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

All right. Here we go. Welcome to the webcast of the Acumen Pharmaceutical session. So Dan O'Connell, CEO, joining us. also Jim Doherty, Chief Development Officer; Alex Brown from the IR team. So guys, welcome. Thanks for doing the back-to-school conference.

[indiscernible] thanks for having us. Pleased to be here.

Awesome. Well, Dan, maybe just kick it off with the -- your -- maybe your vision for -- in Alzheimer's, given the launch of LEQEMBI and Kisunla today, maybe how would you grade that? And how would you look at this as a long-term opportunity? Like what differentiation or what rooms -- opportunity for improvement do you see from the current standards?

Sure. Thanks, Geoff. I think we're encouraged at some of the progress that's been achieved in the space. And the fact that we now have 2 approved -- traditional approved disease-modifying treatment options available to patients. I mean, our view -- we have been pursuing and developing Sabirnetug as an A-beta oligomer-directed antibody. So we think that is a distinct way to address disease pathology and potentially offer a better treatment option for patients in respect of efficacy and safety. And what's unique, Sabirnetug has, from its origins, been intentionally developed to neutralize these toxic species. And so we do think that, that -- our vision is that the field will continue to evolve and grow and that Sabirnetug and oligomer-directed treatment approaches may ultimately be sort of the best approach for patients.

Have you seen anything in terms of the science of how the identification of oligomers being deemed the toxic species, has the literature kind of evolved to where that's becoming more apparent? Or are you aware of studies ongoing outside of Sabirnetug that could also that could also help support that?

Sure, Geoff. So there's a large base of research and evidence in support of oligomers being distinctly toxic species of A-beta aggregation. And this is I mean this goes back over 20 years, even at some of the founding science around acumen. I think the -- that base of evidence has continued to grow. I do think we've also, as a consequence of what's been observed with these first couple of agents, there's been a fixation, if you will, on plaque clearance and in particular, driving up a reduction in the amyloid PET signal, as a means of correlating with a clinical benefit or essentially a treatment benefit for patients. We think the A-beta oligomer hypothesis has yet to be fully clinically validated, but we think we at Acumen with Sabirnetug, are well positioned to provide conclusive evidence, proof-of-concept evidence and evidence and so forth taking treatment and development strategies towards preferentially targeting this or exploiting the mechanism, if you will.

That makes sense I think in a lot of it's diversifying the opportunities, right? So we know that Alzheimer's disease is complex disorder. You were asking earlier about the drugs that are out there and it's fantastic for patients it's the milestone that we finally got into after a tremendous amount of work and investment to treatments that can treat Alzheimer's disease. But I think we're also seeing that no one therapy is going to be able to treat all patients at all stages of disease. And so -- in a lot of ways, this differentiated mechanism of action by going after the toxic oligomers is adding a real opportunity overall to the treatment.

And just given the data that you had thus far, Sabirnetug, the kind of the tolerability and the risk benefit. I think when you -- most people think about this indication having another mechanism added on would be helpful. And so -- what's your view of the combined ability, I guess, as you look forward, obviously, you have to wait to get the data results next year.

Yes, that's of course, that's right, Geoff. And I think -- part of our confidence -- much of our confidence, I should say, in Sabirnetug, is predicated on the Phase I data, right? The INTERCEPT-AD study we ran in 2022 through to 2023 was exclusively in Alzheimer's patients, and it was designed really as a proof of mechanism study. And in that study, we confirm target engagement. So the antibody hitting its intended target being oligomers, a safety signal consistent with a competitive safety profile in respect of tolerability and including RAE. And then we have these biomarker effects, which both on the PET imaging results, we had a modest sort of comparable reduction in the amyloid PET signal, but we also observed a modification of a series of different fluid biomarkers, both in cerebrospinal fluid and plasma. So on a short duration study in a patient exclusive study, we think all of that data holds together and puts us in the path to that optimize product profile in terms of risk benefit with Sabirnetug. And that's the evidence we're seeking to generate in ALTITUDE-AD. I think the future state of treatment will probably involve more than one agent that there are a variety of different sort of points of intervention that physicians and patients will be seeking for optimized treatment. So I think layering on -- there's -- as I know you're aware of this, there's this debate right now between the 2 commercial products of chronic treatment versus treat to clear. And we do think that the disease progression -- the disease pathophysiology continues even in the absence of amyloid -- of a PET signal. And so chronic treatment and addressing some of these other biological mechanisms such as oligomers or tau or inflammatory approaches as we sit here today, would -- I think it's safe to assume that they will be -- there's a future for that -- those types of multiproduct combination strategies.

