Great. Thanks, everyone, for being here. I'm James. I'm one of the associates on the research team at Stifel, and it's a pleasure to be here with Acumen Pharmaceuticals. With us is Daniel O'Connell, the CEO, and Eric Siemers, the CMO. So I have a number of questions, but if anyone has anything, feel free to jump in. But yeah, maybe just to start, we can have Dan maybe just do a kind of a brief overview of the phase I-B data, where things are today, and kind of what's going on at Acumen.
Sure. Thanks, James, and thanks to you and your colleagues for having us at the meeting this year. Always a pleasure to be here in New York in November. So for Acumen, Acumen is a clinical- stage biopharmaceutical company working to advance sabirnetug as a potential next-generation monoclonal antibody treatment for early Alzheimer's disease. And sabirnetug is distinct in the way that it was discovered and developed with a high preference and targeted direction at Aβ oligomers, which we view as the primary neurotoxin in Alzheimer's pathology and a distinct and attractive therapeutic target. And you mentioned our phase I-B results. Yes, so we reported the top-line results last July at AAIC, which demonstrated a robust safety profile, target engagement of oligomers. So we can talk a little bit more on that.
Then subsequently showed both imaging and fluid biomarker effects, even with just three administrations of the drug. We think we've got the right target. We think we have the right antibody or product. I think we're also at a time where the Alzheimer's field is progressing very nicely, that we see on the horizon or on the frontier more success going forward than ever before. We have a couple of approved products right now. The clinical commercial infrastructure is being built out. We at Acumen are really excited about the prospect of contributing something that maybe is safer, more efficacious to the benefit of patients.
Yeah. Yeah. And I guess kind of in that context of just a lot kind of happening with Alzheimer's, you've spoken about how enrollment's kind of been going a little bit faster than you initially anticipated. So I guess, yeah, maybe it'd be great to kind of talk about the enrollment dynamics of your ongoing phase II and kind of what you think is driving that and kind of what timelines might look like now.
Yeah. Thanks, James. So sure. And so what we're currently running, what we refer to as Altitude AD, which is a phase II study that includes two active doses of sabirnetug versus placebo. And that's designed as a roughly 540-patient study with 180 patients per cohort, with a primary outcome measure in what's called the iADRS, which is a cognitive functional composite score at 18 months. So we thought at the start, we had some regulatory interactions end of last year and start of this year. And we're excited to launch the phase II and see how it might go, even in the presence of a first approved product with Leqembi and then anticipating that donanemab would be launched. So I think at the outset, we thought we might need 115, 120 sites across North America and Europe and that we had internal forecasts for how the enrollment might go.
What we've experienced is far greater screening and enrollment than we might have anticipated. And we've now somewhat recently guided that we'll complete the enrollment in the first half of 2025. So that will be first patient dose was May of 2024. We're looking at essentially enrolling within a 12-14-month period for a study of this size. And for a small emerging biopharma like Acumen, I think we're really excited about how the team has executed. And I think putting that execution pin, I think hopefully that will really encourage folks to understand that we're now on a trajectory towards a data readout roughly at the end of 2026, if you do the calculus.
Yeah.
In terms of the enthusiasm, another distinction between the clinical adoption of these first products versus running a global phase III Alzheimer's study, I think the research infrastructure is in place to do these types of studies. I think we benefited from the quality and strength of the phase I results that really drew in some of the top investigators that had sort of a nose or an interest in innovation. Presenting the value proposition to participants with sabirnetug as potentially next- gen with a better risk-benefit profile has also stimulated, I think, a lot of interest and uptake in the phase II.
Yeah. Yeah. No, definitely makes sense. And I do want to dive into the phase II a little bit more, but maybe some just, again, broader Alzheimer's landscape, Aβ kind of sentiment. Obviously, the Lecanemab launch has gone slower than many people expected. And it seems like it's picking up to some degree. But yeah, I mean, I guess, and you kind of touched on it a little bit, but I guess what are you hearing from the community, I guess, as it relates to these first-gen Aβ , what utilization may look like in terms of by the time you guys come around? Just kind of curious how you think this Aβ landscape is going to shift over the next few years.
