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

Welcome to the UBS Virtual Event. I would now like to pass the call over to Trung Huynh.

Excellent. Thanks, Drew. And everyone who's on, thanks for joining. So I have the honor of hosting the next session, the lunch slot for today's Virtual CNS Day here at UBS. My name is Trung Huynh. I'm one of the biopharma analysts here. It's my pleasure to welcome Daniel O'Connell, CEO of Acumen since 2014. Before that, he's been neuroscientist for a number of years now. And forgive me, if I'm making you sound old here, Dan, but over 20 years in value creation venture in neurosciences. And He also cofounded functional neuromodulation, which was developing a DBS, deep brain stimulation therapy in Alzheimer's. So Dan, thanks for joining us today.

Trung, thanks for the invitation. Great to see you.

Awesome. So let's start off with a quick intro for those who don't know what you're doing over at Acumen. Perhaps can you just describe where you are with Acumen today? And also, I noted there you've been in neuroscience for a number of years, and Acumen is an Alzheimer's company. But really that long-term commitment to brain health, it's been a very tough area over the years. There's a lot of larger companies actually have deprioritized investment in this area. So perhaps why are you remaining so steadfast in this quite tricky area?

Sure. Thanks, Trung. So I'll just -- firstly, I'll start with Acumen. So at Acumen, we are singularly focused on advancing novel treatments for people living with Alzheimer's disease. That's sort of our core area of focus. Our clinical asset is sabirnetug, which is positioned as a next-generation monoclonal antibody based on its properties and ability to target what we think is a really optimal target in the disease pathology, which we refer to as amyloid beta oligomers. So we can talk more on the data in support of that target as well as some of the Phase I results for sabirnetug that were reported out previously positive Phase I results. In terms of the space, I think Acumen as a company as an enterprise, just sees this unmet need and this massive opportunity to have an impact on this disease, which has been challenging to address over a number of years. We sort of take the view that the progress and knowledge and science and technology are cumulative. And that over the last 15 years, we've actually developed better insights into which targets to pursue in this disease population, what technologies can better enable the accurate diagnosis and guide development paths. So there's a lot of reason, and now we have a couple of approved disease-modifying treatments, the first couple of products in the clinic today, and those are being adopted to the benefit of patients. But we think we can do more. I think what is exciting for me and for Acumen is the prospect of offering more quality time for people that otherwise have been diagnosed with an early Alzheimer's diagnosis.

So yes, you touched upon here that there has been a glimmer of hope in the last couple of years. LEQEMBI, Kisunla now on the market after I guess, 10, 15, 20 years of R&D effort. But commercially, so far, they've not been as much of a success as some people had hoped for. So could you perhaps put your finger on why that's the case? And then what are some of those clinical and commercial unmet needs you touched upon there that you think is still there beyond these first generation of products.

Sure, Trung. So in terms of the population, in the U.S., there are somewhere in the order of 7 million people that have met the criteria for early Alzheimer's disease, which is mild cognitive impairment and/or dementia associated with Alzheimer's pathology. Those first 2 agents have been approved and are essentially launched into a greenfield site. There have been -- there haven't been established treatments for this particular disease heretofore. So I think the commercial rollouts for these have been -- haven't met the expectations of certain stakeholders. But on the other hand, we're seeing growth in terms of the script rates, and we're seeing the infrastructure, the clinical infrastructure to actually diagnose and deploy these treatments for this population growing incrementally over time here. What's exciting for us is to be working on sabirnetug and looking to read out a substantial proof-of-concept Phase II study in the environment where there's more awareness and desire to have access to better treatment options. So the setup for us, I think, over the next 2, 3, 4, 5 years is really compelling and one, again, where we're focused on improving patient outcomes and improving patient lives.

Okay. Awesome. And you touched upon the Phase I data here. We've had some -- we've had that data for sabirnetug. It's also beta amyloid. So we've had much debate over this mechanism. We have seen data readout for many beta amyloid. So with that data in hand, what gives you the confidence that this is the mechanism that's going to provide a meaningful benefit to Alzheimer's disease patients? And you also touched upon the oligomer side of things for sabirnetug. Why do you see that as differentiating? And what else could differentiate with your lead asset?

