Acumen Pharmaceuticals at Stifel CNS Days: Alzheimer’s Drug Progress

On Tuesday, 18 March 2025, Acumen Pharmaceuticals (NASDAQ: ABOS) presented at the Stifel CNS Days 2025, showcasing their advancements in Alzheimer’s disease treatment. CEO Dan O’Connell highlighted positive Phase 1 trial results for their drug Subernatog, while addressing challenges in clinical infrastructure. Despite a slower-than-expected market launch for A beta drugs, Acumen remains optimistic about future developments.

Key Takeaways

• Acumen’s Phase 1 INTERCEPT AD trial showed promising safety and biomarker results for Subernatog.
• The company is enrolling patients for the Phase 2 ALTITUDE AD study, aiming for completion in the first half of 2025.
• Acumen has a strong cash position with $259 million, ensuring operations into 2027.
• Collaboration with Halozyme for a subcutaneous formulation is underway, with initial results expected soon.
• CEO Dan O’Connell emphasized the potential of Subernatog as a next-generation Alzheimer’s treatment.

Financial Results

• Cash Position: Acumen reported approximately $259 million in cash as of September.
• Cash Runway: The company expects its cash reserves to support operations until the first half of 2027.

Operational Updates

• Subernatog Development:

- Phase 2 ALTITUDE AD study is enrolling approximately 540 patients.

- The first patient was dosed in May 2024, with enrollment expected to complete in early 2025.

• Subcutaneous Formulation:

- Partnering with Halozyme, with Phase 1 results comparing subcutaneous and IV Subernatog expected this quarter.

• Clinical Trials:

- Phase 1 INTERCEPT AD trial showed safety and effective target engagement.

- Phase 2 ALTITUDE AD trial involves two IV doses (35 mg/kg and 50 mg/kg) compared to a placebo.

Future Outlook

• Clinical Development: Acumen plans a confirmatory Phase 3 trial post-Phase 2, aiming for rapid submission.
• Chronic Dosing: Focus on early-stage treatment and precision medicine using fluid biomarkers.
• Differentiation Strategy: High selectivity for toxic oligomers to improve safety and efficacy.
• Regulatory Strategy: Monitoring regulatory developments for new formulations.

Q&A Highlights

• A Beta Drug Adoption: Slower uptake due to lack of infrastructure, but expected to become a cornerstone treatment.
• Amyloid PET Signal: Belief in oligomer proximity to plaque affecting PET signals.
• Dose Selection: Phase 2 doses chosen based on Phase 1 data for potential differentiation in treatment outcomes.
• Interim Analysis: Omitted to maintain regulatory eligibility for the study.

For more detailed information, please refer to the full transcript below.

Full transcript - Stifel CNS Days 2025:

Julian Pino, Associate, Stifel: Hello, everybody. Thanks for joining. My name is Julian Pino. I’m an associate on Palmettois’ 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, focusing 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 and a. Thanks so much.

Dan O’Connell, CEO, Acumen Pharmaceuticals: Yeah. Thanks, Julian. Thanks to you and Paul and the team at Stifel for including us in this year’s CNS days. So quickly on Acumen. Acumen is a clinical stage biopharmaceutical company that is developing a novel therapeutic that targets toxic soluble A beta ligers for the treatment of Alzheimer’s disease.

So our our goal at Acumen is to to develop innovative treatments to preserve quality time for all people impacted by Alzheimer’s. And in this pursuit, we’re leveraging a highly dedicated team with extensive CNS 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 A beta oligomers in Alzheimer’s disease. And a differentiated product candidate in Subveratog, which is an oligomer directed monoclonal antibody that first generated positive 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 five forty patients evaluating two active IV doses versus placebo. We are also evaluating the potential subcutaneous formulation of subunit in partnership with Halozyme and the initial phase one results from a healthy volunteer study comparing PK and exposures of subcutaneous versus IV Subernatrug are expected this quarter.

Julian Pino, Associate, Stifel: Perfect. Thanks so much for that overview. And, so I guess just really quickly just to level set, you did generate some Phase 1b data last year that was super interesting. Did you want to just highlight, you know, hit on some key points there and, yeah, I’ll just leave it there.

Dan O’Connell, CEO, Acumen Pharmaceuticals: Sure. Thanks. So, as I mentioned, Subernatog, formerly known as ACU one hundred and ninety three, is a humanized monoclonal antibody that was discovered and developed to have properties to to to, selectively target, toxic amyloid beta ligomers. And there was an ample base of nonclinical evidence in support of its mechanism and the rationale for targeting, oligomers in Alzheimer’s disease as A beta oligomers are identified as early triggers and persistent drivers of Alzheimer’s pathology. We took SabrinaTug into a exclusively patient only phase one study, what we refer to as the INTERCEPT AD study.

