That's quarter past, I hope. Good afternoon, everyone. I'm Trung Huynh. I look at large-cap biopharma and also mid-cap biotech. I'm joined here with Ting Liu from our team, who also looks at Acumen, and it's my great pleasure to introduce Daniel O'Connell, CEO of Acumen, so thank you very much for coming to our conference.
Thanks for inviting us. A pleasure to be here.
Now, if anyone in the audience has a question, please use the app that you downloaded upon registration. 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 your company. You also just came off a solid 3Q. Perhaps to summarize that.
Thanks. Yes, I'd be happy to. Acumen Pharmaceuticals is a clinical stage biopharmaceutical company working to advance better 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 oligomer involvement in the initiation and propagation of neurodegenerative processes in the disease. We can talk more about that. 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 setting 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 answer with donanemab. So perhaps can you give us some thoughts about the landscape we're at today with Alzheimer's disease?
Sure. Well, I think we are at a very exciting time in the field. In fact, I think that you referenced some of the graveyard and 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'll 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 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 had 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 necessarily to do with Acumen, but the speed of how these drugs have gone off. It seems to be somewhat disappointing. So can you give us any thoughts around?
Sure. I think so. Yeah, 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 yeah, so I think it was a bit of a false narrative that these things were going to be rapidly deployed universally, given the way the system readiness just was not established.
Yeah. Just to that system, what is it? Is it access? Is it not enough hospital infusion centers?
So it's multifactorial, right? 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 the care delivery connectedness. 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're 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, or even to 2027, can you lay out the catalyst path we should be looking at for the company? And your cash position, it looks like it's absolutely sufficient to go to sort of first half of 2027.
Sure. So we have about $260 million in cash on the balance sheet at the end of September, so end Q3. We've guided cash runway into the first half of 2027, and we think that's adequate, certainly to get us to the other side of 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 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 to, in the first half of next year, provide more granularity on when we'll be reading out top-line results.
Excellent. Right. I'll pass Ting on to talk about sabirnetug.
Sure.
Yeah. Congratulations for Stan on the executional progress you 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 full Q2026?
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 2025 and you had 18 months of follow-up, you'll be inside of the end of 2026, roughly, on that basis.
Okay. Yeah, that sounds good.
I think Trung asked about other catalysts. We do have this phase I subcutaneous study that will read out top-line results in the first quarter of 2025. 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 sub-Q optionality for the anti-beta therapy development?
Yeah. So 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 healthcare economics and the like. So it is something that we started at the early part of this year to pursue, move into the clinic, and we've now launched the phase I per plan. And now we'll read out and inform next steps in the first quarter.
Okay. And is there a possibility that you may incorporate a sub-Q cohort into phase II, like for example, open label extension, like what Leqembi ?
Right. Yeah. So in the phase II, we do have 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 sub-Q. I think it's a bit premature to specify how we might advance, but you could think about what you describe would be one option, an OLE sort of arm, or a standalone phase II-A-type study, maybe shorter duration, evaluating biomarker effects, or possibly waiting to add to a phase III program with the expectation of using that larger global study as a part of moving the sub-Q towards a filing.
Okay. Yeah, that's good. Something we thought is quite exciting is that you noted that in your recent conversations with FDA or with the agency that it has led you to believe that phase II now can be a standalone pivotal study with registration eligibility. So we are wondering, should that be our base case assumption or more like an upside case scenario?
I think what we've characterized the phase II as essentially will be confirmatory evidence in conjunction with a confirmatory phase III. As we sit here today, what we might contemplate for phase III is 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 a pivotal study as part of the submission.
Okay. Okay, sounds good, and also you dropped the previous plan of having some interim readouts in the phase II.
Right.
Yeah. And you stated that to preserve the registration eligibility of phase II. So yeah, but then we do see interim analysis in other phase III registration studies, like I think famous ones being Biogen, Leqembi's parallel study. Sorry, not Leqembi. Aduhelm has parallel studies where they had interims. So if 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? Yeah.
Yeah, you put a lot in that thread there. So yes, we had launched the phase II as a phase II/III , or conceived of 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 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 standalone phase II, if the blind is preserved and we don't take the statistical hit, is actually the most significant attractive value inflection for us as a deliverable. I think it also helps create an environment or a moment where for phase III, 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 standalone basis, we felt for regulatory purposes and strategic purposes that conducting the study as a standalone phase II was the most valuable way to deploy the resources that we have on hand.
Okay, that makes sense. Okay, yeah, maybe back to sabirnetug by itself. Okay, so how do you position sabirnetug in the overall anti-amyloid therapy field 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 propensity to bind to neuron synapses, disrupt neuronal 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.
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, on the basis of an oligomer selective product, will have a 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 sort of the immediate synaptic pathology that oligomers are recognized 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 cerebrospinal 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-tau 217, 181, as well as on the amyloid PET. And there we saw pretty, we were kind of taken aback by the rate and magnitude of the reduction in amyloid PET signal even as early as three months with only three administrations.
For us, the differentiation for sabirnetug is really predicated on its mechanism around targeting oligomers and demonstrating either or both of a better safety and/or efficacy profile. 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 know it's only oligomers, or is that proportionally bound to oligomers? Do you also bind to monomers?
