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

That's quarter past, I hope. Good afternoon, everyone. I'm Trung Huynh. I look at large cap biopharma and also SMID cap biotech. I'm joined here with Ting Lu from our team who also looks at Acumen, and it's my great pleasure to introduce Dan O'Connell, CEO of Acumen. So thank you very much for coming to our conference.

Thanks for inviting us. It's a pleasure to be here.

Now if anyone in the audience has a question, please use the app that you downloaded on real registration. And if you ask a question, I should get a prompt on this iPad and I can ask it on your behalf. But with that said, Dan, for those not familiar with Acumen, perhaps can you give a brief introduction about the company. And you also just came off a solid 3Q perhaps to summarize that.

Thanks. Yes, I'd be happy to. So Acumen Pharmaceuticals is a clinical-stage biopharmaceutical company working to advance federal treatment options for patients suffering from neurodegenerative diseases and principally Alzheimer's is our area of focus. We are developing a monoclonal antibody that has distinct properties based on its selectivity for toxic amyloid beta oligomers, which we think are the right target for this patient population due to oligomers involvement in the initiation and propagation of neurodegenerative processes in the disease. We can talk more about that. We -- as you said, we just reported out on Tuesday, third quarter where we highlighted progress in our ongoing ALTITUDE-AD Phase II study in 540 patients and a Phase I healthy volunteer study, interrogating a subcutaneous form of sabirnetug.

Excellent. So just stting the scene for Alzheimer's disease, I think it's gone through a quite big shift over recent years. We've had a graveyard of clinical studies fail through the bapineuzumab years. We had Aduhelm's approval and then subsequent taking off the market. We have LEQEMBI, which is now approved. Sales are what they are. And we've also now seen Eli Lilly enter with donanemab. So perhaps can you give us some thoughts about the landscape we're at today with Alzheimer's disease.

Sure. What I think we are at a very exciting time in the field. In fact, I think that you referenced some of the graveyard in the past, the lack of success previously. But I think the moment we're in right now is a moment of progress and success that has leveraged the 10, 15 years of novel approaches to treating Alzheimer's with disease-modifying approaches. And we do have these two approved products now from Biogen Eisai and Lilly that offer a calculated benefit risk option to patients. And I think we're also at a moment where biomarkers and other tools are going to enable further improvement on those agents. In the future, I think we're going to be in a mode where Alzheimer's is treated principally with an anti-A-beta strategy. I think there's room to improve on the current options, but that will be a cornerstone of treatment. And then potentially combining an a-beta approach with an immune modulating agent or some other possibly a tau-directed agent. But I think it's -- if we look out over the next 10, 15 years, it's going to be a very exciting field to continue to see progress and success largely predicated on what we've learned and some of the tools that are being brought to bear to address this unmet need.

And us as analysts prior to these drugs getting approved and going out, we have quite punchy estimates in for all of these types of things. Just what's your thoughts on investors' expectations on the size of the market? And I know it's not necessary to do the Acumen, but the speed of how these drugs have gone off, it seems to be somewhat disappointing. Can you give us any thoughts around that?

Sure. I think so yes. No, we're cognizant of the investor sentiment on the commercial launch of some of these products. And I think to us, it's actually not a surprise given the fact that this is sort of a greenfield indication where the clinical system readiness was not in place to really adopt and deploy these agents rapidly and broadly, which is I think where the expectation was on the part of investors. Rather, I think we're going to continue to see the infrastructure build out. We have now a couple of products in the marketplace. And once that system readiness is established, I think we'll be in a good position to evaluate next-generation options such as sabirnetug maybe, again, explore sort of the combination approaches. So yes, so I think it was a bit of a false narrative that these things are going to be rapidly deployed universally given the way the system readiness, just was not established.

Yes. Just to that system, what is it? Is it access? Is it not enough hospital infusion centers?