Sure. So a lot of questions embedded there. Let's start with the complexity of a-beta biology, which the amyloid precursor protein produces peptide fragments in a variety of different sizes and forms that can take a variety of different species. So we have a-beta monomer, we have a-beta oligomer, we have a-beta protofibrils, fibrils and then plaques. And so these different aggregated -- monomeric or aggregated forms have different physiological effects. I think a couple of decades of research helped to underpin the notion that support the evidence for targeting a-beta oligomers as a primary trigger in Alzheimer's pathology and one that is a persistent instigator and one that contributes to ongoing neurodegenerative processes. So for instance, the a-beta oligomers have been shown to induce tau hyperphosphorylation that they have a propensity to bind to neurons and synapses and disrupt long-term potentiation, which is the way brain cells or neurons have the ability to communicate and essentially serve as the circuitry of the brain. So we think -- and we think there's ample evidence to support oligomers as a distinct and uniquely attractive target in this disease for patients. And what's also -- what was interesting for us, having read out the Phase I study, was part of the criteria for sabirnetug is its high selectivity for oligomers versus these other species like monomer or plaques. And so sabirnetug has at least somewhat thousand-fold selectivity for oligomers versus monomer. And it's that distinct ability of sabirnetug to see these oligomers, neutralize them, we think is going to have a beneficial effect in the clinic for patients. In the Phase I study, which we undertook exclusively in early Alzheimer's patients, so they had established amyloid pathology. And as a consequence of being in that disease state, we knew we could interrogate aspects of safety, target engagement and principally clinical and biomarker effects. And in this INTERCEPT-AD study, which was designed to help address those early questions in a kind of an early derisking of the program, we showed a compelling safety profile. So there were -- the drug was well tolerated. It had a couple of cases of ARIA, which we can talk a little bit more about. But it was generally well tolerated and serves as the basis for the safety differentiation that we think sabirnetug will have. We also showed target engagement. So we had a novel assay to quantify the level of a-beta oligomer bound to sabirnetug. And in this assay, we found really a dose response that helped shape our strategy for Phase II. What we've -- this is actually the first time in the clinic that actual oligomeric a-beta target engagement has been established in a robust way in patients. So target engagement, safety and then much to our encouragement were the biomarker effects, we saw with just 3 administrations of sabirnetug, so 3 doses, we saw amyloid reduction on amyloid-PET to the degree and rate similar to like LEQEMBI in their CLARITY-AD study. So short duration study established, patient population, we're seeing consistent results across a variety of different both fluid and the imaging biomarkers. So all these to us suggest that a longer duration study such as we're conducting now with ALTITUDE-AD, which is a 540-patient study, 2 active dose arms versus placebo intended to read out on a primary outcome of the iADRS, which is a composite score, but then also evaluating the CDR sum of boxes as well as both imaging and fluid biomarkers. We think that study is well designed and is ongoing and should be a really impactful outcome for the field to help validate the oligomer hypothesis.

Okay. Awesome. Lots to unpack there. Perhaps why don't we start on with the biomarker part. For us, actually, I think it's an area where you've shown a lot of data and you're, I think, leading the way here in terms of the research for biomarkers and target engagement assays that you've done. And you published a lot here. We've seen you've recently published this with that Phase I data you discussed. So where do you think we are now with biomarkers? Do you think we've got the right biomarkers in place for AD research? Or is there still much improvement that's needed there?

Well, there's been a tremendous amount of progress in the development of fluid biomarkers in particular, right? If you go back 10 or 15 years, one of the seminal innovations in the space were the imaging biomarkers. So we have the ability to use radiolabeled PET tracers to actually image in living patients the presence of amyloid plaques. Where the field has gotten to now, the fluid biomarkers, including analytes like phospho-tau 217 and 181 and a few others really provide greater -- consistent resolution and accuracy but on a less invasive basis, right, rather than radiation exposure and getting into a PET scanner. It's a much more efficient and economical way to prioritize, if not diagnose patients. And that's the trend that we foresee that will continue in the future. We're sort of within the range of a more precision medicine in even Alzheimer's disease, whereby depending on which of these fluid biomarkers you may have, it will be indicative of disease etiology and/or state of pathology or state of disease. And this is where those tools being available -- more readily available in the clinic are going to help us identify patients that are best suited for what will be a number of treatments that come to the clinic over the next 3 to 5 years. One of the innovations you mentioned, we've just published the Phase I biomarker paper in JPAD last month. One of the things that we've adopted in the Phase II is using phospho-tau 217 as essentially part of the screening visit. And there's enough concordance between the ratio of 217 in plasma to be a reasonable predictor of what the amyloid PET signal is going to look like. So we've been able to use the 217 fluid biomarker as a very economical, safe and efficient way to prioritize patients that can then go on to have a confirmatory PET. And I think we've presented some of this data, but the negative PET scans for the ALTITUDE-AD study, the Phase II study, have been reduced by more than 50% as a consequence of that prescreen, giving us essentially prioritizing those patients that are more likely to be positive in a confirmatory PET scan.