Yeah. I mean, I'll make a quick comment. Maybe Eric can kind of share his views as well. I mean, I think the demand and interest is out there. I do think that, and internally at Acumen, I don't think this wasn't going to be flip the switch and rapid adoption, just push it out into the clinical space. I think the system readiness is the term that some of the field have referenced, and it just hasn't been there in the clinical setting, and there's a lot of it's multifactorial why it's taking time to build out the greenfield site and establish the infrastructure to identify and then treat patients that are eligible for these first products. I think that's going to continue to roll out.
And for us, looking to read out an innovative program in the late 2026 and with the establishment of some of these other clinical products, I think we're just going to see the space is large enough to support multiple products. And I think we're going to see iterations within the Aβ space. I think we're going to see other targets either pan out or not pan out over the foreseeable future. And we're going to continually see other diagnostic and essentially the biomarker technologies brought to bear on both opening up access, better diagnosis, and better assessment of patients most amenable to treatment, which drugs to be on. So all of that, I think, is sort of the future state of the treatment. And we're excited that we're going to be part of that future and think we have something really important to contribute.
Yeah. One thing I'd add to that is you read that the launch of Leqembi is underperforming. I actually think the expectations were too high. I mean, for a lot of us who've been in the field for a long time, we knew the infrastructure wasn't going to be there on day one because there aren't enough infusion clinics. There aren't enough. There's a certain number of MRIs that have to be done. They have to have PET scans. I mean, all of that was a great part of clinical research and certainly as part of a clinical research program, you can do that. To translate that into clinical practice, that's an initial pretty heavy lift. Now, it'll happen, and it's starting to happen. And we're starting to see the numbers tick up for Leqembi.
But the fact that it was slow at the beginning for a lot of us was not a huge surprise because it's complicated.
Yeah. It's quite a lot.
The other thing to keep in mind is just with these two drugs being approved, I mean, they're not perfect drugs. They don't cure the disease. They have some risk associated with them, but it's a start, I mean, it's a toehold, and you can build on that, so the rapid screening that we've had in our phase II, I think it's because we have really good phase I results. And people seem to like the study design and the protocol and all of that, but I think it's also because the field now has this optimism that we're on the right track, and so we think we got a good start or we have a start with the drugs that are currently approved.
But again, sabirnetug, because of all the development with it, we think has a chance to really be a next-generation drug in terms of safety and efficacy.
Yeah. And I can give you a little bit of an anecdote too in our experience on the biomarker front, right? So pTau217 is one of the pTau of significance. And it looks like 217 has a high concordance with amyloid positivity, which is kind of interesting just to think of the way these different various aspects of the pathology are sort of co-contributing to each other. But we're using this plasma pTau 217 as part of screening visit one to assess patients that basically are eligible to go do a PET scan. And we've cut the negative PET scans in half in the phase II study, which saves cost, time, radiation burden, all of that. So I think these biomarkers are going to be a fundamental enabling element that's going to improve the iteration and sort of the advancement on the innovation side.
Yeah. And other studies are starting to use a similar approach. And what I think is really nice about this is I think you can apply it to clinical practice. And there's a lot of discussion now in the field about, well, wait a minute, now that we have to think about the whole broad population, how do we do this logistically? And having a blood test like pTau217 is really a huge gain for clinical practice. So the whole field is evolving in a lot of ways at once.
Yeah. Yeah, definitely. And obviously, you would be in a position to benefit from a lot of that infrastructure kind of being built out. I guess kind of on that point, one of the other interesting dynamics here is that we've heard, and Biogen has kind of talked about this, of course, there's the infusion capacity, the MRIs, PET scans, all of that. But one of the things they actually talk about that's the biggest bottleneck is just the actual ability for patients to get in to see the neurologist in the sense of there's just so many people, which obviously would be kind of if that persists as kind of a dynamic relevant for kind of all of Alzheimer's. So yeah, I mean, I guess just is that just in terms of reflective of just a lot of interest and patient demand?
Or, just kind of curious how that evolves in terms of just assuming more therapies are coming along and.
I mean, I think it evolves with the biomarkers, again, because I think what all of these treating physicians are looking for is the right patients, who's going to be safe, who's going to benefit. And so to the extent that you can triage or prioritize based on a biological, like a simple blood test, this is somebody who's a good candidate. Let's get them top of the funnel to get in. And that, of course, presumably would lead to more successful sort of outcomes, real-world use. And sort of it then kind of builds on itself in terms of the progress the field has achieved. But these are not things that are going to, again, happen, flip the switch, but evolve over time and ultimately set up a broader treatment paradigm where more patients are accessing and getting access to what is available.