And that was a single ascending dose and then multiple ascending dose cohort study. And in that study, we generated a compelling overall safety profile with a low incidence of ARIA inclusive of some of the elevated dose levels. I mean, importantly, we also observed and were able to establish oligomeric target engagement. And so using a novel method translated from some of the non clinical work that was undertaken in support of the program, we were able to demonstrate ACU 193 or SubarnaTag bound to A beta oligomers in the cerebral spinal fluid of patients that were involved in this study. Not only do we see target engagement, we saw a dose response inclusive of sort of a plateauing effect at the highest dose of sixty milligrams per kilogram in the MAD portion of the study.

So 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. So for instance, in the MAD study, we had two cohorts, one at fifty mgs per kg dosing every two weeks and then one at sixty mgs per kg dosing every four weeks. And with just three administrations of drug in either of those cohorts, we saw a reduction in amyloid PET at a rate and magnitude comparable to, for instance, Lekhembe at their three month PET scan in Clarity AD. In addition to the imaging effects, we saw consistent effects, actually not only statistical, significant effects in cerebral spinal fluid markers of Alzheimer’s neurodegeneration, not only amyloid and certain tau species, phospho tau one hundred and eighty one and two seventeen, but also some synaptic markers, which are really important for our mechanism as we view that oligomers have, toxic properties to neurons and and disrupt neuronal circuits, induce tau hyperphosphorylation, activate immune cells, and really, you know, consequently, induce functional impairment.

So these these observations in phase one were kind of on mechanism for subunitug, as a a ligament 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 two STUDY, THAT WE ARE ENROLLING AT PRESENT.

Julian Pino, Associate, Stifel: EXCELLENT. Great. Thanks for that summary. And and, yeah, I think just the consistency of of the overall target engagement data as well as the, you know, positive surprise on, you know, the the effect on amyloid PET and the biomarkers, it’s all it’s all super exciting and and interesting. And, and of course, you’re now, you know, in in a phase two in in Alzheimer’s with Subernatog.

And, you know, you’ve commented, you know, previously on, you know, the enrollment dynamics so far. I guess, can you just provide a little bit color as to where you are currently and when you expect to complete enrollment in that study?

Dan O’Connell, CEO, Acumen Pharmaceuticals: Sure. So, again, we can’t underestimate the value of the phase two results in the in the patient based study. And really, that’s serving as a foundation for the value proposition of participating in altitude AD. And this, you know, first, you needed to sort of pass muster or pass test with, you know, high quality research sites, investigators that kind of had been in this field, been active investigating other agents, you know, of this mechanism or others. And 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 readily, you know, such 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 five forty patients approximately in this study. So one hundred and 80 patients per dose cohort, two active doses versus placebo. And we enrolled or dosed the first patient in May of twenty four. And we’ve guided to completion of enrollment in the first half of twenty five.

So for a relatively small emerging biopharma company, swimming in the AD space, you know, the key 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. And then again, the subverted type profile of, you know, potentially a better risk benefit profile for people even willing to go into research based studies.

Julian Pino, Associate, Stifel: Doctor. No, absolutely. And, yeah, especially with commercially available drugs and Alzheimer’s in the same class, it’s certainly really impressive. And I think that’s what a lot of investors would like are wrestling with is just trying to understand why is it that some of these A beta drugs have launched a little bit slower than expected, even slower than some of even skeptics predicted. And I guess, what are your thoughts on that?

And any sort of, updated opinion based on what you’ve heard, from people in in the space over the last several months?

Dan O’Connell, CEO, Acumen Pharmaceuticals: Yeah. Sure. Sure, Julia. And I and I I wanna look, I wanna actually take a step back too in terms of the differentiation because the field generally has been at this effort for almost a couple decades, right? And 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. And so I think, you know, we really want to present Subernatog as a distinct and uniquely positioned product given its high selectivity for toxic oligomers. And so that we’ve underpinned, you know, some of the prior data. We’ve done some more recent work that was presented at our R and D day back in October, really highlighting the selectivity for oligomers versus, for instance, monomer, even versus Lekhembe and, adakenumab. And, of course, denanumab has a very different mechanism, which really doesn’t see oligomer.

So the clinical path to differentiation for subernatag, we think, is really robust. I think the clinical adoption of these, you know, first generation products, has been, has not met certain expectations, but I think it’s kind of gone as we might have predicted, given the absence of an established clinical infrastructure to, you know, readily identify and diagnose patients, get them to infusion centers. So, 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 out of 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.

And 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 and adoption over time.

Julian Pino, Associate, Stifel: No. It makes sense. And and definitely appreciate you highlighting the, you know, the differentiation that that can be offered, by Subernatog and, you know, certainly distinct from from denanumab, for example, and and, you know, lecanumab does 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. So I think, you know, we do have a a question from, an investor that’s asking sort of, you know, why do you think it is then that Subernatog is, you know, removing plaque at a level that could be detected by by pet and, you know, is it really differentiated?

