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spk08: Good day, and thank you for standing by. Welcome to the Acumen Pharma Q3 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. 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. Please begin.
spk01: Thank you, Latonya. Good afternoon and welcome to the Acumen conference call to discuss our business update and financial results for the quarter ended September 30th, 2022. With me today are Dan O'Connell, our Chief Executive Officer, Dr. Eric Siemers, our Chief Medical Officer, and Matt Zuga, our Chief Financial Officer and Chief Business Officer. Before we begin, we encourage listeners to go to the Investors section of the Acumen website to find our press release issued this afternoon and 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 afternoon 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 any 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. Now I'll turn the call over to Dan.
spk10: Thank you, Alex. Good afternoon, and thank you for joining our call today. The third quarter was characterized by increased momentum on several fronts for Acumen. The highlights include improved enrollment in the ongoing Intercept-AD trial, fast-track designation for ACU193 from the FDA, and publication of our Intercept-AD trial design and anticipated critical development plan for ACU193. I'd also like to note that our progress comes amid renewed optimism in the Alzheimer's field due to Leucanumab's recent positive clinical trial results, which reinforce the role that soluble A-beta species may play in the disease. I'll start today by discussing our business and operational highlights, and Dr. Siemers will then provide some comments and context on the recent developments for both ACU193 and the Alzheimer's field as a whole. Turning to updates from our Phase I Intercept AD clinical trial of ACU193, the first monoclonal antibody discovered and developed to selectively target soluble A-beta oligomers to enter the clinic. Enrollment is now ongoing at 17 active sites in the U.S. As previously noted during the initial stages of the trial last year, in early 2022, we experienced slightly slower patient enrollment than originally projected. However, in the last four months, patient recruitment and enrollment has accelerated considerably. We are working closely with our partner CRO and clinical sites to ensure timely scheduling of the various visits per the study protocol, which also include imaging conducted at third-party sites. We are pleased that enrollment method is accelerating ahead of the holiday season. I should also note we are very encouraged with the safety profile observed to date in the trial, which aligns with our expectations for ACU193. Based on the trial current status, we are targeting enrollment completion in the first quarter of 2023 and reporting top line results in the second half of the year. In anticipation of moving quickly to a subsequent clinical trial, I want to provide an update on some of the pertinent Phase 2-3 activities that have been completed or are underway. On the toxicology front, the in-life phase of the chronic GLP toxicity study has been successfully completed and the final study report is expected in the first quarter of 2023. Our chemistry manufacturing and controls team, led by Leanne Shank, who joined as head of CMC this June, is working diligently to ensure clinical drug readiness in support of the planned Phase 2-3 study for AC193. We have completed development of our new drug substance production process and produced our first Phase 2-3 drug substance manufacturing lot, We have also completed development of the lyophilized formulation of our drug product. Based on this progress, we are well positioned to scale manufacturing and have sufficient drug supply to meet the requirements of our current development plan. As part of these CMC efforts in our application for the non-proprietary name for ACU193, we have confirmed ACU193 as a consensus IgG2 subclass antibody, which is consistent with our hypothesis that the reduced effector function of this subclass should favorably influence safety outcomes for AC193. We continue to pay close attention to the development of subcutaneous formulations of other antibody products in the Alzheimer's field. Dependent on observed patient dosing information generated in our phase one study, we will assess options for potential development of subcutaneous formulation as part of our AC193 product development plans. Though we were acutely focused on advancing Intercept AD and readying for the next phase of our development plan for the product, we do continuously evaluate the landscape for opportunities that fit with our capabilities and expertise. We are committed to being highly selective in the deployment of capital and evaluating such opportunities, but also appreciate that pipeline expansion could be a path to greater value creation in the future. On a final note, during the third quarter, we continue to expand our senior leadership team adding Derek Meissner as chief legal officer. Derek's legal career has spanned more than two decades at both biotechnology companies and investment firms, and he's a valuable addition to the company and our senior leadership team. With that, I'll hand the call over to Dr. Eric Siemers. Eric?