Yeah, so now it's interesting that Biogen would say that about the neurology being a pinch point. And I'm a little biased since I'm a neurologist, but the world needs more neurologists, no question about it, but even besides that, as the field advances, more people within neurology will want to subspecialize in this sort of thing, and also non-neurologists. There will be some internal medicine docs who will be interested in this, geriatricians, and so it's a little bit like MS was 20 years ago when the first disease-modifying drugs came out. MS, there wasn't a lot you could do beforehand, and then there was a lot of interest, and obviously, there's been a lot of progress, and I think we're kind of at that initial stage right now for Alzheimer's treatments.
Yeah. Yeah, that makes sense. And definitely, if there's a way to more efficiently kind of go through patients, everything, that makes a lot of sense. Okay, sorry. One more kind of broad Alzheimer's question. Recently, AbbVie acquired Aliada, which has anti-Aβ antibody, which is interesting in terms of strategic interest in the space. So yeah, just be curious kind of what you guys thought of that. And then just kind of this BBB technology in general in terms of there's Roche, there's a lot of companies kind of in Alzheimer's trying to do that. Just kind of curious what you think of all those dynamics.
Yeah. The area of enhanced brain delivery has been developing over the last 20 years, right? This technology exists at a lot of companies, big and small. I do think that Roche has been the one that has kind of stuck with it the longest and demonstrated taking gantenerumab, which is a failed monoclonal subQ/IV, putting it in a shuttle construct has a different pharmacodynamic effect. It basically looks safer, maybe has a more pronounced effect on amyloid plaque reduction. I think for that agent, we're all keen to see longer-term outcomes, both in terms of safety and clinical benefit. But it's certainly interesting, the proof of principle that you could take something that didn't work in one format, but then does work or is yielding different results is encouraging.
I think the Aliada, AbbVie deal is a good example of Big Pharma's strategic interest in the space and their confidence that Aβ strategies are going to be pertinent in treating this disease population. That's an early-stage program. We also, AbbVie had terminated a phase II program that was a pyroGlu monoclonal that probably looked a lot like donanemab and probably didn't have a path to differentiation. So I think shutting that internal program down and looking to source external innovation time and again is a model for pharma, right? And look, I think the transaction serves as a reasonable comparable to sort of the value proposition of a differentiated Aβ asset. And we follow that space. We're cognizant of kind of what some of the options are there. But we think that sabirnetug, in its current format, could be a really efficacious and beneficial treatment.
Yeah. So these blood-brain barrier techniques enhance brain delivery. They're interesting, partly because you just need less drug then, but also the difference in safety. Now, it's not the ARIA that Roche is seeing, but it does seem to be less. And so those are two big wins, actually, if you need less drug, but also a better safety profile.
Yep. Yep. Yeah. And it's interesting. So just kind of going back to sabirnetug more specifically, you kind of, there's two doses that you brought into the phase II, and there might be different kind of sources of differentiation either on efficacy or safety. So maybe it'd be good just to kind of walk through those two, your kind of dosing strategy in the phase II and just more broadly how you think about the path of differentiation being on efficacy or safety with the oligomer approach.
Or both.
Or both. Yeah, or both.
But let me yeah, so it's a great question. Just to maybe talk about the phase I data, actually. So phase I, we were in patients. We had single-dose cohorts and multiple-dose cohorts. The multiple-dose cohorts still only had three administrations of drug. So not a lot. But what we found in that phase I study was, first of all, target engagement. We showed that the antibody crosses 0.1%, whatever it is exactly, crosses the blood-brain barrier and binds to oligomers in the central compartment. And for one thing, that sort of proves that the oligomers are there and that sabirnetug binds them. But it also gave us some really interesting biochemical data about when you can stop increasing the dose. The top dose that we had in the phase I was 60 mg/kg. People would ask us, what happens if you don't see anything with that?
You don't see any free, you don't see what if you need more? Well, this target engagement data we got tells us that by the time you get to 60 mg/kg , you're already kind of at the point of diminishing returns. In other words, you've bound up all the oligomers. You're going to be able to bind up. So it gave us really good information to choose doses for the phase II study based on the amount of target engagement. The other thing we got out of the phase I data was, in addition to the target engagement, we had these biochemical biomarkers, which we measured both in spinal fluid and also in blood. But particularly in the spinal fluid, you could really see consistent changes in these biomarkers after just three administrations of drug.