Makes sense. Well, Dan, you mentioned the blood-based biomarkers. So I wanted to ask you on the sort of the diagnosis angle of it. Is it helping you think, raise the awareness, maybe stage patients? Do you -- how do you see it helping you guys? Is it more just helping with enrollment -- the speed of enrollment? I just want to get a view of that. The way it could play out clinically and then also commercially.

Sure. I'll take a first stab at that, and then Jim, I'm sure can follow on. So I think right now, the fluid biomarkers are fundamentally enabling, right? They're creating greater awareness in the population that if you have a suspected case of Alzheimer's disease, there's research that can be done. There are products that you could be -- you could be going on or you could be entering a research study such as we had with ALTITUDE-AD. And we employed of plasma-tau 217 plasma biomarker as part of the screening process. So we do think that, that contributed considerably to the sort of speed and efficiency that we were able to enroll the study.

I think we're in the middle of kind of step change in the precision that we've got around being able to diagnose in Alzheimer's disease. You saw that for the first time with the [indiscernible] right? So you went from a truly clinical diagnosis dementia, and what we found when the [indiscernible] came around that many times, those were not truly Alzheimer's cases. It was dementia for another reason. And it was that precision and that ability to see more data that made such a difference. Same thing is happening again with the fluid-based biomarkers. There are a number of them. There are markers that are more associated with the target amyloid-related A-beta 42:40 ratio be the obvious example. There are the tau markers, which are also a core pathophysiology in Alzheimer's disease, and then we and others are also looking at downstream synaptic markers. So you're getting an awful lot of data on what's happening in the brain for a patient. And it really creates the opportunity to in many ways, stage patients in a way that hasn't been possible before. So to understand where they are in the course of disease, and perhaps create a situation where you can craft the right treatment for the right patient. We know that Alzheimer's disease is not diverse. It's not the same pathophysiology for every Alzheimer's patient. So I think that's where the field is going. There's been explosion of work in biomarkers, both in the number of biomarkers but also in the types of studies that are being done, to really understand where you're seeing signals, what the signals are correlating with. And so I think you're going to see a real improvement in staging and diagnosing individual patients. And I think that only benefits being able to target new treatments.

I think it's going to be more patients seeking more treatments. And essentially, if you think about the funnel and the logistics of the way the commercial products have rolled out, I mean having the ability to prioritize patients from a blood test is a much more efficient when -- way to get the right people into the funnel to go through steps to come on an anti-beta or anti-amyloid product.

Have you guys seen anything? I mean this is genuinely the last real frontier it has been for decades. In terms of unmet needs and the science. Have you seen anything that's maybe noticeable on the AI or machine learning angle to try to put together all these data points, everything from cognition to biomarker data to mechanism data to clinical data like that's even reliably predictive or that could enhance the chance of success?

Well, I think there's a lot of interest in sourcing the data sets that would inform those models. And I think that's the real question the quality of the data set, and there's a massive amount of it. We were just talking about this at lunch, actually. Because and it's like multimodal, whether it's EEG, it's biomarkers, it's clinical assessments. So I think that AI or machine learning will have a contribution to those advances in the future, a lot of interest nothing that I can point to you today off the top of my head that says like these folks haven't figured out.

There's no new discovered like a mechanism or correlation or anything like that through...

No. But I mean the progress of technology, I mean even in the biomarker space, we've seen rapid evolution of a series of different [indiscernible] whether it's [indiscernible] 181 to 217, there are a couple of others that are in mix. As those diagnostic platforms continue to be able to multiplex across a bunch of different targets, you're going to -- you'll extract the things that are most pertinent to a disease population such as Alzheimer's disease.

