Hello, everybody. Thanks for joining. My name is Julian Pino. I'm an associate on Paul Matisse's team here at Stifel. I'm joined here today by Dan O'Connell, CEO of Acumen Pharmaceuticals, where we'll have a discussion of his company focused on the Alzheimer's space. Dan, we'll probably hand it over to you just really quickly for some opening remarks, and then we can just dive into Q&A. Thanks so much.
Yeah, thanks, Julian. Thanks to you and Paul and the team at Stifel for including us in this year's C&S days. Quickly on Acumen, Acumen is a clinical stage biopharmaceutical company that is developing a novel therapeutic that targets toxic soluble beta ligand for the treatment of Alzheimer's disease. Our goal at Acumen is to develop innovative treatments that preserve quality time for all people impacted by Alzheimer's.
In this pursuit, we're leveraging a highly dedicated team with extensive C&S and Alzheimer's drug development experience that is fully committed to better treatment options for people impacted by Alzheimer's, decades of research that supports the therapeutic rationale for targeting toxic beta ligand in Alzheimer's disease, and a differentiated product candidate in sabirnetug, which is an oligomer-directed monoclonal antibody that first generated phase one results in our INTERCEPT-AD trial in early Alzheimer's patients, and which is now advancing as a potential next generation treatment in ALTITUDE-AD, a sizable phase two study involving approximately 540 patients evaluating two active IV doses versus placebo. We are also evaluating the potential subcutaneous formulation of sabirnetug in partnership with Halozyme, and the phase one results from a healthy volunteer study comparing PK and exposures of subcutaneous versus IV sabirnetug are expected this quarter.
Perfect. Thanks so much for that overview. I guess just really quickly, just to level set, you did generate phase I B data last year that was super interesting. Did you want to just highlight, you know, hit on some key points there? Yeah, we'll just leave it there.
Sure. Thanks. As I mentioned, sabirnetug, formerly known as ACU193, is a humanized monoclonal antibody that was discovered and developed to have properties to selectively target toxic amyloid beta ligands. There was an ample base of nonclinical evidence in support of its mechanism and the rationale for targeting oligomers in Alzheimer's disease, as beta ligands are identified as early triggers and persistent drivers of Alzheimer's pathology. We took sabirnetug into an exclusively phase I study, what we refer to as the INTERCEPT-AD study, and that was a single ascending dose and then multiple ascending dose cohort study. In that study, we generated a compelling overall safety profile with a low incidence of ARIA, inclusive of some of the elevated dose levels. Importantly, we also observed and were able to establish oligomeric target engagement.
Using a novel method translated from some of the nonclinical work that was undertaken in support of the program, we were able to demonstrate sabirnetug, or ACU193, bound to a beta ligand in the cerebrospinal fluid of patients that were involved in this study. Not only did we see target engagement, we saw a dose response inclusive of sort of a plateauing effect at the highest dose of 60 mg per kg in the MAD portion of the study. We had safety, target engagement, and then somewhat beyond our initial expectations, we saw both imaging and fluid biomarkers move, particularly at the high dose levels. For instance, in the MAD study, we had two cohorts, one at 50 mg per kg dosing every 2 weeks and then one at 60 mg per kg dosing every 4 weeks.
With just 3 administrations of drug in either of those cohorts, we saw a reduction in amyloid PET at a rate and magnitude comparable to, for instance, Leqembi at their three-month PET scan in Clarity AD. In addition to the imaging effects, we saw consistent effects, actually nominally statistical, significant effects in cerebrospinal fluid markers of Alzheimer's neurodegeneration, not only amyloid and certain tau species, phospho-tau 181 and 217, but also some synaptic markers, which are really important for our mechanism as we view that oligomers have toxic properties to neurons and disrupt neuronal circuits, induce tau hyperphosphorylation, activate immune cells, and really, you know, consequently induce functional impairment.
These observations phase one were kind of on mechanism for sabirnetug as an oligomer-selective antibody and then have really underpinned, I think, a lot of the momentum that we've carried into the ALTITUDE-AD study, the phase II study that we are enrolling at present.
Excellent. Great. Thanks for that summary. Yeah, I think just the consistency of the overall target engagement data as well as the, you know, positive surprise on, you know, the effect on amyloid PET and the biomarkers, it's all super exciting and interesting. Of course, you're now, you know, in a phase II in Alzheimer's with sabirnetug. You've commented, you know, previously on, you know, the enrollment dynamics so far. I guess, can you just provide a little bit of color as to where you are, you know, currently and, you know, when you expect a complete enrollment in that study?
