Acumen Pharmaceuticals, Inc. (ABOS) Earnings Call Transcript & Summary

So good morning, everyone. I hope everyone has had a good conference so far. My name is Chris Tippett. I'm an associate here I'm the HealthCare Investment Banking team at JPMorgan. Today, it is my pleasure to introduce Acumen Pharmaceuticals. And without further ado, I'd like to turn things over to the Chief Executive Officer and President, Dan O'Connell.

Thanks, Chris. Good morning, everyone. It's a pleasure to be here today. We appreciate the invitation to present and thanks to everyone here in the room, great to see some familiar faces and for everyone on the webcast for taking the time to learn more about Acumen Pharmaceuticals. I'm Dan O'Connell, I'm the President and CEO. As Chris indicated, I'm pleased to provide a bit of an overview of the company. And some of the more recent data for our ACU193 program. We think you're going to find the -- as we see the data, it's very encouraging and bodes well for the future of the program and aligns very directly with our unending commitment to bring better treatment options for Alzheimer's patients. This is our legal disclosure. Please refer to our filings with the SEC and on our website, where we accurately -- attempt to accurately describe the risks associated with the business. And so this is -- with that said, Acumen is pursuing a potential best-in-class treatment for early Alzheimer's disease. This slide just gives you a quick summary of some of the elements that we're going to cover in the discussion, in particular the large unmet need in Alzheimer's, why our antibodies target soluble toxic A-beta oligomers, may confer distinct ability to unlock better safety and efficacy for patients. We're going to cover the Phase I results in some level of detail. I want to highlight the quality and caliber of the team responsible for those results and why we're positioned to execute in the future. We're in a strong financial position, and we'll cover that briefly and then talk about milestones and next steps. So the Phase II developments for ACU193, both IV and subcu. That gives you a little bit of an overview. So Alzheimer's is a complex and progressive neurodegenerative disease that affects tens of millions of people worldwide. I'm sure many in this room have a loved one dealing with or touched by the disease either as a patient or caregiver. It's an insidious disease that robs people of their memory and cognitive abilities and ultimately leads to death but not without an increasing requirement for care, as the disease progresses. The patient population that we focus on in our clinical studies is defined as early Alzheimer's disease, made up of patients that exhibit symptoms such as mild cognitive impairment and/or mild dementia. All of those patients have confirmed inlet pathology. We at Acumen are like so many others encouraged by the recent progress and success in the field after years of trying and learning and persisting, the field has clear clinical validation that anti-amyloid approaches to slowing disease progression are successful. We now have established regulatory pathways and emerging payer support for traditionally approved products. The success deserves applause. And I think it's a fantastic moment for patients and for the field. And we do think that there is ample room for improvement, even on the basis of the success. The current anti-amyloid treatments that are just approved or under review, provide roughly a 30% slowing of disease progression. And there is caution with these agents as they do induce a safety issue called amyloid-related imaging abnormalities or ARIA-E. There'll be some discussion of that. This is a dose-limiting safety concern that requires monitoring and follow-up. So it's important to recognize that this unmet need for the field is -- remains significant and will persist into the future. So our work is far from done. And that actually, for us, at Acumen is extremely exciting. So Acumen's founding science, held at targeting a specific form of amyloid in the brain, amyloid-beta oligomers or ABOs oligomers, could address that unmet need I just referenced, basically unlocking significant clinical benefit with less risk of ARIA. A vast library of literature dating back to the late '90s implicates soluble nonfibular amyloid-beta oligomers as the molecular agents responsible for Alzheimer's associated memory and cognitive decline and Alzheimer's neurodegeneration. These data show that A-beta oligomers bind to neurons at synapses and impair synaptic signaling and long-term potentiation, a standard surrogate for memory and cognitive function. A-beta oligomers also have repeatedly been implicated in the hyperphosphorylation of tau, which actually is significant in the sense that tau is actually another biomarker for the disease, which is most closely associated with symptomology and disease progression. So we view A-beta oligomers as a distinct and attractive drug target to address unmet needs in Alzheimer's disease. So ACU193 is our potential best-in-class immunotherapy for early -- early Alzheimer's disease. ACU193 is directed towards A-beta oligomers. It was rationally designed as such and has high selectivity for oligomers versus monomer and plaques. So at least 500-fold greater selectivity for oligomers over monomers and 85-fold selectivity for oligomers over fibrils. In addition, ACU193 was designed as an IgG2 with reduced effector function and thus may have a lower rate of ARIA, as a consequence of that tamp down inflammatory effect. So this selectivity for oligomers and the isotype of the antibody is the mechanism by which we think ACU193 can achieve best-in-class efficacy and safety. I'll note that ACU193 was discovered in partnership with Merck. Merck did an extensive preclinical profile to establish the attributes of the antibody. Acumen today has a full rights to the program. And all of the intellectual property and no future financial or other obligations to Merck. From a regulatory perspective, we have a Fast Track designation for ACU193 from the FDA. And we recently completed an encouraging end of Phase II meeting with the FDA in the fourth quarter, and