So on that same thing with a diagnostic test. I guess, what are you hearing from physicians using it? Obviously, you guys have accredited that use of the two accelerate the enrollment process and also get the trial up and running a little bit faster, I guess, what are you hearing from actual kind of physician usage?

So I think it's increasing is the short answer. Certainly, our trial is kind of a real-world example of the benefit that having that kind of quickly accessible data can offer. I think that as i was saying a few minutes ago, we're really in the midst of a lot of studies ongoing. Looking at how these various markers can be correlated. And I think as more of that data comes around, coupling that with the ease of use and the sort of rapidity of getting results back, I think more and more physicians are going to continue to use the data. You're already seeing that, but I think that, that's only going to increase as more of the survey data comes in.

At the AAIC meeting in Toronto earlier this summer, we presented a poster on some of the economies and efficiencies that using the 217 assay yielded in the ALTITUDE-AD study. And I mean the cost differential between the blood test and a PET scan is a factor of 10 or more. And so that -- that alone is just a good indication of how the progression of these better diagnostic, more efficient and yet it's precise measures come to open up the clinical market.

And then moving forward, obviously, with the diagnostics using for p-Tau 217, are there other biomarkers that you guys are looking up behind the scenes? Or do you think it's going to say to say that p-Tau 217 is kind of like the clear real winner here?

I certainly think 217 is the one that's drawn the most attention, and it does seem to be a very sensitive marker and there's a lot of work trying to understand how well it correlates with the drug effects and things like that. There are also a lot of studies looking at as patients progress in disease, how the 217 signals change. So definitely a lot of interest in that market. And I think in the short term, that does mean that's the one that we're going to learn about the most about in a short period of time. But I do think there will be other markers that kind of get added to that list. I mean one of the real opportunities with a plasma-based system is you don't have to do a single marketer and you can get multiple signals from the same sample from a patient. And so I think you're going to see rather than things supplanting 217 because I do think it's going to turn out to be one of the most sensitive and most useful markers. You'll see other things added along with it.

Yes. And [ equipment ], I mentioned the fluid biomarkers in Phase 1 and the ALTITUDE-AD. I mean some of the -- we looked at A-beta, some of the tau species, but also some of the synaptic markers of neurogranin and [ BAM2 ]. And as we think about the toxicity of oligomers, the evidence over 20 years suggests that they have a propensity to bind neurons, induce calcium influx, disrupt neuronal signaling and essentially result in the loss of -- synapse loss. So as we see like a short duration study such as INTERCEPT and Sabirnetug at the higher dose levels, demonstrating not only significant changes, on a dose dependency on neurogranin and [ BAM 2], I mean that's really at least compelling in terms of our mechanism, how ultimately that might yield the differentiated efficacy profile that we look for Sabirnetug.

And along those same lines, we talked about combined ability. I mean, everyone says beta amyloid and tau are probably the 2 toxic species that you want to get rid of sooner than later, but it doesn't -- so far, it doesn't look like tau is as effective. I mean, any updated thoughts of whether that is still a viable strategy in your view or whether tau is simply more of a biomarker and less of a disease kind of modifier?

Well, I'd first offer that tau is still a promising therapeutic target in the disease, presumably. I think what we have observed or experienced is in the A-beta spaces taken us 25 years to get to where we are right now, and we're still debating about plaque clearance versus proto firewalls versus oligomers. And tau biology is an order of magnitude more complex than A-beta. And so I think we've learned -- if you're tracking tau, we've learned kind of what not to do, which is what we also did in the amyloid space with Monomer targeting agents and so forth or pan-amyloid targeting agents like [indiscernible]. There are a couple of studies. There are some ongoing programs that might read out in the next 12 to 18 months in the tau space that would help inform what to do in terms of a tau-directed intervention. So I think it's -- the jury is still out, but it is a consequence of learning what not to do and then ultimately focusing in on the thing that is most therapeutically beneficial.

Yes. And those -- they talk about -- sometimes talking about A-beta being the trigger and tau being the bullet. The fact that we have an oligomer-directed agent that's had downstream effects on tau species again, is sort of encouraging, but to think that you could be doing both in oligomers-directed agent and then augmenting with tau directed product or treatment is that possibility still is very much exists.

