Good morning, everyone. Hope everyone has had a good conference so far. My name is Chris Tippett. I'm an associate here on the healthcare investment banking team at J.P. Morgan. 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, and 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 gonna 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 our website, where we attempt to accurately describe the risks associated with the business. 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 gonna cover in the discussion, in particular, the large unmet need in Alzheimer's, why our antibodies target soluble toxic Aβ oligomers may confer distinct ability to unlock better safety and efficacy for patients. We're gonna cover the phase I results in some level of detail. Wanna 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 subQ. 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 the disease 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 amyloid 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 is 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 this success.
The current anti-amyloid treatments 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 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.
Acumen's founding science held that targeting a specific form of amyloid in the brain, amyloid-beta oligomers, or AβOs, 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 nineties implicates soluble, non-fibrillar amyloid-beta oligomers as the molecular agents responsible for Alzheimer's-associated memory and cognitive decline in Alzheimer's neurodegeneration. These data show that Aβ oligomers bind to neurons at synapses and impair synaptic signaling and long-term potentiation, a standard surrogate for memory and cognitive function. Aβ 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.
We view Aβ oligomers as a distinct and attractive drug target to address unmet needs in Alzheimer's disease. Oops, sorry. So ACU193 is our potential best-in-class immunotherapy for early Alzheimer's disease. ACU193 is directed towards Aβ 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 in inflammatory effect.
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 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 gonna turn to the INTERCEPT-AD dataset, 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 robust target engagement, you know, which is kind of a 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 a 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 five cases, about 10% of the overall population exposed to ACU193, and then interestingly, no ARIA-E in the E4 homozygotes, which is a genetically predisposed population with higher risk of ARIA. 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 and/or exposure to engage Aβ oligomers without tripping up or hitting a safety ceiling. So this is the study design. So this is a first-in-human, single ascending dose, multiple ascending dose, all in patients. So a total of 62 patients were enrolled.
48 of those were exposed to ACU193 at one or three doses at varying dose levels, and then 14 of the patients were randomized to placebo. The MAD cohorts were given a total of three doses, and in any of those cohorts, we dosed, excuse me, at 10 milligrams per kilogram 3x , and that was every four weeks, 60 milligrams per kilogram every four weeks. Then we had our cohort seven was 25 mg/ kg dosing every two weeks. So one of the central, novel, and most instructive outcomes from the phase I study was the robust, direct target-related engagement of Aβ oligomers, something that has never been before demonstrated in the way that we've done it.
Our team did a remarkable job constructing a novel immunoassay to evaluate target engagement, and we're extremely proud of the accomplishment and the type of data that was obtained using the assay and ACU193. 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 cerebrospinal fluid, so the drug, the 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 ACU193, our antibody, bound to an oligomer in patient CSF.
As you move up the dosing curve, these are all individual plots in this representation. So as you move up the dosing from, you know, 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 doses 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 on, as measured on PET. So these are the two high dose cohorts, the 25 and the 60 mg.
In the 25, we have all eight of the subjects having a reduction in the centiloid value after only three administrations of drug. And so that, in aggregate for that group, there was roughly a 21% reduction in amyloid PET. In the highest dose cohort, we had seven out of eight patients that observed a reduction in PET centiloid. And in total, that group had a 26% reduction, again, after three doses in only three months. So to put some of those results into context with what's been shown elsewhere, this is ACU193, the high dose, 25 and 60 mg doses, in orange and purple in the circle.
We have other notable antibodies that have been, you know, directed at various amyloid species and their reduction. What is conspicuous to our view is that sort of the level and rate of decline for ACU193 is consistent with Leqembi and donanemab. So, the 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, you know, we view the mechanism of ACU193'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 fibrillar plaques. Excuse me. 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 gonna 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 eight to 10 years. So we have...
You know, everybody, presumably, people are aware that, you know, amyloid plaques and tau tangles are the two, you know, primary pathological hallmarks of the disease, and biomarkers are well-established for those, including the Aβ42/40 ratio for amyloid, species of tau, such as phospho-tau 181 and 217. You know, the Aβ42/40 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 symptomatology 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 you know, we hadn't necessarily anticipated, what we're most encouraged about in terms of the 193 biomarker effects, is that after three administrations, you know, 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 de-risking and strong support for the drug effect of 193. So real quickly, these are the CSF biomarkers. So this is, you know, 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 VAMP2.
I think if, as we look at the synaptic markers, you know, those are most closely aligned with our mechanism for 193. So if we think of, you know, Aβ oligomers as directly toxic to neurons at synapses, you know, these are kind of the elements that we would perhaps anticipate. And now, you know, looking at some early phase data to support that mechanism is highly encouraging. These are, this is just the 60 mg/ 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.