Sure. Again, you know, we can't underestimate the value of the phase II results in the patient-based study and really that serving as a foundation for the value proposition of participating in ALTITUDE-AD. This, you know, first, you know, needed to sort of pass muster or pass test with, you know, high-quality research sites, investigators that kind of have been in this field, been active investigating other agents, you know, of this mechanism or others. Really, I think those results, as well as our team's ability to go out and engage with sites that are, again, experienced, knowledgeable, and, you know, essentially motivated to participate in what is coming next in this field, that early launch of the study instilled a lot of momentum on the front end.
We, as I mentioned, it's 540 patients approximately in the study, so 180 patients per dose cohort, two active doses versus placebo. We enrolled or dosed the first patient in May of 2024, and we've guided to completion of enrollment in the first half of 2025. For a relatively small emerging biopharma company swimming in the AD space, you know, the enrollment has gone well. I think the team has been executing, and I think it's a testament to the awareness generally of people and the recognition that there is something that can be done for if you have a diagnosis of Alzheimer's disease. Then again, the sabirnetug profile of, you know, potentially a better risk-benefit profile for people even willing to go into research-based studies.
No, absolutely. Yeah, especially with, you know, commercially available drugs and Alzheimer's, you know, sort of in the same class, it's certainly really impressive. I think that's sort of what a lot of investors, you know, sort of would like, you know, are wrestling with is, you know, just trying to understand, you know, why is it that some of these A beta drugs have launched, you know, a little bit slower than expected, even slower than some of, you know, even skeptics predicted. I guess, what are your thoughts on that and any sort of updated opinion based on what you've heard from people in the space over the last several months?
Yeah, sure, Julian. I want to actually take a step back too in terms of the differentiation because the field generally has been at this effort for almost a couple of decades, right? We've seen, you know, we're now only talking about a short list of, you know, either approved or actively viable agents in this class, but there was a whole bunch of learning that was achieved around selectivity and profiles and binding affinities. I think, you know, we really want to present sabirnetug as a distinct and uniquely positioned product given its high selectivity for toxic oligomers. That we've underpinned, you know, some of the prior data.
We've done some more recent work that was presented at our R&D day back in October last year, really highlighting the selectivity for oligomers versus, for instance, monomer, even versus Leqembi and aducanumab. Of course, donanemab has a very different mechanism, which really does not see oligomers. The clinical path to differentiation for sabirnetug, we think, is really robust. I think the clinical adoption of these, you know, first-generation products has not met certain expectations, but I think it has kind of gone as we might have predicted given the absence of an established clinical infrastructure to, you know, readily identify diagnosed patients, get them to infusion centers. It has been a heavy lift, kind of a greenfield effort on the part of the first, you know, commercial companies looking to launch these treatments into the clinic. I think we're seeing, you know, progress.
We do foresee a future where, you know, A beta treatments are going to be the cornerstone of Alzheimer's treatment for the foreseeable future. There will be other complementary mechanisms that likely come to bear over time, but that, you know, this class generally and lowering amyloid in one form or another, we think is going to, you know, continue to command clinical attention and adoption over time.
No, makes sense. I definitely appreciate you highlighting the, you know, the differentiation that can be offered by sabirnetug and, you know, certainly distinct from donanemab, for example. You know, Leqembi does have some oligomer engagement. I guess just on the other side of that coin, you know, you did see, you know, a signal on amyloid PET when it was not necessarily expected. I think, you know, we do have a question from an investor that's asking sort of, you know, why do you think it is then that sabirnetug is, you know, removing plaque at a level that could be detected by PET? You know, is it really differentiated? Curious to hear your thoughts there.
Sure. No, I mean, look, we get the question a lot. I think that there is some uncertainty as to the definitive explanation, but we do know that oligomers are in the presence, adjacent or otherwise in what can be characterized as a halo surrounding plaque, that there's an on and off rate. Given that proximity to plaque and given some binding affinity for fibrils, it's likely to be some combination of a depletion and an equilibrium shift of the toxic species, which we think is mechanistically on target. It may also be the case that there's some direct fibril or plaque interaction that is, as a consequence, leading to the reduced PET signal, as we understand the PET signal to be really showing us the neuritic plaque as opposed to soluble aggregates such as protofibrils or oligomers or what have you.
I think, you know, we're kind of in the mid-innings of this field that, you know, really I think sabirnetug stands as really still the most advanced oligomer antibody that really should help inform whether greater preference and affinity for these soluble toxic aggregates is a mediator of safer more efficacious treatment than, you know, frank plaque removal and clearance of, you know, essentially eliminating the PET signal.
Yeah, totally makes sense. Yeah, I guess just one more question just on just sort of the space more broadly in competition. You know, you think you mentioned how you think, you know, this broader class will be sort of a mainstay of treatment. I think what people are trying to better understand is, you know, at what rate do these get used eventually at steady state? You know, do you have any thoughts on that? Yeah, I'll just leave it there.
