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spk14: you know, associations which has been done with other biomarkers such as tau-181 or 217 where, you know, where at least some modeling-based studies can tell you to what extent you might see a change, you might need to see a change in these two biomarkers so as to kind of have an impact in either CDR-SP or IDRS. Thanks.
spk03: Yeah, maybe I can try to take that one too. As far as the use of the IDRIS versus the CDR Summit boxes, one of the things that was interesting in the recent draft guidance was that they no longer called out the CDR Summit boxes. And they've actually presented it at public meetings, the idea that in the previous draft guidance where they did mention the CDR Summit boxes, they didn't mean to endorse that as sort of the only scale. But what they did say in this most recent draft guidance is that a scale that's a composite of cognitive measures and functional measures may have real utility. And that's what the IDRIS is. It's a combination of cognitive measures from the ADAS-COG and then functional measures from a scale called ADCS-ADL. So we think that is very positive, actually, in terms of our use of the IDRIS. I would assume that Lilly, since in the trailblazer studies, that's their primary, they were happy to see that. So, yeah, I think that's a really good clarification from FDA in terms of that, those kind of scales. In terms of correlations between plaque reduction and clinical benefit, I think what's really becoming a consensus opinion now is that you actually have to get plaque below a certain threshold. And this is something that we at Acumen have been saying for a long time, is that if you're going to target plaque, you have to basically get rid of it. And so the goal seems to be, based on existing data, that you want to get below 25, say, centilloids, or at most 30. So if you want to, if your target is plaque, that's what you need to do. But again, our target's not plaque. Our target is oligomer. So it'll be interesting to see what effects we have on plaque. But with our differentiated mechanism, that's really not the construct of our development plan. Thank you.
spk08: I show no further questions at this time. I would now like to turn the call back over to Alex Braun for closing remarks.
spk12: Thanks, Michelle, and thanks for everyone for taking the time to tune in today. We are always available at the company for any follow-up questions. Please be in touch and have a great day. Thanks.
spk08: This concludes today's conference call. Thank you for your participation. You may now disconnect. Thank you. you Thank you. Thank you. Ladies and gentlemen, thank you for standing by. Welcome to Acumen Pharmaceutical's full year 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 like now to turn the conference over to Alex Braun, Head of Investor Relations. Please go ahead.
spk12: Thanks, Michelle. Good morning and welcome to the Acumen Conference call to discuss our business update and financial results for the year ended December 31st, 2023. With me today are Dan O'Connell, our Chief Executive Officer, Dr. Jim Dougherty, our President and Chief Development 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 Investor section of the Acumen website to find our 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 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 our corporate presentation, our press release issued this morning, and our most recent annual and quarterly reports filed with the SEC for important risk factors that could cause our actual results to differ materially from those expressed or implied in the forward-looking statements. We undertake no obligation to update or revise the information provided on this call or in the accompanying presentation as a result of new information or future results or developments. After our prepared remarks, we'll open the call for Q&A. Now I'll turn the call over to Dan.