So curious to hear your thoughts there.

Dan O’Connell, CEO, Acumen Pharmaceuticals: Sure. No. I mean, look, we get the question a lot. I think that, there is some uncertainty as to the the definitive explanation, but we 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. And so, given that proximity to plaque and given some binding affinity for fibrils, it’s it’s likely to be some combination of, a depletion and an equilibrium shift of the of the toxic species, which we think is is mechanistically on target.

But 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. So I think, you know, we’re kind of in the mid innings of this field that, you know, really, I think Siburnatug stands as really still the, 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 and clearance of, you know, essentially, eliminating the the pet signal.

Julian Pino, Associate, Stifel: Mhmm. Yep. Totally makes sense. And, 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 a 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? Do you have any thoughts on that? And, yeah, I’ll just leave it there.

Dan O’Connell, CEO, Acumen Pharmaceuticals: Yeah. Well, well, I think, you know, we take the position that the 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 learned. So it’s not just, you know, clear the pet signal and come off treatment. I mean, I think there’s a there’s growing evidence.

I think, Biogen and Acyte 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 that and the justification for chronic treatment, which probably, you know, does align with with our thinking that these soluble aggregates, you know, are persistently present. And, you know, to the extent that they’re damaging circuits and neurons, they should be they should be targeted. So that, you know, we, you know, we’re still we got we have a phase two to read out as the primary, clinical proof of concept. But ultimately, I would envision, these chronic dosing paradigms are very likely to go hand in glove with some of these fluid biomarkers, right? We’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, you know, 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 the next five to seven, you know, timeframe that, you know, we think, you know, subunitag is going to be advancing in late development. Mhmm.

Julian Pino, Associate, Stifel: No. It definitely makes sense. And I think it it already shows FDA’s, you know, open to that with biogenetic size approval of, you know, a maintenance sort of less frequent IV dosing. And 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 Subernatug, you selected at sort of a mid dose and a high dose.

Would you be able to just explain the rationale there and what your expectations are?

Dan O’Connell, CEO, Acumen Pharmaceuticals: Yeah, sure. So real quickly, in the phase one, we had these single ascending, multiple ascending doses. In the MAD dose cohorts, we had, ten mgs per kg and then fifty mgs per excuse me, twenty five mgs per kg dosing every two weeks, and then, sixty mgs per kg. And so what we elected to do as a consequence of the target engagement, a lot of PKPD modeling for the doses in phase two, we elected to take forward a top dose of fifty mgs per kg. And I should mention, this is dosing Q4W, so every four weeks.

So less frequent than the can be, you know, sort of similar to what the nanomab is doing in terms of monthly IV dosing. Dosing. So, fifty mgs per kg as the high dose and then thirty five mgs per kg as what you characterized or maybe we did previously as a mid dose. And so, 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.

And they may equivocate on efficacy. I mean, we don’t know. So it’ll be it’s going to be interesting to see, how those read out. We think there are multiple ways for us to read out the, ALTITUDE 80 study in a positive way for Subernatog. And it’s really going to come down I mean, the simplest way for us to describe it is, you you know, the risk benefit profile.

I mean, we I don’t think, the current agents, get, you know, materially safer or more efficacious in the real world. And I think there’s been some, you know, maybe they, we know how to manage them and we can deal with it. But there’s some unique properties to subunitide that suggest it may be, even safer. And the real home run will be if, in fact, you know, having a preference for these toxic species and and going at those in a primary direct fashion can unlock greater efficacy. And that’s, you know, really, kind of our goal at Acumen and with SubarnaTug is to unlock that, you know, optimal sort of risk benefit profile for patients.

Julian Pino, Associate, Stifel: Totally makes sense. Appreciate the explanation. And, I guess for the ongoing program, you’ve elected to to not conduct an interim analysis. Just curious how you think that impacts your, the utility of of sort of this trial and, you know, its sort of role in the overall program, if you will.

Dan O’Connell, CEO, Acumen Pharmaceuticals: Yeah. I mean, you know, the interim has been out of out of play for some time. We made this decision a while back, basically, as a consequence of some regulatory interactions. You can go back to to to ’23, where there was a lack of concordance between regulatory authorities. And 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.

So we think there’s the most expeditious path to a submission is to complete this phase two, move quickly into phase three, a single confirmatory phase three, and really be in position to to file, you know, as part of that package. So the the the viability, utility, and and value of, an interim analysis as was maybe originally contemplated prior to going into some of those regulatory interactions seem to be voided as a consequence of, those discussions.