And just to follow up, you hit the nail on the headwind. I mean it's just taken a long time to get to where we are with just beta amyloid. Do you think that the tau biomarkers are from a regulatory standpoint are they robust enough or they would take maybe shorter-term kind of changes to p-Tau 217. Like is there -- because I look at like the HEP C angle, right, like that went from 48 weeks to basically 4. Right, is that's -- the 4-week was predictive of what you'd see. We're not going to go on that speed. But like is there a 3-month or a 6-month biomarker trial in Alzheimer's that you could feel confident in using biomarkers that you drug -- a drug has an effect?

For drug effects, probably yes, for regulatory purposes, I don't know that I'm ready to -- or I would be willingness to say that agency is willing to accept or extend the label. But I do think those biomarkers are faster turns on what's working and what's not from a development derisking standpoint.

Yes, I think it's fair to say we're not there yet. But I would also say this is part of the promise is that there's enough data emerging and individual markers that assuming enough data gets generated, you could see making an argument to the regulator to do something like that. And they're certainly paying close attention to the science that's emerging and they are engaging in conversations. But I think they're appropriately going to be pretty conservative, and they're going to want to see a lot of data before they go down road like that.

And on the AI and machine learning piece, is there other -- is it the company that don't -- why is the data quality not there? I guess there's not maybe a third-party repository of data that could everyone could look at? I'm just trying to think of like the companies want their own access to their own data and they're not going to share.

Well, there's an interesting -- let me see -- so there's an interesting dynamic now that the space has gone commercial and I've been in this space for an extended period of time longer than I might care to admit. And it had been a very collaborative work, data sharing, impetus and precompetitive strategies were kind of maybe in the last 10 years, we're kind of more than normal. I think there's a little bit more of a proprietary siloing now, where people don't want to enable a competitor unnecessarily in the space. But so I don't know that there's a quality -- it's the data sets, it's quality, but it's also scale, diversity, how well characterized those data sets are. So some companies that have been in the space for an extended period of time, they have unique insights applying AI to those...

And maybe will we learn anything from the commercial, if we do follow on the...

Yes, the real-world evidence, absolutely. I mean we're already starting to see some of that and kind of most prone to do -- to benefit from all of that stuff gets back translated, I think, into really kind of stepping closer towards a personalized medicine for like getting the right patients on the right drugs.

And I know you're not in the prediction business, but if you had a win for ALTITUDE-AD, what would you say that will look like? Is it preliminary? Is it numerical? Is it what -- I mean you're probably not going to get too much stats on it, but I don't know, just help us out.

I mean it's a reasonably powered Phase II, intended to be a proof-of-concept study. We're prepared for all outcomes, including an upsized success one, where that extended dosing of a oligomers-directed -- oligomers-directed antibody yields a pronounced efficacy benefit and does not have the ARIA liability associated with plaque clearance. So mean, yes, I'm not -- I can't predict, but I'm certainly encouraged to think that we have a real possibility of having that outsized success with ALTITUDE.

Yes. And I can't remember. I think we've talked about this, but if you think about the Lilly's strategy of only having the drug onboard and removal all the plaque then that's it versus the Biogen strategy of having on board 18 months and the clinical trials are indefinitely commercially. Is there evidence for keeping it on board while you clear plaque completely?

Yes. I mean I think if you look at the Lilly data or the Eisai and Biogen data, chronic dosing with the right agent seems to be until a patient progresses out of a particular stage of disease seems to be appropriate. I mean the best evidence, I think, in support of chronic dosing is that gap period that Eisai had with LEQEMBI, which was they stopped dosing, they weren't sure if they were successful, and then when the study was successful, they put people back on treatment after, I think, on average about 12 or 18 months. And the PET signal increased over that period of time, modestly, but other the p-Tau 181, some of the A-beta 42:40 ratio, all of the other biomarkers sort of came back online, if you will, in the absence of the intervention. So that would suggest that keeping people on treatment while they're not whether they have an advanced to moderate disease or frank [ dementia ]. And where you can keep -- and this is where being able to monitor the biomarkers becomes clinically relevant where you're sort of assessing progression not only on clinical measures, but on the biomarkers and not relying exclusively on an amyloid PET, right? I mean that's the one of the -- if you take a step back and you look at Donanemab as a pyroglu A-beta directed antibody that's designed to clear plaque, I mean they deplete target. So it doesn't make sense to actually keep people on Donanemab in the absence of plaque. And yet there's other A-beta biology that continues to advance the disease as supported by the ASI data.