You know, 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, you know, run these assays and look for effects. And so we've delineated the three doses administered for each of, you know, in this cohort, and you can see sort of a consistent drug effect. And, you know, after the drug is no longer on board, if you will, we see all three of these biomarkers kind of, you know, return to levels consistent with the placebo.
This is, again, just the consistency and totality of the data suggests to us that ACU193 has a, has a distinct mechanism and, and surely is producing a drug effect in these, in these patients. This is a slide to put more context. So we, we've kind of put, ACU193, in red here with the stars against Aβ42/40 ratio, p-tau181 and, and neurogranin. And we're seeing ACU193, you know, sort of consistent with some of the observed effects for lecanemab. So, you know, for early phase study, we think this really underpins, the de-risking that's been achieved today and why, the probability of success in, phase 2 is, elevated for ACU193. So, you know, so that's sort of the efficacy profile.
So we've got the three legs of the stool here are the target engagement, unique, distinct, 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 two different matrices and across a number of important markers, including the synaptic markers. Real quickly on a safety profile, you know, well, the overall safety profile looks good. We have five cases of ARIA, three at the higher doses. One was symptomatic. All of them resolved relatively quickly.
We had no cases of ARIA in the 13% of the population that was E4 homozygotes, and this is, you know, supportive again, given the dose levels that we've employed in the study and the safety observed. We have this what we characterize as broad therapeutic index, ability to push dose and really, you know, drive target engagement without hitting a dose-limiting ceiling. So I wanna 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. We 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 subQ formulation and had an encouraging end of phase II meeting with the FDA. So I think as we look at, you know, 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 Health Ventures and pulled down the first $30 million of that.
We have guided to second half of 2026, but we feel very comfortable with the cash on the balance sheet. Now, sort of on to next steps. So this is the ACU193-201 study, which is a phase II/III study design, intended to evaluate the efficacy, safety, and tolerability of ACU193 over an extended period of time. There are three dose arms in this study with upwards of 180 patients per arm. We are dosing at 30 mg/kg and 50 mg/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, 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 subQ products in the A-beta space. We looked at that landscape and sought technology and 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 subQ as, you know, an option for patients, and we're committed to moving forward on IV and think subQ is a possibility and sort of expanding the choices for patients. So just real quickly, you know, the Alzheimer's space is at a point of inflection.
We now have approved products. We have clinical validation on our target. There's a real interest in expanding access, and, you know, we're embracing that moment. We think ACU193's selectivity for oligomers really do present a unique opportunity for it to differentiate as 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 two treatment arms that I mentioned, and then launching the subQ of safety, sort of a PK bioavailability study in healthy volunteers, for subQ in the middle part of 2024. 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, feel free to raise your hand. We'll bring a microphone over to you. Or online as well. I forgot online.
I can kick things off as well. Oh, this one works too. So you talked a little bit about your recently announced partnership with Halozyme. Did the Leqembi subQ data influence at all or the impact of the potential of your subQ formulation?
Yeah, great question. So I think at the front end, you know, a year ago, from where we were, I think there was this anticipation that, and this hypothesis that subQ, Aβ antibodies were gonna have an intrinsic safety advantage, that basically this question of Cmax versus AUC were gonna mitigate some of the ARIA issues.
And so, you know, we wanted to understand whether there was an option for 193 moving forward on subQ. And we think, you know, subQ is gonna be important, but we don't view subQ as the end-all and be-all and the only commercial option that's gonna be part of the future state of treatment. We think it's really gonna be more about multiple options, both IV and subQ. Yeah, we're really pleased to have Halozyme as our partner, given their experience moving products to subQ. Like I said, I think it's really more of a complementary option that you know is we're hopeful to bring forward.
Thank you very much.
I guess, moving to the next subject, do you think plaque reduction is in line, in line with IV is sufficient for approval of a subQ dose?
Well, that's a big question. You, yeah, I'll invite Eric Siemers, our Chief Medical Officer, to make a comment.
Yeah. So as you know, aducanumab was given accelerated approval based on plaque reduction, with accelerated approval being in regulatory language reasonably likely to predict clinical benefit. And then so they did receive the accelerated approval, but there was a 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, as 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, you know, plaque reduction from a regulatory standpoint, would the FDA give an 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.
Great. Thank you. I guess one more question from my side. Can you share the clinical development plan for subQ, or is there a potential, I guess, for. I guess, can you talk a little bit more about that?
Sure. You wanna take it?
Yeah. 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 subQ. Beyond that, we're still developing the plan. So it's very early stages for that.
You know, Chris, we've had the benefit in a couple of respects to sort of follow what others... what's worked, what hasn't for others. And so, we, you know, we like the distinct properties of 193, and, you know, we'll evaluate precisely how to carry that forward once we get the PK bioavailability data from this phase I study.
Thank you. Any final questions from the audience? Well, thank you very much all for being here, and, you know, thank you very much for your time and your presentation. It was wonderful to have you.
Thanks for having us.