So it's multifactorial, right? Like that's just -- and that's the complexity of launching a product such as Eisai and Lilly are doing, where the infusion centers are not connected to the imaging centers. There just isn't that the care delivery connectedness. They are separate to that, there was uncertainty around reimbursement and approval for reimbursement. So it's a multifactorial kind of thing that I do think we are now seeing substantial progress, maybe again, not to the satisfaction of the Street. But certainly, in terms of broadening access to patients and allowing for the right patients to go on these treatments in the care of the right clinical management teams.

Okay. Excellent. And just going forward, come 2025, perhaps can you -- well, even to '27, can you lay out the catalyst path we should be looking at for the company.

Sure.

And your cash position, it looks like it's absolutely sufficient to go to sort of first half of '27.

Sure. So we have about $260 million in cash on the balance sheet at the end of September. So -- and Q3. We've guided cash runway into the first half of 2017, and we think that's adequate, certainly to get us through to the other side of the data on the Phase II ALTITUDE_AD Phase II study. That study, as I mentioned, we had our first patient enrolled in the second quarter of this year. And we've now guided that we'll complete enrollment in that 540-patient study in the first half of next year. I think the rate of enrollment has been -- has far exceeded our expectations, quite frankly. And so we have been moving very quickly to address the demand and interest in participating in the study and are excited now that in the first half of next year, provide more granularity on when we'll be reading out top line results.

Thanks. I'll pass to [indiscernible] on to talk about sabirnetug.

Congratulations, first Dan, on the execution on progress you've made in the past year. So as you mentioned, the Phase II study is going very well. It's exceeding expectations. And if we are now looking at enrollment completion in the first half next year, and then it's an 18-month study, should we expect some top line from that study in 4Q 2026?

Right. So I think that's the calculus that you could presume as an 18-month study, we have a primary outcome on a composite clinical score called the iADRS, and we'll be looking at secondary measures. And we would expect to read out it is an 18-month primary outcome. So if we enroll in the first half of '25 and you had 18 months of follow-up, you'll be inside of the end of '26 roughly with that -- with sort of -- on that basis.

Okay. Sounds good.

I think trying to ask about other catalysts, we do have this Phase I subcutaneous study that will read out top line results in the first quarter of '25. And that will be principally a bioequivalence, bioavailability study to help inform what future next steps we might take in pursuit of a subcutaneous formulation for sabirnetug.

Okay. How important is it to have a subcu optionality for the anti-beta therapy development.

Yes. So we -- I think optionality is the key word is having choices. And I think that patients and caregivers and physicians are going to want to exploit a variety of different options in a variety of different settings. So we think of subcutaneous as complementary to an IV form. I think we are committed to a path towards having a subcutaneous option available for patients. It certainly would afford greater convenience, possibly different health care economics and the like. So it is something that we are -- we started at the early part of this year to pursue -- move into the clinic, and we've now launched the Phase 1 per plan, and that will read out in for next steps in the first quarter.

Okay. And is there a possibility that you may like incorporate a subcu cohort into Phase II, like, for example, open label extension, like what can be [indiscernible].

Yes. So in the Phase II, we do have a per protocol open-label extension, which is expected to run at least 12 months. I think we're not in a position in advance of having the Phase I bioavailability data and knowing precisely what frequency and volumes we would take forward with the subcu. I think it's a bit premature to specify how we might advance but you could think about what you described would be one option, an Eli Lilly, sort of arm or standalone, a stand-alone Phase IIa type study, maybe shorter duration evaluating biomarker effects. We're possibly waiting to add to a Phase III program with the expectation of using that larger global study as a part of moving the subcu towards a filing.

Okay. Yes, that's good. Something without is quite exciting is that you noted that in your recent conversations with FDA or with the agency that it has -- you believe that Phase II now can be a stand-alone capital study with registrational eligibility. So we are wondering, should that be our base case assumption or more like upside case scenario?