spk12: Thanks, Dan, and good afternoon, everyone. We are delighted that the FDA recently granted Fast-Track designation to ACU193 for the treatment of early Alzheimer's disease. This underscores the potential clinical utility of ACU193 in this patient population with such a high unmet need for additional disease-modifying therapies. To this end, we are committed to designing an efficient and innovative clinical development plan for ACU193. We recently published an article in the Journal for Prevention of Alzheimer's Disease that outlines the design of our ongoing phase one intercept AD trial for ACU193 and the planned criteria for advancing to a phase two, three clinical trial based on recent advancements in clinical research methods in Alzheimer's disease. As we detail in the article, the criteria for advancing from a phase one to a phase two, three trial will be based on safety and tolerability, pharmacokinetic parameters, and target engagement at doses that have acceptable safety and tolerability. While we have not finalized the design for the Phase 2-3 trial, we do anticipate it would begin with a patient sample size typical of a Phase 2 trial. An interim analysis would then determine whether to increase the sample size to meet the statistical power of a typical Phase 3 trial. This interim analysis may be based on several cognitive measures and various biomarkers, for example, a correlated tau in the blood and cerebrospinal fluid. Tending discussions with regulators, if the interim analysis is positive and the trial is expanded, the Phase 2-3 trial could potentially serve as a registration trial. Considering the design of a Phase 1 intercept AD study in patients with early AD, and the adaptive design of the planned Phase 2-3 study, this innovative clinical development plan could allow us to evaluate oligomers more rapidly as a promising therapeutic target for Alzheimer's disease patients. Looking at the field more broadly, the recent positive Phase 3 clarity AD trial results from the CANAMADS underscore the progress the field is making in the fight against Alzheimer's disease. It has also driven a renewed look at the role that soluble A beta species rather than deposited amyloid plaques may play a major role in the pathology of Alzheimer's disease. The Gantt and Urimath graduate study results announced today describing a negative readout for a plaque-targeting monoclonal antibody further supports the importance of these soluble species. The amount of plaque lowering with Gantadurumab was reportedly less than expected, and we look for a more complete assessment of the relationship between plaque lowering and slowing of disease progression at the upcoming CTAD meeting. Lacanumab was designed to target what are known as protofibers, which are soluble and is a similar approach to ACU193 targeting A-beta oligos, which are also soluble. We view these similarities as important to the ACU193 program, so I'll take a minute to discuss them in more detail. The relationship between A-beta and Alzheimer's disease is complex in that A-beta may exist as soluble species, which include monomers, oligomers, and protofibers, or insoluble species, which include fibrils and amyloid plaques. The fact that amyloid plaques begin to deposit 15 to 20 years prior to the onset of cognitive symptoms is now well established. Following the appearance of plaques, cow hyperphosphorylation begins to occur with the development of neurofibrillary tangles, and synaptic degeneration begins with the inevitable eventual occurrence of cell death in the brains of patients with Alzheimer's disease. This temporal course and other data suggest that depositing amyloid plaques are not themselves toxic. However, we believe that amyloid plaques can be one source of the soluble A beta species that are toxic, which includes the proto-fibrils targeted by licanumab, as well as the forms of oligomers that are targeted by ACU193. Many years of research indicate these soluble species inhibit a normal electrophysiologic activity of brain cells known as long-term potentiation, and they disrupt neuronal function. Considering these data together, since ACU193 and leucanumab both target similar soluble A-beta species, we believe the recent announcement of a statistically significant benefit from leucanumab in a Phase III trial improves the probability of success for ACU193. Importantly, leucanumab exhibited a lower rate of ARIA-E than other monoclonal antibodies that directly target plaque, even though it does lower plaque load based on PET imaging. This finding suggests that targeting soluble Aβ species such as protofibrils or Aβ oligomers rather than plaque directly may lead to a better safety profile. Gantanerimab's ARIA rate of 25% announced today further highlights the safety challenge with antibodies that directly target plaque. A somewhat lower rate of ARIA for Gantanerimab compared to Atacanumab and Dananumab would be consistent with less plaque reduction for Gantanerimab compared to Atacanumab and Dananumab. ACU193 appears to have little or no binding to plaques based on animal studies and ex vivo studies using autopsied human brain tissue of patients with Alzheimer's disease. For these reasons, we are hopeful that minimal or no ARIA will occur with ACU193 in the clinic. The development of therapies with less ARIA and greater or equal efficacy will continue to be an investment opportunity for the foreseeable future and Alzheimer's disease. And with that, I'll turn the call over to Matt.