we'll talk a little bit more about that as we go on here. So I'm going to turn to the INTERCEPT-AD data set, and this is just sort of a checklist summary of the elements and results that we believe provide the path towards differentiation of ACU193 on both efficacy and safety measures. So the first of these is a robust target engagement which is kind of the first in the field in the way that we pursue target engagement, I think really supports the mechanism of the drug, as well as informs dose selection, and we'll talk a little bit more about that. Another finding that supports efficacy is the rapid reduction in amyloid plaque, as measured on amyloid PET. And that was consistent with other successful antibodies. We'll show you some of that data. And then the third is the movement of fluid biomarkers, both in CSF and plasma demonstrating a drug effect of ACU193, and impacting downstream elements of the disease. And so really important finding in an early phase study and then the safety profile, safety being the primary objective of the Phase I looks really good. Overall, a compelling safety profile. We had limited incident of ARIA-E, only 5 cases, about 10% of the overall population exposed to 193. And then interestingly, no ARIA-E in the E4 homozygotes, which is a genetically predisposed population with higher risk of ARIA. This -- the doses we pushed and sort of the safety profile we have, we think, sets us up for a broad therapeutic window. And by that, we mean we have the ability to push dose, cover -- provide enough coverage or exposure to engage A-beta oligomers without tripping up or hitting a safety ceiling. So this is the study design. So this is a first-in-human signal ascending dose, multiple ascending dose, all in patients. So a total of 62 patients were enrolled. 48 of those were exposed to ACU193 at 1 or 3 doses, at varying dose levels. And then 14 of the patients were randomized to placebo. The MAD cohorts were given a total of 3 doses and any of those cohorts, we dosed at 10 milligrams per kilogram, 3 times, and that was every 4 weeks, 60 milligrams per kilogram every 4 weeks. And then we had our cohort 7 was 25 mg per kg dosing every 2 weeks. So one of the central, novel and most instructive outcomes from the Phase I study was the robust direct target-related engagement of A-beta oligomers. Something that has never been before demonstrated in the way that we've done it. This -- our team did a remarkable job constructing a novel immuno assay to evaluate target engagement. And we're super -- we're extremely proud of the accomplishment and the type of data that was obtained using the assay in 193. So our target engagement was so definitive. We basically have -- this is essentially an Emax curve. So we have on the left-hand side or the Y-axis, the concentration of ACU193, from cerebral spinal fluid, so the drug CSF concentrations. And then on the x-axis is the concentration representative of the target engagement complex. So the target engagement for us is the direct complex of 193 or antibody, bound to an oligomer in patient CSF. So as you move up the dosing curve -- these are all individual plots in this representation -- and so as you move up the dosing from -- get to the 25 Q2W or 60 Q4W, you're kind of leveling off in terms of the increase of target engagement. So we think this was really instructive as we were picking dosage for the Phase II study, and we'll talk a little bit more in detail on that in a second. So the second most interesting and encouraging finding in the Phase I study was the rapid and significant reduction in amyloid signal, as measured on PET. So these are the 2 high-dose cohorts, the 25 mg and the 60 mg. And in the 25, we have all 8 of the subjects having a reduction in the centiloid value after only 3 administrations of drug. And so that in aggregate for that group, there is roughly a 21% reduction in Amyloid PET. In the highest dose cohort, we had 7 out of 8 patients, that observed a reduction in PET centiloid. And in total, that group had a 26% reduction again after 3 doses and only 3 months. So to put some -- those results into context with what's been shown elsewhere. This is ACU193, the high-dose 25 mg and 60 mg doses in orange and purple in the circle. And we have other notable antibodies that have been directed at various amyloid species in their reduction. What is conspicuous to our view is the sort of the level and rate of decline for 193 is consistent with LEQEMBI and anetumab. And so, just a significance of that is that those agents that have been able to reduce amyloid signal on PET below 25 or 30 centiloids have yielded clinical slowing that's been of clinical benefit and serves as the basis for a biomarker justification for approval with the agency. So for early data and limited dosing, we think we're on that trajectory towards plaque clearance, species clearance. And I should say that we view the mechanism of 193's clearance of amyloid as really more predicated on a shifting of the equilibrium. So clearing, we're maxing target engagement of oligomers, removing those from the scene. And then as a consequence, there's a reduction in the fibrolic plaques. So one of the most dynamic and important dimensions to Alzheimer's treatment development today is the advance of Alzheimer's biomarkers. And these are fluid biomarkers. And I think there's consensus that the fluid biomarkers are going to provide greater maybe earlier and more specific establishment of pathology, even more so than the imaging modalities that have been kind of the gold standard for the last 8, 10 years. So we have -- everybody -- presumably people are aware that amyloid plaques and tau tangles are the 2 primary pathological hallmarks of the disease and biomarker -- biomarkers are well established for those, including the A-beta 42:40 ratio for amyloid species of tau such as phospho-tau 181 and 217. The A-beta 42:40 ratio goes down in patients. And the p-taus are prone to increase with disease. And again, the tau signal is most closely aligned with symptomology and disease progression. There are other markers that are now coming online that help to interrogate the synaptic