So between the target engagement data and these biochemical biomarker pieces of data and a little bit of plaque reduction from the phase I, we triangulate all those things and that led us to those doses. But just based on the target engagement, both of those doses could be efficacious. And so the 35 mg/kg could be efficacious, as well as, of course, the 50. And then it just becomes a matter of comparing efficacy and safety and then picking the right dose for phase III.
Yep. Yep. That makes sense. And yeah, you've touched on some of these biomarkers a lot. And we've seen with pTau, there's pTau 181, 217. There's just a lot of different kind of biomarkers, and it's very much an evolving space. So I guess, yeah, I guess what is your kind of perspective on kind of those different biomarkers? What's most informative or you think is most relevant in terms of it's indicative of a clinical benefit? And I just know you guys have presented a lot of data, so it'd be great to just kind of hear your thoughts on.
Yeah. I mean, coming out of the phase I, it's the totality of the data. And because it's consistent across these different antigens, I think that one of the elements that we report on are these synaptic markers, so neurogranin and VAMP2, and one being a presynaptic sort of marker and one being a postsynaptic, and essentially a measure of general neuronal health. And if you go to the origins of the oligomer hypothesis, which is that these aggregates are diffusible and basically can bind to neurons in the synaptic cleft and essentially disrupt circuits and lead to tau hyperphosphorylation, these other things. So I think it's the synaptic markers as well as the phospho-tau markers. And then we had GFAP too. We had sort of an inflammatory.
So it really is our confidence in the target and the agent is significantly enhanced as a consequence of just that small phase I study.
Yeah. The other thing is that this biomarker field just continues to evolve pretty rapidly. So right now, I don't know, pTau217 is sort of the biomarker du jour. But by the time we get to the end of the phase II study, I'm sure there will be other biomarkers that will be very informative. In the phase II study, we'll be saving some samples for spinal fluid and plasma to look for whatever the new biomarker is that we'll want to evaluate in our phase II study.
Yeah. Yeah. That makes sense. And yeah, it's compelling how kind of consistent the story is across all these biomarkers, for sure. So yeah, I mean, I guess maybe on kind of this phase II, at one point, there were talks about potentially doing an interim, and that's not the case anymore. It'd just kind of be good to get how that picture's kind of evolved and kind of why you're not doing an interim?
Yeah. I mean, I think so, as I mentioned, we visited with the regulatory authority, well, FDA, and had a written interaction with EMA, and it became clear that the value inflection of a standalone phase II with a clean readout that could be registration- quality and eligible for being supportive evidence to go along with a single pivotal phase III is sort of the best value for money exercise, so the board, the company, we've sort of determined that that's the deliverable that we want to sign up to, and we're really encouraged at the rate of enrollment and the fact that we will read out roughly late 2026 so that we have cash into 2027. The setup, I think, for us is predicated on focusing on execution and not having some confounding analysis that takes a hit on alpha or jeopardizes the blind or any of those things.
So I think that's sort of the background. Again, we do get that question with, I think, understandably, but that's really not part of the current strategy and mindset of what we're doing.
Yeah. And the phase II really is just basically a small phase III. So it's registration- quality. Again, we expect it to be part of a BLA package of supportive evidence. So it plays a key role in this, obviously.
Yeah. Yeah. No, definitely. That makes a lot of sense. And yeah, I guess as you think about that readout, I mean, obviously, it's great if there's a really strong p-value and everything. But I guess kind of there's obviously going to be a lot of data again with these biomarkers. What I guess are you thinking about is a clear win on kind of the clinical endpoints? Is it you're just looking for a p-value, or is it more about the totality of the data? Just kind of curious what your thoughts are into kind of those data. Because obviously, Alzheimer's phase II, it's a challenging kind of.
Yeah. I mean, I think it's going to be totality of data and where we are in the moment, right? Because I think we can't yet anticipate precisely the way we'll be thinking about study outcomes as well as regulatory strategies. And so until we see the data, I think it's not going to be a binary p-value is the only determinant of success. I do think that there's going to be a little more nuanced than that would be my. I mean, I hope we just kill it on the p-value. But I think there's a lot of optionality in the ways that the data could read out and support moving the program forward and so forth.