Julian Pino, Associate, Stifel: Understood. That’s clear. Great. And, you know, you mentioned in in the very beginning of the discussion, the, the ongoing collaboration with Halozyme for the subcutaneous formulation. Can you just describe the decision to partner with them, where things currently stand and, yeah, expectations for, you know, what exactly we’re going to get with respect to this data, over the the next, couple weeks or several days.

Dan O’Connell, CEO, Acumen Pharmaceuticals: It’s a yes, and we’re it is this quarter, and it is March. So the the choice to to partner with Halozyme was was a pretty obvious one for us. I mean, they are, the most established leader in co formulation, subcutaneous formulations with seven approved products, if I remember correctly, maybe eight, you know, a long track record in enabling subcutaneous products. So 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. So that’s all been of great benefit to Acumen as, you know, we don’t have a tremendous amount of that expertise in house. So good partner by definition. For the top line results, you will have initial results this quarter. So it’s very close to being time the witching hour.

We’re basically looking for general p PK and drug exposure comparison between sub q and IV. And I will also mention, you know, this is a healthy volunteer study. So 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 subcu, so we can get some insights into kind of the exposures and and what the next steps might be for advancing a subcu option.

Julian Pino, Associate, Stifel: Mhmm. Got it. Totally makes sense. And 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 the contemplation there would be helpful.

Dan O’Connell, CEO, Acumen Pharmaceuticals: Yeah. Those are, 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 the phase one data, you know, discuss the implications with our partners and and assess next steps. I also think we we’re paying close attention to what’s happening elsewhere and with the regulatory bodies because I think that’s 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.

So 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 new formulations for existing kind of products, if that makes sense.

Julian Pino, Associate, Stifel: Totally makes sense. And, I guess, is there anything in the phase two, IV study that you’re looking at that you think could inform dosing for the sub q specifically?

Dan O’Connell, CEO, Acumen Pharmaceuticals: Well, I think I mean, I mean, I think the phase two, dose, you know, the comparison we just described between thirty five and fifty Mhmm. Certainly, you know, is gonna inform what a sub q strategy or ultimately a sub sub q strategy should should, you know, what form it might take. So I think that’s also a consideration for us, you know, in at some point in the future.

Julian Pino, Associate, Stifel: Mhmm. Then also with respect to safety, we’ve seen Lilly, have some interesting data where they reported lower ARIA for denanumab with a revised titration schedule. Any thoughts on that? And is that something that, you know, Acumen may potentially consider in the future?

Dan O’Connell, CEO, Acumen Pharmaceuticals: Yeah, Julie. Yeah. And in fact, I was at the I think that was CTAD in, in the fall where they presented sort of that dose titration adjustment that did appear to make an impact on the rates of 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 fifty mg per kg dose cohort actually involves two administrations at thirty five mgs per kg. So we, you know, even back in May, you know, when we launched the study, had kind of, you know, as a consequence of input from, you know, our our leadership and CMO determined we would use that, you know, to, mid doses essentially as you’re onboarding patients and then titrating to 50.

So, you know, I think that’s, it does seem that that ARIA rates generally in this population are principally exposure driven, you know, that we’ve seen, you know, more, you know, the notion that sub Q was going to have an intrinsic safety benefit hasn’t played out in terms of the, in studies or in practice. So, I do think, titration strategies and patient stratification, I mean,

Julian Pino, Associate, Stifel: I think it would

Dan O’Connell, CEO, Acumen Pharmaceuticals: be helpful, and we’re still seeing, you know, rates of aurea in E4 carriers and particularly in E4 homozygotes, you know, dramatically higher than in, you know, in non carriers and the general population. So, 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 gain greater insights into that and maybe Subirnatog, which, of course, you know, didn’t have any ARIA in at least six C4 homozygotes exposed to higher levels of drug, you know, maybe there is some, diverse biology and mechanisms that allow for subiratog to proceed in that population in a way that, these other first agents haven’t been as beneficial.

Julian Pino, Associate, Stifel: Totally makes sense. Great. I do see that we’re 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? And then just really quickly, if you could also remind folks of, Acumen’s cash runway, that would be helpful too.

Dan O’Connell, CEO, Acumen Pharmaceuticals: Yeah. Sure. So I mean, this has been a great discussion, Julian. I appreciate your time. We’re super excited about the progress we’re making with Subirnatog and the prospect of offering patients better treatment options in the future.

In terms of cash and runway, at the September, we had about $259,000,000 in cash on the balance sheet. We’ve guided to first half of twenty seven as our runway. And I think the, you know, we have these upcoming milestones or catalysts around the phase one subcu study this quarter and then guiding to completion of enrollment of the altitude eighty study in the first half of this year. Excellent. So we’re spending time with the company.

Julian Pino, Associate, Stifel: Perfect. Great. Well, that about wraps up our conversation. Thanks again, Dan, for joining us to discuss Acumen. Really appreciate it.

And thanks, everybody, for tuning into the webcast.

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