injury, neuronal health, as well as inflammatory and astrocyte activation. What we hadn't necessarily anticipated, what we're most encouraged about in terms of the 193 biomarker effects is that after 3 administrations, we're moving multiple of these pathological biomarkers in the right direction. And so for an early phase study, this, to our view, represents significant derisking and strong support for the drug effect of 193. So real quickly, this is the -- these are the CSF biomarkers. So this is across the amyloid pathology. So there's a sort of a dose trend on the 42:40 ratio. We have phospho-tau 181 is significant at the high dose level, same with neurogranin and VAMP-2 and I think as we look at the synaptic markers, those are most closely aligned with our mechanism for 193. So if we think of A-beta oligomers, as directly toxic to neurons at synapsis, these are kind of the elements that we would perhaps anticipate and now looking at some early phase data to support that mechanism is highly encouraging. We also look, this is just the 60 mg per kg dose cohort. This is in plasma. And so on the left-hand side, we have GFAP, which is an astrocyte marker in the middle, we have phospho-tau 181, similar to the CSF marker. And then 217, what is interesting about this slide in particular is that with plasma, it's a more accessible matrix. It's easier to get. You can get more time points to run these assays and look for effects. And so we've delineated the 3 doses administered for each of -- in this cohort. And you can see sort of a consistent drug effect. And after the drug is no longer on board, if you will, we see all 3 of these biomarkers kind of returned to levels consistent with the placebo. So this is, again, just the consistency and totality of the data suggests to us that 193 as a distinct mechanism and certainly is producing a drug effect in these patients. This is a slide to put more context. So we've kind of put 193 in red here with the stars against 42:40 ratio p-tau181 and neurogranin. And we're seeing 193 sort of consistent with some of the observed effects for lecanemab. So we're -- for an early phase study, we think this really underpins the derisking, that's been achieved today and why the probability of success in Phase II is elevated for 193. So that's sort of the efficacy profile. So we've got the 3 legs of the stool here, are the target engagement, unique, distinct and oligomer selected -- specific, I should say, plaque reduction on par or potentially as good with the benchmark out there today, lecanemab and then the consistency of the biomarker effects across in 2 different matrices and across a number of important markers, including the synaptic markers. Real quickly, on safety profile, the overall safety profile looks good. We have 5 cases of ARIA, 3 at the higher doses. One was symptomatic. All of them resolved relatively quickly. We had no cases of ARIA-E in the 13% of the population that was E4 homozygotes, and this is supportive, again, given the dose levels that we've employed in the study. And the safety observed, we have this -- what we characterize as a broad therapeutic index ability to push dose and really drive target engagement without hitting a dose-limiting ceiling. So I want to just quickly mention the team behind these impressive results. I mean we have a phenomenal team. Acumen is a small company, but we have a highly experienced and dedicated team. We had a remarkable year last year, whereby we completed the Phase I, within 30 days of database lock, we presented the results at a major international meeting at AAIC. We then went on and established a partnership with Halozyme to develop a subcu formulation and had an encouraging end of Phase II meeting with the FDA. So I think as we look at sort of the execution strategy and the accomplishments last year was a remarkable year, and we've got a phenomenal team at Acumen, really dedicated to our mission. Just to touch on the cash position. We're in a strong financial position at September 30, we had about $283 million in cash on the balance sheet. In November, we closed a senior secured debt facility with K2 HealthVentures and pulled down the first $30 million of that. So we have guided to second half of '26, but we feel very comfortable with the cash on the balance sheet. Now sort of on the next steps. So this is ACU193, 201 study is a Phase II/III study design, which is intended to evaluate the efficacy, safety and tolerability of 193 over an extended period of time. There are 3 dose arms in this study with upwards of 180 patients per arm. We are dosing at 30 mg per kg and 50 mg per kg, and those are Q4W dosing. Primary outcome measure, we will employ in the study is the iADRS. And this study is guided to start in the first half of this year, lots of activity and work being done as we speak. I'll comment on the Halozyme partnership. So as I think there's been strong interest in evaluating the possibility of subcu products in the A-beta space. We were looked at that landscape and sought technology partners to work with us in this area. And we -- Halozyme is sort of the gold standard in that field. We were encouraged to draw them into a partnership. And we view subcu as an option for patients. And we're committed to moving forward on IV and think subcu as a possibility in sort of expanding the choices for patients. So just real quickly, the Alzheimer space is at a point of inflection. We now have approved products. We have clinical validation on target. There's a real interest in expanding access, and we're embracing that moment. We think ACU193's selectivity for oligomers, really do present a unique opportunity for it to differentiate us best-in-class on efficacy and safety. We think the Phase I results credibly support -- provide a foundation for the path towards that differentiation. And we're excited to launch the Phase II in the first half of this year, with the 2 treatment arms that I mentioned. And then launching the subcu safety -- sort of a PK bioavailability study in healthy volunteers for subcu in the middle part of '24. So with that, thank you for your time, and we look forward to keeping you updated on our progress.