Yeah. And that's what phase II is for, right? I mean, you want to show efficacy. And in our case, we want to show clinical efficacy. And if we hit a positive p-value, I mean, that's great. But we're going to look at the totality of the data to make the decision in terms of how to go forward and, again, even picking the doses. But when you think about it, the phase III for the approved drugs were like 900 in arm and we're at 180 in arm. So it's a pretty small study. But we get the right results, and then we really power it up and do phase III.
Yep. Yep. That makes sense. And the Lecanemab phase II was an odd kind of study design. And donanemab barely, I think it was like 0.04, but.
It was really close.
Yeah. And they missed on the CDR. They hit on the iADRS. Yeah. Wow. And I was just going to say, that's a good example, actually, of so Eli Lilly for donanemab, they had the iADRS as their primary outcome for both the phase II and the phase III. But the regulators are actually more familiar with the CDR. And so in the phase II, they hit on the iADRS, but they actually did not hit on the CDR. In the phase III, they hit on both. But the real question would have been if they didn't hit on the CDR in the phase III , would that have been a problem? Who knows? But the point is, the fact that they didn't hit on the CDR in the phase II was not an issue.
Yeah. No, totally. That makes sense. Awesome. So yeah, I mean, I guess now you're also working on a subQ formulation. So it'd be great just to kind of get the rundown on where things stand there and kind of how you're thinking about bringing that.
Sure. Yeah. So we partnered with Halozyme on a subQ strategy. And in the fourth quarter of this second half of 2024, launched a healthy volunteer subQ study, phase I study to evaluate the bioavailability, essentially IV versus subQ. And we'll have those results reported out in the first quarter of next year. And that'll help inform kind of what our next move might be for subQ. And we can conceive of a variety of different options of what next step to take in the clinic. And I think until we see the data, it's going to be we're going to kind of wait and sort of wait and see how that shakes out. I think we're very much committed to subQ as a complementary option to IV. I think we do envision a future situation where IV and subQ coexist for us or others.
I mean, I think there's a good rationale to providing both options to patients, possibly in this kind of induction maintenance kind of mode, particularly to the extent patients benefit from seeing a physician and getting into the clinic and so forth.
Yep. Yep. And I guess as it relates to the subQ, is there any specific considerations around? I mean, obviously, we'll have to see the data. But just in terms of what dose, because obviously, you're studying multiple doses in the IV setting.
Right. Yeah. So exactly. I think we have internal benchmarks as to what we envision as a competitive product profile. And that has to do with volume frequency of dosing. And that's sort of the internal metric that will assess what subQ strategy makes sense for sabirnetug.
Yeah. Because I mean, the dose is obviously important. But for subQ, the volume is particularly important. So we have to look at the volume and the frequency. And once we get our phase I data, then we'll have a lot better read on what the permutations are there.
Yep. Yep. That makes sense, and yeah, I mean, I guess as you think about the potential options, is it including it just right away in the phase III or sort of with lecanemab, right? It was in the OLE kind of switch in de novo patients from placebo. I guess what are some of the potential options there?
I mean, you just laid them out. I mean, we are benefiting from observing kind of what is working, what might not from a regulatory and development perspective. And I think we're not in a position to determine today what makes the most sense. I could see we can envision a variety of different options, including waiting for the phase III and adding as part of the OLE there.
Yeah. I mean, one thing we're working towards is to try to decrease the white space between the end of the phase II and the beginning of the phase III. So that's one of the things that figures into the equation.
Yep. Yep. That makes sense. Great. And then, I mean, you've talked about. You mentioned it briefly earlier. Just in terms of your runway and cash and kind of ability to kind of invest in both developing a subQ and bring this phase II kind of forward, it'd be great to just kind of get those thoughts in the last minute here.
Yeah. Last minute. So end of Q3, end of September 30th, we had $260 million in cash on the balance sheet. We've got it to first half of 2027 on the basis of that, completing the subQ phase I, completing the Altitude AD phase II study. And so I think we're in a healthy capital position to execute on the plans that we have right now on our plate.
Yep. Makes sense. Well, we have about a minute left if there's any questions in the audience or if there's anything else you think I didn't ask that should be highlighted.
No. I mean, I'll put a plug out there for our team just in the way that we've gone as a small organization, gone and executed essentially running a Big Pharma-like sizable phase II program. We're about 60 people. And we've had the benefit of working with good partners, good sites, and investigators. And it's been just amazing to see how rapidly this phase II has enrolled.
Yeah. Awesome.