Well, I think what we've characterized the Phase II as essentially will be confirmatory evidence in conjunction with the confirmatory Phase III. So the -- as we sit here today, what we might contemplate for Phase III as a single global subsequent Phase III as the primary Phase III with the Phase II supporting that Phase III. I think the importance for the Phase II is that it's a well-designed, randomized, double-blind, placebo-controlled study, and we hit significance, and it does meet the bar for serving as that pivotal as a pivotal study as part of the submission.

Okay. Okay. Sounds good. So -- and also, you dropped the previous plan of having some interim readouts in the Phase II. Yes. And you stated that to preserve the registration eligibility of Phase II. So we -- yes, then we do see in tariff analysis in other Phase III registrational studies, like -- I think famous ones being Biogen, LEQEMBI's, like parallel -- sorry, not LEQEMBI, aducanumab parallel studies where they had interims. So interims, they are designed as futility analysis, you can still preserve alpha. So why not still have the interims that help you monitor to some extent on the efficacy and safety.

Yes. There's -- you put a lot in that thread. So yes, we had launched the Phase II as a Phase II/III or conceived as a Phase II/III contiguous study that would run as -- essentially using an interim to scale to Phase III. And what we determined after interacting with the agency with -- in both U.S. and European regulatory bodies was that the interim might not serve the purpose of getting us to Phase III in a way that we had envisioned. And so a stand-alone Phase II, if the blind is preserved and we don't take statistical hit is actually the most significant attractable value inflection for us as a deliverable. I think it also helps create an environment or a moment where for Phase II, we've got a lot of optionality as to how we would progress potentially doing that study with a partner. And so rather than trying to embark on the global Phase II, III on a stand-alone basis, we felt from regulatory purposes and strategic purposes that conducting the study as a stand-alone Phase II was the most valuable way to deploy the resources that we have on hand.

Okay. That makes sense. Okay. Yes, maybe back to sabirnetug by yourself Okay. So how do you position Subrnatag like in overall anti-amyloid therapy fields these days.

Sure. So sabirnetug for those that are unfamiliar with the program. I mean, it has kind of an interesting history. It's a program and a company that originated out of some academic labs at Northwestern and USC and was predicated from the get-go on identifying first accepting or characterizing the toxicity associated with amyloid beta oligomers. So oligomers, unlike monomers or amyloid plaques, have these distinct and replicable deleterious effects, including a propensity to bind a neuron synapses, disrupt neural signaling, contribute to tau-hyperphosphorylation. And so for all of these reasons, going back now 20 years, oligomers presented as a distinct and attractive target to slow down the disease progression in principally in Alzheimer's disease. So sabirnetug was raised against and directed towards these oligomers, which is different than some of the prior agents that were unsuccessful and maybe hit monomer or -- and now we have agents that are principally directed towards plaques and fibrils. So sabirnetug has this unique mechanism and epitope, and we think sabirnetug as a basis -- as -- on the basis of oligomers-selective product, we'll have better safety and efficacy profile. Basically, that's the differentiation. And that's predicated based on not trying to disrupt or binding to vascular based plaque and inducing higher rates of ARIA. And particularly on the efficacy side, looking at neutralizing, reducing or otherwise eliminating the sort of the immediate synaptic pathology that oligomers are recognized and as contributing to. So we think sabirnetug and the Phase I results, quite frankly, for us were important because we did that Phase I study in patients. So they had target on board. We had a novel target engagement assay developed to help us show a dose response in terms of sabirnetug, getting into the central compartment, in the cerebral spinal fluid, engaging with oligomers and really moving that signal of target engagement as we moved up the dose escalation in the multiple -- actually, in both SAD and the MAD portions of that study. In addition to that target engagement signal that was dose proportional we did observe effects on fluid biomarkers, both phospho-tau217 and 181 as well as on the amyloid PET. And there, we saw pretty -- we've kind of taken back by the rate and magnitude of the reduction in amyloid PET signal even as early as 3 months with only three administrations. So for us, the differentiation for sabirnetug is really predicated on its mechanism around targeting oligomers and demonstrating either or both of better safety and more efficacy profile. And we think the ALTITUDE-AD study is well designed to really underpin and confirm that hypothesis and that treatment possibility for patients.