spk06: Thanks, Alex. Good morning, and thanks to everyone who's joining us today. 2023 was a landmark year for Acoma. Our monoclonal antibody for the treatment of early Alzheimer's disease, AC193, which recently received its non-proprietary name, Sobernitug, delivered positive and exciting phase one results first presented at AAIC last July. You'll hear more about these results and how they serve as the cornerstone for establishing Sobernitug's differentiated therapeutic profile later on this call. More recently, we welcomed Dr. Jim Daugherty to Acumen as President and Chief Development Officer. Jim brings many years of experience in CNS drug development, and we're delighted to have him join our leadership team. We believe Acumen entered 2024 from a position of strength. We remain highly focused on the execution of key program and strategic initiatives to further establish the therapeutic potential of Subirnatug as a best-in-class treatment option for the substantial early Alzheimer's patient population. This month, we presented additional CSF biomarker data and details about our A-beta oligomer target engagement assay from our Phase I Intercept-AD study at the International Conference on Alzheimer's and Parkinson's Disease, or ADPD, in Lisbon, Portugal. We will also present analyses at the American Academy of Neurology meeting in Denver this April, which will introduce the development plan for Sobernatug and the results from Intercept-AD to this broad group of practicing and academic neurologists. If you haven't already taken a look at our phase one results in their entirety, I encourage you to go to our website where you can find archived presentations, webcasts, and releases detailing the suburnatug beta. For us, it's difficult to overstate the significance of these results and how they position suburnatug in the broader anti-A-beta field. We knew going into our phase one study that suburnatug possessed high selectivity for A-beta oligomers, Why does this matter? Unlike A-beta monomers and insoluble amyloid plaque, A-beta oligomers are toxic in distinct and important ways, in particular to neurons and synapses. Our approach with Subirnatug is to selectively target toxic A-beta oligomers and, as a consequence, to protect synapses in a way that may provide additional therapeutic benefit to patients, especially from an efficacy perspective. The intercept AD results exceeded our expectations and provide a substantial amount of data indicating Suburitug's drug effect. Overall, we see multiple paths towards Suburitug's next-generation differentiation on efficacy, safety, or both, any of which would be beneficial to patients as compared to existing options. I'm pleased to note that we are making great progress with the launch of our phase two study, Altitude AD, which remains on track to initiate in the first half of this year. Simultaneously, we are also on track to initiate our subcutaneous phase one study, expected for mid-2024. And with that, I'd like to hand the call over to Eric.
spk03: Thanks, Dan, and thanks to those listening in to the call today. I'm very pleased with the progress with the clinical development of Subirnatug last year and thus far in 2024. With our achievements last year, we are well positioned to potentially deliver a differentiated treatment to the Alzheimer's community. I'll provide a brief update on feedback we have received from the scientific community on our Phase I Intercept AD results, and then review our study design for our next trial, Altitude AD. Recall that our Phase I top-line results were announced in July of last year at AIC, and we had subsequent updates throughout the second half of the year on the fluid biomarker results as those were analyzed. The totality of the Phase I data has only recently become available and can now be evaluated by the broader external community. We believe the fluid biomarker results have helped to relate the mechanism of suburnatug to its downstream pharmacologic activity. As first reported in July, a dose-dependent increase in target engagement approaching an Emax was found in CSF. and a reduction in plaque measured by amyloid PET was seen at the highest doses of Subirnatug in the multiple ascending dose cohorts. Importantly, after just three administrations of Subirnatug in the multiple ascending dose portion of the study, patients demonstrated downstream improvements across tau and amyloid biomarkers in CSF, which are the two main pathologic hallmarks of Alzheimer's disease. Remarkably, There were additional clear effects on synaptic biomarkers, suggesting Subirnatug's target engagement of neurotoxic oligomers may protect synapses after only three administrations of drugs. As Dan mentioned, our team recently returned from ADPD in Lisbon. The feedback to our data package at medical conferences has been very positive. The excitement around our Intercept-AD results cause us to be even more enthusiastic about beginning our next study, Altitude-AD. Altitude-AD is planned as a randomized, double-blind, placebo-controlled, three-arm study designed to evaluate the clinical efficacy, safety, and tolerability of suburnatide with approximately 180 participants per arm for a total of 540 participants with MCI or mild dementia due to Alzheimer's disease. We intend to use the IDRIS at 18 months as the primary outcome measure. The study is planned to include a one-year open-label extension. Based on the results from Intercept AD, the doses for Altitude AD will be 35 milligrams per kilogram and 50 milligrams per kilogram, both dosed every four weeks. Extensive PKPD modeling of our Phase I data, especially with regard to target engagement and consideration of safety data, led to the selection of these doses. Both of these dose levels may produce clinical efficacy, and we are keen to see whether they will differentiate in terms of the overall benefit-risk ratio. Importantly, this study is designed as a registration-eligible study for subvernitog and we look forward to providing further updates as the study initiates and progresses. In short, our phase one results have allowed us to move to our next study that will more definitively investigate how uniquely targeting A-beta oligomers may lead to a best-in-class treatment for patients with Alzheimer's disease. And with that, I'll turn the call over to Jim.