Yeah, great question. So the term in the field, the term of art, is preference, right? And for instance, recently we had an R&D day, October 2nd, 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 there, sabirnetug really doesn't see monomer. It has 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 an aducanumab or even a gantenerumab. And certainly, solanezumab, the original Lilly antibody, was directed at monomers. So we think monomer is a naturally occurring form of the protein.
To the extent that you're wasting the limited amounts of antibody that get 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 to synapses. And those we think are a more robust and potent target for disease modification. And one where we think that given the discovery paradigm for sabirnetug, targeting oligomers a priori, 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.
Yeah. Okay, excellent.
Yeah.
And yeah, as you mentioned, you've shown really good dose response from phase I study across different metrics. And you were selected 35 mEq and 50 mEq/kg going forward for phase II. You have great knowledge from phase I, and you've done PK/PD modeling. So if we compare what 35 mEq or 50 mEq/ kg monthly can achieve versus Leqembi and 10 mEq / kg biweekly in terms of plaque reduction or plaque clearance, the dynamics, also the depth, how do you think those two doses will compare?
Right. Yeah. So in the phase I study, we took doses upwards of 60 mEq/kg. And I think I'll mention in the phase I, we did have a total of five cases of ARIA-E out of the 48 subjects exposed to sabirnetug. Three of those cases came at 60 mEq/kg, so that high-dose cohort. Only one of all of the five 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 mEq/kg, we get near maximal or approximate maximal target engagement based on the assay.
Maybe we'll get a little bit lower ARIA, I think, as was observed at 60 mEq/kg, and then the 35 mEq / kg sort of brackets the other end of the efficacy signal, right? We don't want to not have fulsome target engagement. So the team worked closely with a group called Certara, 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 levels differentiate there and/or on ARIA, right? That'll be the other question.
Okay. So 50 mEq/ kg will cover, I think, when you say target engagements, like those CSF, like oligomer.
Oligomer, that complex.
Oligomer complex.
The antibody bound to oligomers.
How about, because antibody, which is a nice price that also reduces plaque. So how do you think those levels will help clear plaques? How quickly will it be, how deep will it be, mostly compared to Leqembi?
Right. So in the phase I, the 60 mEq/kg, three doses dropped the amyloid PET signal in line with Leqembi, so about 25% reduction over three months. And that's with three administrations where in three months, you would have had six administrations of the 10 mEq/kg biweekly for Leqembi. So I think that it's likely that the reasonably likely to anticipate the 50 mEq/kg dose will be in line with that 60 in that range of that 60. So a 25% amyloid reduction at three 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, we are not trying to treat the PET scan, right?
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 hypothetically, if 50 mEq/kg led to better efficacy in terms of both, you already noted oligomer binding, but also deeper plaque clearance, but also better biomarker responses overall, but it has slightly higher ARIA rate than 35 mEq/ kg. Do you need to choose one, or you might bring both forward, both, yeah, to registration and also to phase III?
Yeah. Great question, Ting. 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, there's multiple ways 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 II to inform precisely which next doses and/or populations we think are going to be most beneficial to treatment.
Okay. Would you consider intermittent dosing at some point, similar to donanemab dosing regimen?
Yeah, 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 Biogen and Eisai is saying chronic treatment in perpetuity. And I think there's probably the best case for patient is somewhere probably in between, 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 shown that just because the PET scan has been treated doesn't mean there isn't other species and soluble oligomers and disease progression.
I think there's got to be sort of an in-between there where 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.
Right. Yeah, it makes sense. And many of your competitors, they're also moving into earlier lines and even in the prevention setting. Yeah, what are some of your most recent strategic thinking in that front?
Yeah, 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'll probably inform how much priority. But certainly, if we have a safe and efficacious agent in early AD, vis-à-vis reading out ALTITUDE-AD, moving into a preclinical paradigm would be, I think, warranted and quite frankly, quite attractive.
Sounds good. And looking forward to future development for sure, too. Maybe on the next waves of anti-amyloid beta development, we heard lots of interest into the Brain Shuttle technology, which we haven't yet bring up today, and Roche trontinemab. So yeah, they also showed some good safety data at recent CTAD meeting, too. 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 pharma? Yes.
Yeah. 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 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 basically a different profile as a consequence of taking a gantenerumab, which kind of is not particularly selective, hits 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 great proof of principle.
I think you're going to see continued interest in enhanced brain delivery approaches. I mean, you mentioned the AbbVie Aliada 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 billion-dollar revenue opportunities in the next three to five 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 ante 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 and growth will continue to be established and grow.
I think there's a lot of enhanced brain delivery technologies that have been out there, and I think we're going to see more. I know Denali is working on a program as well. They had 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. Yeah, thanks, Dan. And I think that's also the end of my questions here.
It's a good opportunity to just talk about, you were at CTAD. What did you think of the tau data we saw recently from UCB?
Yeah, UCB reported out their 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 how to read 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 orders 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 are intracellular tau, there's extracellular tau. I think it just is something that hopefully we'll continue to pursue, but we're not on a cusp of a breakthrough, I think, 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 with people on stage is 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 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 I subQ 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'll 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.
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 robust phase II data as a consequence of having enrolled a study so successfully.
Excellent. We'll make you accountable for that this time.
All right.
Thank you very much. Thank you for the time, and thanks for joining us.
Thank you so much.
Thank you, everyone.