Do you specifically -- do know it's only oligomers or is that is proportionately bound to oligomers. Do you also [ monomers ]?

Yes. Great question. So the term in the field, [indiscernible] is preference, right? So -- and for instance, and we've recently, we had an R&D Day October 2, where we presented some more nonclinical or preclinical evidence in support of the preference for oligomers versus, say, monomer and did that on a relative basis to some of the other agents like aducanumab and LEQEMBI. And they're sabirnetug really doesn't see monomer. Like -- it has a very low preference. It has about a 9,000 fold selectivity for oligomers versus monomer, which is pretty substantial, especially in contrast to some of the other agents like in aducanumab or even gantenerumab. And certainly, solanezumab, the original Lilly antibody was directed at monomers. So we think monomer is a naturally occurring form of the protein. And to the extent that you're wasting the limited amounts of antibody that gets into the central compartment, hitting that naturally occurring form is counterproductive to the treatment objective. We think plaque is sort of more of an end stage. I mean plaques are not robustly neurotoxic. I mean they contribute to some inflammatory effects, but they're sort of the end-stage of an aggregation process that happens over many, many years, oligomers are diffusible. They're smaller. Again, I mentioned the propensity to bind the synapses. And those, we think, are a more robust and potent target for disease modification and one where we have -- we think that given that the discovery paradigm for sabirnetug targeting oligomers A priority and the evidence that we've now generated not only preclinically, but even in Phase I, we've got the right target and the right antibody.

And yes, as you mentioned, you've shown like really good dose response from Phase I study across like different metrics. And you've selected 35 and 15 mg per kg going forward for Phase II, you have great knowledge from Phase I. And you've done PK/PD modeling. So there, if we compare like what 35 or 50 mg per kg monthly can achieve versus LEQEMBI and 10 mg per kg by weekly in terms of plaque reduction or plaque clearance, like the dynamics, also the depths, like how do you think those two doses will compare.

Right. Yes. So in the Phase I study, we took doses upwards of 60 mg per kg. And I think we -- I'll mention in the Phase I, we did have total 5 cases of ARIA-E out of the 48 subjects exposed to sabirnetug. Three of those cases came at 60 mg per kg. So that high dose cohort. Only one of all of the 5 cases was symptomatic and that was a fairly modest self-resolving case of symptomatic ARIA. So we do think that the safety profile for sabirnetug is supported by the Phase I results. I think when we did -- and then we took a target engagement assay, and we did a variety of modeling and found that at 50 mg per kg, we get near maximum approximate maximal target engagement based on the assay. Maybe we'll get a little bit lower ARIA, think as was observed in 60. And then the 35 mg per kg is sort of brackets the other end of the efficacy signal, right? Like we don't want to not have a fulsome target engagement. So the team worked closely with a group called [ Certera], did a bunch of modeling and we found that even between peak and trough drug exposure based on the PK and the Phase I, 35 and 50 gave us ample coverage of our intended target principally being oligomers. I think it will be interesting. I mean we'll see how the study reads out. We think both 35 and 50 are in the zone of efficacious doses for the primary outcome, which is the iADRS. I think the secondary effects on biomarkers, whether they be imaging or fluid biomarkers will be interesting to see if those dose levels differentiate there and/or on ARIA, right? That will be the other question.

Okay. So the 50 mg per kg will cover I think when you see target engagement like those CSF, like oligomer?

Oligomer, that compound [indiscernible], the antibody bound to oligomers.

Yes. How about -- like because you antibody like which is a nice price that also reduced plaque. Yes. So how do you think those two -- those levels will help like clear plaques, like how quickly will be -- how deep it would be mostly compared to LEQEMBI.