spk09: Thank you, Eric. Good afternoon, everyone. Our complete third quarter and year-to-date 2022 financial results are available in the press release we issued this afternoon and in our 10-Q filed today. With approximately $200 million in cash and marketable securities on the balance sheet at September 30th, We ended the third quarter in a strong financial position, which provides us with the runway to achieve multiple clinical development milestones. Based on our current operating plan, we expect our cash to last through 2025. R&D expenses were approximately $8.3 million in the third quarter. The increase over the prior year period was primarily due to the increased activity in the ongoing intercept AD trial. G&A expenses were $3.1 million in the quarter, with the increase over the prior year period primarily the result of increased headcount. This led to a loss from operations of $11.4 million in the quarter. In conclusion, we remain well financed to execute against our strategic priorities. We look forward to reporting top-line data for Intercept AD in the second half of 2023 and will remain 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?
spk08: Certainly. Ladies and gentlemen, if you do have a question, please press star 11 on your telephone. Please stand by while we compile the Q&A roster.
spk07: One moment. And our first question will come from Paul Matisse of Stiefel. Your line is open.
spk04: Hi, this is James on for Paul. Thanks for taking our question. Maybe just to clarify kind of on the exact kind of dynamics in enrollment and how they're playing in, you know, with the delay here. Just be great to understand, you know, I see you're kind of expanding clinical sites, but it'd be great to understand, you know, what you think is maybe causing But the way, if at all, if that's kind of what is baked into the, you know, later readout in second F23. And then just a second question specifically on, you mentioned, you know, everything in the blinded safety data looks good, but I was wondering if you could speak to anything more specific and if you're seeing kind of any instances of ARIA or any sort of specific signal, that'd be great. Thanks so much.
spk10: Thanks, James, for your question. We were anticipating both of those coming through early in the Q&A session, so thanks for putting them on the table. In terms of the updated guidance for 23, you know, I think many of the aspects of kind of where we are with enrollment are kind of legacy from late 21 and early 22. So the momentum has picked up considerably, which is why we've elected to guide to completion of enrollment in the first quarter and In terms of top line results, we've traditionally guided within a six-month window and have sort of essentially shifted to the back half of the year, you know, based on where we are in the study. In terms of safety, I can't go further than to say that, you know, as of where we are today, we are very encouraged at what the blighted data have suggested on review, kind of standard review as the study has progressed, and consistent with kind of the original thesis for AC193, and its safety profile on various aspects of clinical safety measures. But I won't elaborate more than that, but I think we are, as I've stated, encouraged with what we have observed to date. Great. Thanks.
spk08: One moment. Our next question will come from Tom Schrader of VTIG. Your line's open.
spk11: Good afternoon. Thanks for taking the question. I had a question on the assays to measure A-beta oligomers directly in their complexes with antibodies. How easy are those? How ready are those sort of for prime time? Is that something you think you could use from an interim look, and is it something you think you could follow with time, or is it a more elaborate assay? I'm just curious where that is in terms of being useful in a clinical trial setting.
spk12: Well, yeah, thanks for the question. It's a very pertinent one. That assay is under development. We have a prototype of that already, but the sensitivity is being increased. I should mention that rather than trying to measure oligomers directly, what we are trying to measure is the oligomer bound to the antibody, bound to 193. And the reason for that, as I think you probably know, the reason is the oligomer concentrations are very low in spinal fluid. They're symptomatic in range. And so you're trying to take just the oligomer concentrations as low to begin with, and then when it gets lower, it just becomes technically not feasible. But what we do want to do in our study is show the target engagement, and really by definition, that is antibody 193 bound to the oligomers. That concentration, obviously, will go up with dosing. And that's the assay that we're actually working on. Now, to get to the question about interim, there's no interim analysis for our phase one study, per se. We do blinded looks at safety data routinely. But there's no formal interim analysis. Now, we will do an interim analysis for the phase two threes, as I mentioned. We're still working out the details of what all might go into that. I think our target engagement really will probably come out of this phase one study. I don't know that we'll need that as part of the interim in the phase two to three, but again, we haven't finalized the design of the phase two, three study yet.