Yeah, I think, you know, we take the position that chronic treatment while a patient remains within a relatively early stage of disease, you know, should be warranted. I think that, you know, we probably have more to learn. It is not just, you know, clear the PET signal and come off treatment. I mean, I think there is growing evidence, I think Biogen and Eisai are really the ones that are pushing the envelope on, you know, not only the evidence, but also expanded label for, you know, chronic treatment and the justification for chronic treatment, which probably, you know, does align with our thinking that these soluble aggregates, you know, are persistently present. And, you know, to the extent that they are damaging circuits and neurons, they should be targeted.
That, you know, we're still, we have a phase II to read out as the primary clinical proof of concept. Ultimately, I would envision these chronic dosing paradigms are very likely to go hand in glove with some of these fluid biomarkers, right? Where you're better able to identify and stage patients that have either been naive to treatment and get them on the right agents, you know, agent or agents, and then ultimately figure out, you know, what frequency of dosing, what is happening in the disease pathology such that you can have almost a semblance of a more precision medicine in Alzheimer's. I do think that's maybe not in the next two years, but certainly in the next five to seven, you know, timeframe that, you know, we think, you know, sabirnetug is going to be advancing in late development.
No, it definitely makes sense. I think it already shows FDA is, you know, open to that with Biogen and Eisai's approval of, you know, a maintenance sort of less frequent IV dosing. I think, like you said, sort of the staging of these patients, that'll certainly help inform this more precision approach as you've alluded to. I guess just honing in on the dose selection for sabirnetug, you selected sort of a mid-dose and a high dose. Would you be able to just explain the rationale there and what your expectations are?
Yeah, sure. So real quickly, in phase I, we had these single-ascending, multiple-ascending doses. In the MAD dose cohorts, we had 10 mg per kg and then 25 mg per kg dosing every two weeks and then 60 mg per kg. What we elected to do as a consequence of the target engagement, a lot of PK/PD modeling for the doses in phase two, we elected to take forward a top dose of 50 mg per kg. I should mention this is dosing Q4W, so every four weeks. Less frequent than Leqembi, you know, sort of similar to what donanemab is doing in terms of monthly IV dosing. So 50 mg per kg as the high dose and then 35 mg per kg as what you characterized or maybe we did previously as a mid-dose.
We do think that those doses may differentiate in terms of the amyloid PET reduction. They may differentiate in terms of the frequency or incidence of ARIA. They may equivocate on efficacy. I mean, we do not know. It is going to be interesting to see how those read out. We think there are multiple ways for us to read out the ALTITUDE-AD study in a positive way for sabirnetug. It is really going to come down, I mean, the simplest way for us to describe it is, you know, the risk-benefit profile. I do not think the current agents get, you know, materially safer or more efficacious in the real world. I think there has been some, you know, maybe we know how to manage them and we can deal with it.
There are some unique properties to sabirnetug that suggest it may be even safer. The real home run will be if, in fact, you know, having a preference for these toxic species and going at those in a primary direct fashion can unlock greater efficacy. That is, you know, really kind of our goal at Acumen and with sabirnetug, to unlock that, you know, optimal sort of risk-benefit profile for patients.
Totally makes sense. Appreciate the explanation. I guess for the ongoing program, you've elected to not conduct an interim analysis. Just curious how you think that impacts the utility of sort of this trial and, you know, its sort of role in the overall program, if you will.
Yeah, I mean, you know, the interim has been out of play for some time. We made this decision a while back basically as a consequence of some regulatory interactions, even going back to 2023, where there was a lack of concordance between regulatory authorities. It became impractical to contemplate, you know, using an interim in the, you know, which would really jeopardize the eligibility of the study to serve as a registration sort of eligible study. We think there's the most expeditious path to a submission is to complete this phase II, move quickly phase III, a single phase III, and really be in position to file, you know, as part of that package.
The viability, utility, and value of an interim analysis as was maybe originally contemplated prior to going into some of those regulatory interactions seemed to be voided as a consequence of those discussions.
Understood. That's clear. Great. You know, you mentioned in the very beginning of the discussion, the ongoing collaboration with Halozyme for the subcutaneous formulation. You know, can you just describe the decision to partner with them, you know, where things currently stand and, yeah, expectations for, you know, what exactly we're going to get with respect to this data over the next couple of weeks or several days?