Right. So in the Phase I, the 60 mg per kg, three doses dropped the Amyloid PET signal in line with LEQEMBI. So about 25% reduction over 3 months. And that's with three administrations where in 3 months, you would have had six administrations of the 10 mg per kg biweekly for like LEQEMBI. So I think that it's likely that the -- reasonably likely to anticipate the 50 mg per kg dose will be in line with that 60 -- in that range of that 60. So a 25% [ amyloid] reduction at 3 months and presumably with chronic administration over the course of 18 months, you'll continue to see presumably a reduction in the PET signal. It will be interesting to see if 35 matches. I mean our -- we are not trying to treat the PET scan, right? Like that -- we are more interested in the clinical benefit as measured on clinical instruments and whether a preference for oligomers does produce a more pronounced effect in those measures even more so than on the Amyloid PET.

Okay. And like hypothetically, this is -- if like a 5 mg per kg led to better efficacy in terms of both like -- you already noted oligomer binding, but also deeper PET clearance, but also like a better biomarker like responses overall, but it has slightly higher ARIA rate than 35 mg per kg. How -- do you need to choose one or you might bring both forward like both to registration also to Phase III.

Yes. Great question, [indiscernible]. This is why I think I'm so excited about the ALTITUDE_AD study and the dose levels we've chosen because I think there are multiple ways this -- multiple is for us to win one arm versus two, both arms, looking to identify populations that are most amenable to treatment. I should mention that in the Phase I, we had no cases of ARIA-E in the six E4 homozygotes that were exposed to drug. And so if you look at these other agents, they have a higher rate of ARIA in carriers and in particular, on E4 homozygotes to sort of the inclusion of getting approval for that population, particularly in the U.K.. So we're going to have a lot of information coming out of the Phase I to inform precisely which next dose doses and/or populations, we think are going to be most beneficial to treatment.

Okay. Would you consider intermittent dosing at some point like similar to donanemab, like dosing regimen.

Yes. I think it's kind of -- we're at an interesting point where -- and I was just at the CTAD meeting in Madrid a couple of weeks back now, where because we have commercial products. There's marketing and commercial messaging that's occurring, whereby to my view Eli Lilly is thinking treat to clear and then going off drug and they're kind of dug in on that message and then biogenesis is saying chronic treatment in perpetuity. And I think there's probably -- the patient -- best case for patient is somewhere probably seen, whereby you establish a biomarker-driven perhaps clinical-driven effect over an induction phase and then you look at some form of maintenance intermittent dosing because we know these other species exist. I think Eisai and Biogen have credibly show that just because the PET scan has been treated, doesn't mean there isn't other species and then soluble oligomers in disease progression. So I think there's got to be sort of -- and in between there, we're keeping patients on a treatment regimen while they're in this early course of disease would seem to be the right choice to make for patients.

All right. Yes, it makes sense. And many of your competitors, they're also moving into earlier lines and even in the prevention setting. Yes, what are some of your most recent strategic thinking in that front?

Yes, there's a lot of strategic thinking on that front for sure. I think the action is maybe out in the future but there's a couple of recent papers actually to support the notion that [ A-beta ] oligomers really spike early in that preclinical phase before plaques are being layered down. So an agent like sabirnetug, I think, which high preference and selectivity for that species could be a really attractive agent to put into that preclinical population. That's not on our immediate horizon. I think we'll see a couple of other readouts from other agents in that population in the next couple of years that will probably inform how much priority. But certainly, if we have a safe and efficacious agent in early AD vis-a-vis reading out ALTITUDE-AD moving into a preclinical paradigm would be, I think, warranted and quite frankly, quit attractive.