spk11: Okay. If I can follow up with a question from your prior life, where are you in your thoughts on using cow pathology in as a recruitment? Is that very much still in flux? Do you think it's a good idea? Just, you know, you're going to be one of the next people to design a big trial. Right.
spk12: Yeah, it's a very interesting question. I think the programs that are using TAL topology as part of an inclusion-exclusion criteria, and as you know, it's sort of a Goldilocks approach where you have to have a little bit of TAL but not too much. I think from a scientific standpoint, that's very defensible. I think from a practical standpoint, I'm not sure how that would play out, especially in clinical practice. I mean, the idea that you have to be positive for amyloid and then positive for tau, and by the way, it has to be just the right amount of tau, not too much, not too little. I think that from a practical standpoint could be quite difficult in practice. But scientifically, I understand the rationale for
spk11: Got it. Thanks for the detail.
spk06: One moment. Our next question will come from Colin Bristow of UBS.
spk08: Your line is open, Colin.
spk05: Hi, this is Yihan for calling. Thanks for taking our question. We have two questions. So the first one is that what are you specifically looking for or paying attention to add the CTAD presentations, for example, for your competitors? And the second question is that, what level of cognitive slowing do you think it is clinically relevant? Thank you.
spk10: Thanks, Xi. So I think, oh, go ahead, Eric.
spk12: Well, yeah, so in terms of the CTAD meeting, and I think you referred to the presentation zone, which are on consecutive days, you know, we're looking forward to those presentations. We've seen press releases for both studies. Obviously, one was positive and one was negative, but to really understand the results, I think we need to see more of the data, and we're looking forward to seeing those presentations. As far as your second question about being clinically meaningful, this is actually has become quite an important question, I think, for the field. And there's a number of efforts to understand this better, including efforts by the Alzheimer's Association. Generally, there's been a relatively broad consensus that slowing disease progression by 25% or more is clinically meaningful. So 27% for leucanumab, based on that consensus number. it would cross that threshold. The other thing to point out is that I don't think anyone expects that one drug will cure this disease. And so if licanumab slows progression by 27%, the next drug that's used in combination therapy with licanumab might slow it another 25%, 30%. By the time you get two or three drugs having an effect, then it will be very, very obvious that this is clinically meaningful. But you have to start someplace, and you can't start with the expectation that a single drug is going to cure the disease or have some huge effect on the disease. I think that's what the field is trying to understand right now, but generally, I think I personally think, and I think a lot of people in the field would think that 27% crosses the threshold for clinical meaningfulness.
spk06: Thank you, very helpful.
spk07: One moment. Our next question will come from Judith Brummer of Credit Suisse. Your line's open.
spk03: yeah hi guys thanks for taking the questions first just Dan to follow up on on the enrollment commentary around you know issues from 2021 is is that largely coveted is there anything else you'd call out whether it's you know competing against other late stage trials or uh you know publicly available information from those late stage assets
spk10: Yeah, thanks, Judah. I think that the legacy issues in 21 were certainly COVID-mediated in terms of site activation and access to patients and getting stuff, standing up that study in the course of that pandemic. I think we've tried to get a sense of whether, to the best of our understanding, our sites were not necessarily competing with other studies at sites per se. We are doing a phase one study in patients. So I think that sort of the value proposition and the ask of, you know, getting patients enrolled, we refined that messaging on, you know, in multiple formats. And I think, you know, a lot of the steps that we've taken, a lot of kind of the ground game that we've rolled out over the course of this year has really impacted the current momentum in the study. So I don't think we can attribute the current progress, and I know we're obviously updating with a a shift to the back half of the year or second half of the year, but certainly the progress is a result of lots of little things that we've gotten right over the course of this year as we've made additions to the team and explored some other avenues towards recruitment. So, again, we're really encouraged with the progress and the operational kind of elements that are in play right now, which is why we've elected the guide to the first quarter enrollment.
spk03: Understood. And then just to follow up on what I think is new commentary in the prepared remarks around business development, and obviously you hired a chief legal officer. Anything you could elaborate on regarding, you know, your thoughts around business development? Would it be, you know, assets, you know, that would kind of work in conjunction with 193 or farther than that?
