussions with payers on sort of, you know, acceptable levels of RER, how that might compare to Lucanumab or anything else that comes between now and then?
spk08: Yeah, thanks, Judith. Good question. So, I think, you know, in terms of A lot wrapped into that. I think in terms of the safety profile, we continue to believe that oligomer-targeting antibodies such as 193 may offer an attractive safety profile relative to plaque-targeting antibodies. And Leukemia does have a rate of RAE in 12.5%, so that's sort of a safety benchmark that we use internally. in terms of the dropping the 25 megs per kg uh you know that becomes a dose level but that may be more amenable to a subcutaneous formulation so that was actually part of the consideration in early february as we contemplated what to do really with cohort seven like what made the most sense from a programmatic standpoint so that was um you know and we'll see we've as i mentioned earlier on the call we've looked at a couple of different options as to moving 193 at some point into a subcutaneous format. And that modified dose for cohort seven does provide important PK information that will help inform the prospects of that. We haven't had any payer interactions per se. I do think that as we've envision the next study, we've always anticipated, you know, routine MRI scans for safety and other, you know, for general development purposes. I think that study is much more likely to be instructive as to what would be required commercially. So, we just won't have enough, you know, chronic exposure in this, in the intercept AD study to definitively say what's required from a safety and really what's required from the overall, you know, this is a phase one study in terms of the Thank you.
spk16: As a reminder, to ask a question, please press star 11 on your telephone. Stand by for our next question.
spk01: I show no further questions at this time.
spk16: I would now like to turn the conference back to Alex for closing remarks.
spk12: Thanks, Michelle. Thanks, everyone, for joining us today. As always, we're available for follow-ups if you have any additional questions, so please reach out to us at the company, and have a great Monday.
spk16: This concludes today's conference call. Thank you for participating. You may now disconnect.
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