So it could be that you have, say, a foundational oligomer that maybe has not picked up on a PET scan, but constantly being clearing it out.

I mean that -- I mean at that level of description, I can assure you that's the case. I think the complexity of which is at protofibrils or large oligomers or small oligomers. I mean, there's a variety of different species. And these things, they do work kind of in an equilibrium. So I do think that plaque clearance does have secondary effect on reducing presumably a secondary effect on reducing oligomer levels. But I think most of the evidence that we've seen would support chronic dosing again, while a patient is kind of within that early AD space. Now the other area that's of great interest to us in the near -- at some point in the future is this preclinical Alzheimer's population where they're A-beta oligomers pathology is pronounced. Like that's really the initiation phase of disease as aggregation is starting and where you're having presumably like subtle effects on neuronal and synaptic health, that don't present as clinical symptomology yet and essentially, the horse is leaving the barn and sort of the process has started, and we'll continue to advance in the absence of some intervention.

Makes sense. I guess changing gears a little bit, I guess, over the weekend,LEQEMBI subcutaneous formulation was approved for maintenance dosing. We know that you guys are developing a subcutaneous formulation yourselves, I guess, if there's any color around that, how the company is thinking about the subcutaneous formulation or kind of greater what do you think it means for the field as a whole?

Yes, absolutely. And as you say, there is now an approval for maintenance for subcutaneous formulation. And I think we, like everyone else thinks that one of the major things you gain with a subcutaneous formulation is much more flexibility and ease of use to administer the drug. And so there are likely to be patients who will want to retain an IV approach, but there are probably a lot of patients who would like to be able to switch over and use a subcutaneous strategy. Some recent studies were just discussed at AAIC suggesting that for a number of patients they're readily able to do that and master themselves. So definitely, we feel like that's going to be a value to any treatment is to have that ability. And so as you say, we have run a Phase I study in healthy volunteers with a formulation that a [ Comex ] formulation that will allow for larger volumes to be delivered. And we -- based on the results from that study, we're continuing forward with our approach with subcutaneous -- we really kind of want to see the results from the ALTITUDE-AD before making too many next steps with a subcutaneous approach. So what we've been saying is we're likely to complete that study and then based on results, look at including an arm or component in our Phase III study that we will be doing to follow on with the subcutaneous formulation.

That's sort of our first approach to subcutaneous. We've also announced recently a collaboration with JCR Pharmaceuticals. I know you guys know about for a blood-brain barrier approach. We're calling it enhanced brain delivery or EBD. So in our view, in the EBD approach, we already love the profile of Sabirnetug, as James been saying, but if we are able to increase the fraction of a drug that's being delivered into the CNS, that gives us a lot of flexibility with dose and with formulation and with amount delivered. And so that would be a second opportunity to go to a subcutaneous administration.

Awesome. Also on your collaboration with JCR. There are some other players looking at transferring -- in the transfer I guess, what do you think differentiates I guess, your now new approach as opposed to other players field?

As we looked pretty thoroughly at the opportunities that are out there and the strategies that are out there. And as you say, a number of people who are targeting transferring as the shuttling mechanism to get into the brain. There are -- just as an aside, there are a number of other proteins that form -- play a similar role. So there would be other possible targets as well. But we landed on transferring because there's the most clinical validation for transparent in these sorts of products. And then in the case of JCR, they have clinical experience. They have a marketed product called IZCARGO that's approved in Japan for Hunter syndrome. And we like their experience and we like the epitope that their technology binds to. What they've seen with this cargo is they have not seen signs of anemia with their drug. So that's something that we'll, of course, will need to be played out with the collaboration to see if that holds, but we're definitely attracted by their approach to targeting transferrin receptor and the lack of anemia that they've seen with their IZCARGO product.