spk10: Yes, so I think the color I'd add to that, Judith, it's a great question, and thanks for picking it up there. I mean, we did want to make some comment in the script as business pipeline expansion has always been part of our business strategy. I think on the heels of Lacanumab's success, and as Eric noted, kind of what we perceive as a higher probability of success for 193, I think that the pipeline expansion criteria and priorities are more aligned with 193 going forward and looking for things that are complementary, supplemental, or additive to that asset. So beyond that, we don't have a specified timeframe. I do think as we look at deployment of capital, we're pretty judicious, and I think we are looking for things that are going to be near-term, have reasonable capital requirements, and also have specified milestones that would be appreciated and valued by shareholders and potential investors.
spk03: Great. Thank you.
spk08: One moment. Ladies and gentlemen, if you would like to ask a question, please press star, then zero. And excuse me, that's star 11 on your touchtone telephone. Again, please press star 11 for any questions. Our next question will come from Charlie Yang of Bank of America. And Charlie, your line is open.
spk02: Oh, hi. This is Charlie. I'm for Jeff. So I guess my first question is, you know, regarding how CTAP presentation from the Canon map and Canon Neuromap, like what kind of data, you know, specifically maybe more of a biomarker set that you would like to see that can, you know, help, you know, with, you know, gaining more confidence with your assets. And the second of all is regarding the computerized cognitive function test, Are there any kind of data or publication out there that can correlate that to the CDR solid boxes or other kind of more of a traditional cognition measurement and which we can use, you know, to somewhat kind of extrapolate the data from the phase one result? Thank you.
spk12: Well, yeah, thanks for that question. to dive into there. Yeah, as far as the CTAP presentations, there are a lot of biomarker effects that we'll be interested. Things like phosphatidyl and plasma or spinal fluid, I think, will be important for both, actually, compounds, lacanumab and cantinurumab. I think one of the important things about lacanumab, based on a press release, is that at least according to the press release, they were seeing very early separations between drug and placebo and clinical measures, even at six months, which is fairly remarkable. So we'll want to take a close look at the time course of the effect, which, and again, we haven't seen the graphs in the press release, but you expect the effect to grow over time with the disease-modifying therapy, so we'll be looking carefully for that. So I think those are, there's just a lot to look at in those studies and they will guide us in terms of the design of our phase two, three. As far as your other question regarding the COX-A computerized battery and its relationship with the CDR, even in our phase one study, we're measuring, we're doing CDR and obviously we're doing the COX-A battery This will be a small sample size, but it'll be the first attempt to actually see how those measures line up with each other. The CDR, as you may know, there's six items. Three of those are cognitive measures, three are more functional measures. That's a little bit different than our COGSATE battery where these are all computerized tests that, you know, you'd have to say were just cognitive measures. There may be a little dissecting out to be done too, but again, the reason for putting the computerized testing in this phase one study to start with is we think it should have less variability than the CDR summer boxes, which does have a certain amount of subjectivity to it. And actually, especially in a small phase one study, would give us a better chance of picking up a drug signal if one is there.
spk02: Thank you. Just a quick follow-up. Regarding the potential timing for Phase II initiation, is 2024 still roughly that timeframe for the trial to initiate, or is there going to be perhaps some sort of delay to either late 2024 or early 2025?
spk10: Yes, so Charlie, we have just guided the notion that we are looking to start that Phase II-III study as expeditiously as possible. We recently did receive the fast track designation from the FDA, which we think is going to be kind of reaffirms our notion that 193 potentially meets a large unmet need. We'll use the fast track as well as I think our previously disclosed plans to have an FDA engagement principally around an end of phase two type interaction with them to discuss the merits of the phase two, three design. We obviously will need the data set from Intercept AD as part of that briefing document, and there will be some regulatory time associated with the review and the discussion. But I think our goal is certainly to launch that Phase 2-3 study in early 2024, and I don't think we can guide beyond that, but I do think it's, based on our best estimates, certainly a 2024 event and Early in the year is our stated objective internally with the team.
spk02: Great. Thank you.
spk06: Great. I think that is it for Q&A.
spk01: Okay. That's it for Q&A. Thank you so much. for your interest, and should you have any questions, please don't hesitate to contact us at the company. All right, have a good night.
spk08: This concludes today's conference call. Thank you for participating. You may now disconnect.
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