spk05: Thanks, Eric, and good morning, everyone. I prefer to thank Dan and the entire team at Acumen for their warm welcome. I've been on board for nearly two months now, and in that time, I've grown even more excited about the potential for A-beta-oligomer selectivity to offer a next-generation Alzheimer's treatment. At its heart, I see the Subirnatug program as testing a very clear hypothesis. A-beta-oligomers are neurotoxic amyloid species in the brain. By targeting these oligomers, Subirnatug may offer a differentiated profile of compared to other AD therapies, including the potential for greater efficacy or reduced side effects like ARIA. The phase one intercept AD results show that Subirnatug can indeed bind to its intended target and improve downstream Alzheimer's biomarkers. We believe there is great potential for this approach to be beneficial to patients, and it's incumbent on us to progress our clinical program efficiently and strategically to maximize Subirnatug's value for patients and shareholders. To support the Altitude AD trial, we have contracted with a highly experienced CRO with a strong track record in AD that should provide advantages for trial recruitment and site readiness. As Dan mentioned earlier, we are also planning to initiate a phase one bioavailability study in Healthy Volunteers for a subcutaneous formulation of Subirnatug in mid-2024. We believe a competitive product profile for Subarnatug includes a subcutaneous option to offer additional flexibility and convenience for patients and caregivers, and we have a productive collaboration with Halazyme for that work stream. Before I turn the call over to Matt, I'd like to take a moment to highlight the excitement we observed at the 2024 ADPD conference a few weeks ago. We're clearly entering a new era for the diagnosis and treatment of Alzheimer's disease. with novel therapeutics, increasingly more precise biomarkers, and diagnostics that will, in turn, help the field develop even better treatments. Having just recently joined Acumen, I can clearly sense the team's pride in how the Intercept AD biomarker data have contributed to the perception that AD is a treatable disease. In particular, the effects observed on downstream fluid biomarkers after only three administrations of drugs underscore the potential of Subbernatug in targeting A-beta oligomers for the treatment of early AD. We believe Subbernatug's clinical development will continue to move the field forward from this perspective. And now I'll hand the call over to Matt to discuss the financials.
spk02: Thanks, Jim. As a reminder, our full year 2023 financial results are available in the press release we issued this morning and in our 10-K we will file later today. We ended 2023 with approximately $306 million in cash and marketable securities on the balance sheet, which provides us with financial resources to deliver against our strategic objectives. The increase from the prior year is due to the net proceeds from our public offering last July of approximately $122 million. as well as approximately $30 million from K2 Health Ventures as part of the debt financing we announced in November of up to $50 million. Our cash on hand is expected to support our current clinical and operational activities into the first half of 2027. R&D expenses were approximately $42.3 million in 2023. The increase over the prior year was primarily due to increased costs related to materials, drug manufacturing costs, consulting, and personnel. G&A expenses were $18.8 million in 2023, with the increase over the prior year primarily the result of costs related to personnel and consulting. This led to a loss from operations of $61.1 million in 2023. Our positive phase one results in 2023 are a clear reflection of our strong drug development capabilities, which we have further elevated with Jim's experience and insight. We are well capitalized to execute on our upcoming phase two altitude AD study and to develop a subcutaneous formulation. We are committed to delivering on the opportunity ahead of us and look forward to providing additional updates this year as we advance Sobernatug for the benefit of patients, caregivers, and shareholders. And with that, we can open the call for Q&A. Operator?
spk08: Thank you. 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.
spk07: The first question comes from Nina Betrito-Garg with DB.