Yes, it is this quarter and it is March. The choice to partner with Halozyme was a pretty obvious one for us. I mean, they are the most established leader in co-formulation, subcutaneous formulations with 7 approved products, if I remember correctly, maybe 8, you know, a long track record in enabling subcutaneous products. That for us was a clear choice. They've been good business partners. They've helped us think through, you know, sort of the formulation strategy and kind of really where we might fit in terms of the product profile. That's all been of great benefit to Acumen as, you know, we don't have a tremendous amount of that expertise in-house. A good partner by definition. For the top line results, you know, we'll have initial results this quarter. It is very close to being time, the witching hour.
We're basically looking for general PK and drug exposure comparison between subQ and IV. I will also mention, you know, this is a healthy volunteer study. We're not looking, for instance, for amyloid PET or biomarker or anything of that nature. This is really just an initial comparison of IV versus subQ so we can get some insights into kind of the exposures and what the next steps might be for advancing a subQ option.
Got it. Totally makes sense. I guess what may those next steps be, you know, assuming this is positive? Would it be like a small, you know, exploratory, you know, AD study? Would you even consider moving, you know, a small cohort directly into pivotals? I guess even just any thoughts on contemplation there would be helpful.
Yeah, those are great suggestions. Those are questions, those are suggestions. I think it's still TBD for us. I think we have some ideas. I think we are also very much, I mean, we're keen to see phase I data, you know, discuss the implications with our partners and assess next steps. I also think we're paying close attention to what's happening elsewhere and with the regulatory bodies because I think that also helps to inform what the, you know, which rank order priority of next steps makes sense from a program advancement standpoint, right? I mean, I think that's the, you know, at our core, we're trying to move this as quickly as possible.
We want to be, you know, internalize not only the data, but also external environment and kind of where the regulatory authorities are on, you know, evaluating, you know, new formulations for existing kind of products, if that makes sense.
Totally makes sense. I guess, is there anything in the phase II, IV study that you're looking at that you think could inform dosing for the subQ specifically?
I think, I mean, I think the phase II dose, you know, the comparison we just described between 35 and 50, certainly, you know, is going to inform what a subQ strategy, ultimately a subQ strategy should, you know, what form it might take. I think that's also a consideration for us, you know, at some point in the future.
Also with respect to safety, we've seen Lilly have some interesting data where they reported lower ARIA for donanemab with a revised titration schedule. Any thoughts on that? Is that something that, you know, Acumen may potentially consider in the future?
Yeah, Julie, yeah, and in fact, I was at the, I think that was CTAD in the fall where they presented sort of that dose titration adjustment that did appear to make an impact on the rates of ARIA, which is, you know, good for the, you know, patients, you know, going on that treatment and good, you know, for, you know, advancing the field. I guess you should know that in the phase two, our 50 mg per kg dose cohort actually involves two administrations at 35 mg per kg. So we, you know, even back in May of, you know, when we launched the study had kind of, you know, as a consequence of input from, you know, our leadership and CMO determined we would use that, you know, 2 mid-doses essentially as you're onboarding patients and then titrating to 50.
You know, I think that's, it does seem that ARIA rates generally in this population are principally exposure driven, you know, that, and we've seen, you know, more, you know, the notion that subQ was going to have an intrinsic safety benefit hasn't played out in the, in sort of the, in studies or in practice. I do think titration strategies and patient stratification, I mean, I think it would be helpful. And we're still seeing, you know, rates of ARIA in E4 carriers and particularly in E4 homozygotes, you know, dramatically higher than in, you know, in non-carriers and the general population.
There's got to be something to the A beta biology and whether it's CAA or other things that ultimately will help, you know, if we can, you know, gain greater insights into that and maybe sabirnetug, which of course, you know, didn't have any ARIA in at least six E4 homozygotes exposed to higher levels of drug, you know, maybe there is some diverse biology and mechanisms that allow for sabirnetug to proceed in that population in a way that these other first agents haven't been as beneficial.
Totally makes sense. Great. Do you see that we're getting, you know, we're about to be up on time. Just anything else that, you know, you wanted to mention before we wrap up here? Just really quickly, if you could also remind folks of Acumen's cash runway, that would be helpful too.
Yeah, sure. I mean, this has been a great discussion, Julie. I appreciate your time. We're super excited about the progress we're making with sabirnetug and the prospect of offering patients better treatment options in the future. In terms of cash and runway, at the end of September, we had about $259 million in cash on the balance sheet. We've guided to first half of 2027 as our runway. I think, you know, we have these upcoming milestones or catalysts around phase I subQ study this quarter and then guiding to completion of enrollment of the ALTITUDE-AD study in the first half of this year.
Excellent.
Excellent time with the company.
Perfect. Great. That about wraps up our conversation. Thanks again, Dan, for joining us to discuss Acumen. Really appreciate it. Thanks everybody for tuning into the webcast.