What's aspirationally using a transport or transferrin or however mechanism you get across the blood-brain barrier? What's your view of where this theoretically could go in terms of the dose? Could you cut the dose half by 90% -- Like, I don't know the number. It seems like I don't know -- I think it's less about, in my opinion, the dose and more about maximizing the effect size. Because you can run into, I mean, ARIA, et cetera. How do you think that, that will all kind of shake out from the transport side of things?

Yes. Well, I mean, as Jim is suggesting, I think having that greater fraction of drug in the central compartment in the brain interstitial space through this receptor-mediated transport has advantages. I think with Sabirnetug, we don't -- relative to plaque-directed antibodies we're not running into a dose limiting ceiling. In the Phase I, I think we conclusively showed that. So for us, it's really more about these EBD approaches seem to have a combination of potentially an intrinsic safety benefit just in terms of avoiding all CAA plaque because of the capillary delivery, the lower dose requirements to get -- achieve an equivalent efficacy and all of the safety and thereby just the convenience of doing that in a subcu format.

So I think there's -- yes, there's -- the those pieces as you look around the it's sort of like a somewhere between a 3 or fivefold reduction in the dose levels that are equivalent to IV is sort of, I think, the benchmark out there.

Okay. And what sort of time frame do you think you can get to, say, a proof of concept?

Well, we've guided to preclinical candidate designation early '26. So we're actively working with our partners at JCR, a profile -- different carriers in different cargo's or payloads. So the JCR transferrin carrier technology, there are a variety of different configurations on the front end of that. And then we're looking at Sabirnetug and Sabirnetug-like payloads or cargo's. And we have under the terms of agreement, which I would say, really capital-efficient way for a small company like ours to get into validated space fiscally responsible deal that we think we'll have the preclinical data sets early next year, to then, in a perfect world, those are adequate to help us move towards IND and then getting in the clinic in '27.

Yes. Okay. So that makes sense. Just from the landscape, I know the recent Prothena data sort of not optimal. That's another company in the space that people had a lot of hopes for. Any like higher level of views of that I mean that's the way the is in the...

I think you putting it in the category of Alzheimer's is a challenging and occasionally humbling space to be active in. And I think that we have -- we definitely have a very different epitope and mechanism and feel like we're on the right path with Sabirnetug in terms of that risk benefit profile for patients.

Yes. What's your view of the -- because I know the Denali's and [ Electors ] of the world that have had novel mechanisms of action. I mean -- I mean, as we talked about earlier, it's not like this is a completely met -- medical need. I mean, so but you're adding risk on top of an already high risk indication if it's not a proven sort of validated mechanism. But there is still a need to do something different, right? Is there a mechanism that you think is -- looks interesting that's outside of the beta-amyloid kind of tau access, either inflammatory. I mean people are talking about the GLP-1.

GLP-1 is going to be -- could be very interesting this year with the EVOKE readouts. I mean that -- I don't think I'm not in the business of making predictions, but if that were positive or directionally -- even just directionally positive, I think it would usher in a lot of enthusiasm for [ complementoring ] A-beta tau strategies with GLP-1 approach. I think the TREM2 space is still -- still has some potential, I think there's more learnings to be had there, but this whole inflammation component of Alzheimer's pathology, certainly an area of -- that we should continue -- the field should continue to pay attention to.

Got you. Okay. Ross, do you have any? No. Okay. Any final thoughts? Are you good? You cover everything?

Well, I think we covered a lot of ground. I do think it's -- it really is an exciting time for the space. And even on that last question, I think there are so many possibilities when you consider inflammatory approaches, for example. But one of the challenges is -- there are a lot of different possible combinations to look at. So when we talked earlier about biomarkers and how that's going to be useful you can envision efficient trials in the future are going to allow you to look at combinations in a different way.

Yes. To me, it seems like this is ripe for sort of AI and like let's try to check that box in the next couple of years to see, if we can uncover a novel mechanism or staging or some element.

And you think about that technology coming on, Geoff, in a situation where the population -- the unmet need will persist, right? This isn't going to go away overnight. I don't think anybody is going to sort of steal the bacon here. So I guess it's sort of continued progress and exciting time in some of those enabling technologies, whether it be the AI and/or biomarkers or some combination. Certainly improves probability of the success in the future and better options.

Thank you, guys.

Thank you very much.