spk08: Your line is open.
spk13: Hey, guys. Thanks for taking my question. So, I was just wondering about, I know you mentioned recently that you may consider doing an interim analysis in the Altitude A-B study. in order to determine whether or not you should start a phase three study, can you just walk us through, I guess, the rationale for doing that interim analysis, some of the protocol adjustments that you're expected to make in altitude AD based off of recent regulatory feedback, and then anything you can share in terms of how you're thinking about the criteria for that interim analysis would be great. Thank you.
spk06: Thanks, Nina. This is Dan. Maybe I'll quickly take that. So, great question. In terms of the interim analyses, these will not be analyses that change in any way the altitude AD protocol. They're really intended to provide some early visibility on data to allow us to make a decision as to whether to progress towards a Phase III study. So these are not futility analyses. They're no longer expansion analyses, but they will be employed just for the purposes of getting some early visibility in an effort to potentially minimize the white space between the phase two and the phase three.
spk13: Okay, got it. That's super helpful. And then I guess any changes that you may consider making to the altitude AD design based off of feedback from the planned to Nanomab ADCOMs?
spk06: Thanks, Nina. So I don't think we have any a priori expectations to make changes based on the outcome. The outcome, you know, is an interesting development for the field, certainly should serve as a good venue for exploring some of the considerations associated with the Trailblazer 2 design and the view of all the Nanomab data set. We do, as perhaps you're referencing, we anticipate using the IDRIS at 18 months as our primary outcome measure in Altitude AD and you know, barring some unforeseen change in development with the adcom, you know, we'll continue to use the address as our primary.
spk13: Awesome. Thank you.
spk08: One moment for our next question. The next question comes from Thomas Schroeder with BTIG. Your line is open.
spk11: Hey, good morning. This is Tom. Thanks for taking our questions. So, for sub-Q, is maintenance therapy an immediate application for sub-Q dosing? And what are your thoughts on integrating a sub-Q dose option in the open-label extension part of the Altitude AD study? Thank you.
spk06: So, Song, thanks for your question. And I think the quick answer on that is the next phase of development for sub-Q beyond phase one has yet to be determined or decided. So our immediate focus is on getting this phase one healthy volunteer bioavailability PK study done as a means to really inform what the next dosing strategy and study might be for phase two. As you mentioned, there are a couple different options that might be available to us in the future, but I think for the near term, we're focused on executing the phase one as the primary gate prior to describing in greater detail the phase two plans. Thank you.
spk08: One moment for the next question. The next question comes from Paul Matisse with CIFL. Your line is open.
spk09: Hi, this is James on for Paul. Thanks for taking our question. Maybe just a quick one on the phase two, I guess. Can you talk about how you know, you powered the study and, you know, what you're looking to see in terms of, you know, being a clear win there. And then maybe just quickly on, again, following up on this interim, just, you know, at a high level, curious if you're thinking about biomarkers or clinical scales or just kind of a collection of both of those data sets. Just curious, you know, what you can share in terms of what that may actually consist of. Thanks so much.
spk06: Thanks, James. And Eric, do you want to take that one?
spk03: Yeah, sure. Thanks, Dan. So for our Phase 2 Altitude AD study, as I mentioned, it's 540 participants with 180 per arm. That, for the IDRIS, gives you pretty typical power for a Phase 2 study. So we feel like that should really answer the question in terms of how the program develops. We'll also look at a variety of biomarkers, most of which we looked at in our phase one study too. And so it'll be really interesting to see after 18 months of treatment how those biomarkers respond since we actually already saw a response after just three doses in essentially three months. So we're looking forward to that. In terms of what goes into the interim analyses, we're not going to get into details about that. I guess I can say that it's an algorithm that doesn't include just one thing. And again, as Dan mentioned, the utility of that is to reduce the white space between a phase two and a phase three trial because if the algorithms look positive, one of the things that tells you is that the study design of the phase two study is good. And a lot of times what creates white space in drug development programs is redesigning studies. And if we don't have to do that, that will cut down on our white space. So that's how we plan to use those algorithms. Thanks. That's super helpful.