So if there's any questions from the audience at this time, raise your hand, bring the microphone over to you. Online as well. I can kick things off as well. This one works too. So you talked a little bit about your recently announced partnership with subcutaneous. Did the LEQEMBI subcu data influence at all or the impact of the potential of your subcu formulation?

Yes, great question. So I think at the front, a year ago from where we were. I think there was this anticipation that in this hypothesis that subcu A-beta antibodies were going to have an intrinsic safety advantage that basically this question of Cmax versus AUC were going to mitigate some of the ARIA issues. And so we wanted to understand whether there was an option for 193 moving forward on subcu. And we think subcu is going to be important. But we don't view subcu as the end-all and be all and the only commercial option that's going to be part of the future state of treatment. We think it's really going to be more about multiple options, both IV and subcu. And we're really pleased to have also as a partner given their experience moving products to subcu. And like I said, I think it's really more of a complementary option that is we're hopeful to bring forward.

And I guess, moving to the next subject, do you think plaque reduction is -- in line with IV is sufficient for approval of a subcu dose?

Well, that's a big question. I'll invite Eric Siemers, our Chief Medical Officer, may care to comment.

Yes. So as you know, aducanumab was given accelerated approval based on plaque reduction with accelerator approval being, in regulatory language, reasonably likely to predict clinical benefit. And so they did receive the accelerated approval, but there was real difficulty with the payers in this case, CMS, who were not willing to reimburse a drug that got accelerated approval. So it becomes not so much of a regulatory issue. I think it's a payer issue. Now if you move on to LEQEMBI, it actually initially was given accelerated approval for the same reason. But then after their Phase III results were available and they had clinical efficacy, they were given traditional approval. And with traditional approval, now CMS seems to be -- well, they reimburse the drug, they reimburse PET scans, that kind of thing. So yes, plaque reduction from a regulatory standpoint, would the FDA given accelerated approval to another drug based on plaque reduction? They might. But if payers don't pay for it, it probably really doesn't matter.

I guess one more question from my side. Can you share the clinical development plan for subcu? Or is there a potential, I guess, for -- I guess, can you talk a little bit more about that?

Yes. So -- we've really just started working with Halozyme who, again, are just terrific partners for us. And so we would anticipate probably a single-dose study in volunteers just to compare IV PK with subcu. Beyond that, we are still developing the plan. So it's very early stages.

Chris, we've had the benefit in a couple of respects to sort of follow what other -- what's worked, what hasn't for others. And so we like the distinct properties of 193, and we'll evaluate precisely how to carry that forward once we get the PK bioavailability data from this Phase I study.

Any final questions from the audience? Well, thank you very much all for being here. And thank you very much for your time and your presentation. It's wonderful to have you.

Thanks for having us.