Sounds good. And looking forward to future development for sure, too. Maybe on the next wave of anti-beta -- anti-amyloid beta development like we heard lots of interest into the Bring Shadow technology, which we have to bring up today at Roche trontinemab. So yes, they also shown some good safety data at recent CTAP meeting too. So -- and also recently, AbbVie acquired Aliada, who's developing kind of similar technology on that front for Alzheimer's. How do you think competition from all those big pharmas.

Yes. So the enhanced brain delivery as a mode of increasing antibody exposure in the central compartment has been a concept and something that the industry has pursued for 20 years. It's always -- it's sort of been out there. I think what has been interesting about the trontinemab Roche data is they now have patient evidence and clinical data that shows a failed antibody, such as gantenerumab in what their commercial term is brain shuttle that it has a basically a different profile as a consequence of taking gantenerumab, which is kind of hits -- is not particularly selective. It's a little bit of everything, putting it in a shuttle. And as a consequence of that, producing a pretty rapid and robust clearance of amyloid plaques and not inducing ARIA to the rate that was observed in earlier studies. So it's a great proof of principle. I think you're going to see continued interest in enhanced brain delivery approaches. I mean you mentioned the AbbVie-Alita deal. I think that's certainly very interesting. I think AbbVie is sort of working their business development strategy in the context of how they're going to source $1 billion revenue opportunities in the next 3 to 5 years. I took that transaction as an indication of big pharma's interest in the Alzheimer's space generally and knowing -- and if you look at the price they paid, the anti to get into that space and have a differentiated profile is pretty significant. So I think the anti-A-beta, it's a good indication, too, that anti-A-beta as a modality, whether it's shuttle enabled or selective for the right species is going to be a cornerstone for Alzheimer's treatment and that the commercial evolution of growth will continue to be established and grow. I think there's a lot of enhanced brain delivery technologies that have been out there. I think we're going to see more that. I know that Eli is working on a program as well. They had a collaboration with Biogen previously. So it's going to be kind of a dynamic period here where we continue to build on the recent success and interrogate other modalities and other ways to build on what we have today.

Sounds good. Yes. Thanks, Dan. And I think that's also end of my questions.

It's good opportunity to just talk about -- you were at CTAD. What did you think of the tau data we saw recently from UCB.

Yes. UCB reported out there microtubule-binding region selective tau antibody that they had been developing in collaboration with Roche. And Roche had opted out of that partnership about a week before the presentation. So no one was sure what to read how that circumstance. But I think the data showed that we're still years away from understanding how and where to intervene in the tau pathology paradigm, right? Tau biology, I think, is order of magnitude more complex than a-beta pathology or biology. And so it's certainly Tau as a target is most closely associated with cognitive deficits and disease progression. There were intracellular tau, there's extracellular tau. I think it just is something that hopefully will continue to pursue but we're not on a cusp of a breakthrough, I think, in -- with tau approaches.

Excellent. So we're in the last couple of minutes here. Last question. We hope to have you here again this time next year. One of the things Ting and I have been asking in our talks of people and stages to give us if we're back this time next year, what are the Three things you hope to have ticked off, and we can start and put you on the hook for that for this time next year.

Yes. So I appreciate the question, Trung. So I think for us, it's all going to be about reading out the Phase 1 subcu in the first quarter, understanding what our next step might be for that formulation approach, completing the enrollment of ALTITUDE-AD in the first half hopefully on the earlier half of the first half, and that will be an exciting development when we're able to relay that. And then knowing that just seeing the evolution of the field, both the commercial clinical setting and adoption of these treatments and knowing that there's a greater awareness that the field is -- these treatments are here to stay, and there's something to be built upon and sources of innovation such as Acumen and sabirnetug will garner more attention and interest going forward, particularly once we have certainty that we're staring down the robust Phase II data as a consequence of having enrolled the study. So successfully.

Excellent. Well, we'll make you accountable for that. Thank you very much. Thank you for the time and thanks for joining.

Thank you so much.

Thank you very much, Dan.

Thank you.