spk08: One moment for the next question. The next question comes from Colin Bristow with UBS. Your line is open.
spk10: Oh, hi, this is King on for Colin. And thank you for taking our questions. Just a quick one following the earlier question on the sub cue formula. Since the earlier question was more centered around for maintenance study. So for sub cue as the initial therapy, like, like, as in the upcoming subcube bioavailable study, what dosing choice and dosing schedules are you currently thinking, especially with regards to Esai's recent pushbacks for sub-Q dose as initial therapy? Do you think it's reasonable to start with some lower doses and test out for the safety first?
spk07: Thank you.
spk06: Thanks, Tang. Eric, go ahead, please.
spk03: Yeah, no, I think... Those are all great questions and all questions that we really don't have any answer to at this early point. I mean, we don't have even our healthy volunteer data yet. So those are all things to be considered. I think it's interesting that broadly in the field, people are talking about maybe starting off with IV administration and then switching to sub-Q and as more of a maintenance dose. So that's not just something that we're thinking about. It's something that a lot of people are thinking about. But we'll just need to get actual data before we start to narrow things down on those questions.
spk10: Okay, thank you. And maybe a quick follow-up question, if we may. So how do you view some of the evolving data in the field, including the most recent update from Rush's Chantigny map? Thank you.
spk06: Sure, I can take that. I think, you know, we noted the ADPD, the tritinamab data, which is early but encouraging. You know, we take the view that targeting oligomers is a differentiated mechanism from a gantanarumab shuttle construct, which is the tritinamab. And so, we're very much committed to, you know, exploiting the oligomer targeting mechanism of suburnatug and generating evidence in support of it as a treatment option and feel that the field in general is large enough to accommodate a variety of different product formats and options. So, it's interesting and something we're looking at, but staying very focused on execution for subverting.
spk08: One moment for our next question. The next question comes from Jeff Meacham with Bank of America. Your line is open.
spk04: Good morning. This is Jason on for Jeff. Thank you so much for taking our questions and congratulations on the progress. I wanted to ask maybe a little bit more broadly. We've seen the publication of a number of recent studies that have found that a number of the signals or biomarkers for amyloid beta appear quite some time before the symptoms I think specifically regarding the ratio of a beta 42 to a beta 40 pops up 14 years prior to the onset of symptoms and I'm curious has that influenced you know, the design of some of your clinical studies, do you think you may need to go a little bit earlier or do you feel that kind of early AD is sufficient enough for kind of either reversal of the symptoms or delaying them?
spk03: Yeah. So, Dan, you want me to take that one? Great question. So, yeah, the One of the ways that the field has made some real progress in the last 10 years and maybe the last 20 years is the understanding of this fact that, as you point out, that you develop the plaques 15 to 20 years before you develop any symptoms. And there has been a thought in the field that if you were going to target amyloid or A-beta in one way or another, that because of that time period, you actually had to do it before people had any symptoms at all. And there are ongoing studies, and there have been ongoing, there have been studies of what's called preclinical Alzheimer's disease. So in other words, you have the plaques, but you don't have any symptoms yet. Thus far, none of those studies have been successful. I think there's a lot of reasons for that. Partly it's the study design is much more complicated, the studies need to be longer, there's some technical reasons why that's a challenge. But what's really important, I think, is that for drugs like Lacanumab and Denanumab and potentially even Atacanumab, you're seeing a signal in people who have either MCI or mild dementia with Alzheimer's pathology. And the reason why that's so important is that means you don't have to go all the way back to that preclinical stage where the study designs are much more challenging and not as well worked out. So we feel really good about the fact that we're in this population of MCI plus mild dementia. Other drugs are starting to see a signal there. And apparently what that means is that's not too late in the process. And that's, I think, a really good insight for the field broadly.
spk04: interesting thanks for the the color and then maybe a quick follow-up if I may the FDA released draft guidance for Alzheimer's earlier this month I think one of the big takeaways here is that really codified the the drive or push to maybe shorten the length of clinical studies potentially using again kind of biomarkers and other indicators rather than waiting for several years that it might take to detect a meaningful change. And I'm again kind of curious, has that translated to your discussions with the regulators? And again, are we thinking ahead to maybe a shorter phase three if need be?
spk03: Yeah, having read the draft guidance, like a lot of times for these draft guidance, it's a little hard to read between lines. And they certainly did have some language in there about shortening timelines based on using biomarkers. But then they talk about a validated biomarker, but then what does validated really mean? So there's still a number of things that need to be worked out. It may be that they were directing some of those comments to just taking an antibody that is IV and then converting it to sub-Q. I think that's probably the most straightforward case for more of a reliance on the biomarkers. But at this early stage, we've not really considered using a biomarker alone to try to get accelerated approval for Subirnatug because Of course, the payers, at least to this point, haven't really offered to reimburse for accelerated approval. So, we'll continue to watch that very closely, but at this point, I don't think we have enough information to make any real changes in what we would anticipate would be our Phase 3 design.
spk04: Got it. Thank you again for the color.
spk08: One moment for our next question. The next question comes from Ananda Ghosh with HC Wainwright. Your line is open.
spk14: Thank you. You know, the first question is probably what are some of the advantages of IADRS over CDR-ASB and, you know, the rationale behind choosing IADRS over CDR-ASB for the ATTITUDE study? And the second thing is, you know, there has been a lot of correlations made based on how much of plaque reduction you are seeing and what's the probability of success in terms of, you know, some of these anti-abeta immunotherapy trials. Are there other, you know, associations which has been done with other biomarkers such as tau-181 or 217? where at least some modeling-based studies can tell you to what extent you might need to see a change in these two biomarkers so as to kind of have an impact in either CDR-SP or IDRS. Thanks.
spk03: Yeah, maybe I can try to take that one too. As far as the... use of the IDRIS versus the CDR Summit Boxes, one of the things that was interesting in the recent draft guidance was that they no longer called out the CDR Summit Boxes. And they've actually presented at public meetings the idea that in the previous draft guidance where they did mention the CDR Summit Boxes, they didn't mean to endorse that as sort of the only scale. But what they did say in this most recent draft guidance is that a scale that's a composite of cognitive measures and functional measures may have real utility. And that's what the IDRIS is. It's a combination of cognitive measures from the ADAS-COG and then functional measures from a scale called ADCS-ADL. So we think that is very positive, actually, in terms of our use of the IDRIS. I would assume that Lilly, since in the trailblazer studies, that's their primary, they were happy to see that. So, yeah, I think that's a really good clarification from FDA in terms of that, those kind of scales. In terms of correlations between plaque reduction and clinical benefit, I think what's really becoming a consensus opinion now is that you actually have to get plaque below a certain threshold. And this is something that we at Acumen have been saying for a long time, is that if you're going to target plaque, you have to basically get rid of it. And so the goal seems to be, based on existing data, that you want to get below 25, say, centilloids, or at most 30. So if your target is plaque, that's what you need to do. But again, our target's not plaque. Our target is oligomer. So it'll be interesting to see what effects we have on plaque. But with our differentiated mechanism, that's really not the construct of our development plan.
spk01: Thank you.
spk08: I show no further questions at this time. I would now like to turn the call back over to Alex Braun for closing remarks.
spk12: Thanks, Michelle, and thanks for everyone for taking the time to tune in today. We are always available at the company for any follow-up questions. Please be in touch and have a great day. Thanks.
spk08: This concludes today's conference call. Thank you for your participation. You may now disconnect.
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