And you touched upon the potential differentiation in terms of safety that you saw come out of the Phase I study. How important do you think are the low rates of ARIA in the E4 homozygous patients. In the Phase I, we show -- you showed no ARIA-E amongst a lot of the patients, all the homozygous patients. So just really how important could this be to replicate in your Phase II coming out?

Yes. Thanks, Trung. So in terms of the safety profile and the potential for sabirnetug, it's kind of multifactorial because -- principally because of sabirnetug's propensity to bind into oligomers and not plaque, we think that gives it an intrinsic ability to have a lower rate of ARIA-E, in particular. In -- it's also an IgG2, which has a reduced effector function, so that may contribute to lower inflammatory effects and ARIA as well. In the Phase I of the 48 subjects exposed to a dose of sabirnetug, we had 5 cases of ARIA. 3 were at the high dose of 60 mg per kg, one was at 10 mg per kg and one was at 25 mg per kg. So overall, a relatively low rate of ARIA. There was only one case deemed to be symptomatic of the 5. And so we think that, again, is a well-tolerated and potential path towards differentiation on safety. We had 6 E4 homozygous, none of which developed ARIA even with exposure to drug, including some of the higher doses. So it could be, again, that because of the epitope and the selectivity for -- of sabirnetug, it may not see the types of plaques that are resident in -- particularly in E4 carriers or E4 homozygous. So it's an important facet of the program and why it's positioned to succeed. I did want to go back to the clinical benefits or the efficacy question, which we think can be addressed in Phase II, which is one where oligomers due to that synaptic neurotoxicity may be a more acute and beneficial way to provide clinical benefit to patients. And precisely how that manifests, we'll see in the Phase II. But there's -- as I mentioned, there's a tremendous amount of nonclinical evidence to suggest that these oligomeric species are potently toxic and that neutralizing them with a selective agent like sabirnetug should really present as a differentiated efficacy profile. And that's really what we're all about is offering a better risk benefit to patients relative to the first generation products that are now available in the clinic.

And moving on to the catalysts that we're going to see over the next year or so. The next big one is the Phase I subcu data. I think top line is fairly soon. What should we be looking at...?

Yes, we've run a healthy volunteer Phase I study that will read out first quarter of '25. So that's we're sort of tracking for that as we sit here today. And then the other upcoming guidance is the completion of enrollment in ALTITUDE-AD, which has guided to first half of '25. And I'll mention that we had our first patient enrolled in ALTITUDE-AD in May of '24. And as I mentioned, this is a 2 active doses versus placebo, 540 patients study, we've noted that the study has enrolled more quickly or more rapidly than we might have anticipated, which I think is a consequence of the greater awareness just generally of people seeking even research options to be -- to prevent the progression of their Alzheimer's disease. And I also think it's a consequence of the Phase I data that actually provides a compelling example of how sabirnetug may be a differentiated next-generation asset in the -- for the treatment of this devastating disease.

And digging into that Phase II data, which is going to be the big one, you selected 35 mg per kg, 50 mg per kg every 4 weeks. When you look at your PK/PD model, do you expect to have a comparable or deeper plaque clearance when you're comparing that to drugs that are on the market today?

Well, Trung, we did -- for the Phase II dosing strategy, we did leverage the Phase I target engagement data, which showed essentially a plateauing effect whereby going higher than 60 mg per kg was unlikely to produce greater target engagement. And that was really, again, an important finding in that study to give us confidence that we don't need to push sabirnetug higher than 60 mg per kg. We also -- I mentioned the 3 cases of ARIA at that 60 mg per kg dose. So as a consequence of some PK/PD modeling, we elected to take forward 50 mg per kg dosing Q4W, every 4 weeks, and then 35 mg per kg. And we think that the 50 mg per kg dose may yield greater amyloid PET reduction. It may have a slightly higher rate of ARIA than 35 mg per kg. And the 35 mg per kg may be more of a oligomer-centric dosing piece, right? Because you just -- it may have all of the target engagement but not some of the collateral plaque effects. But this is why we're running the study. I mean both of those dose levels we think we'll have effects on amyloid plaque. We are, from a clinical benefit perspective, believe that neutralizing the soluble aggregates, which are distinct from plaque may actually be a path towards better treatment for patients. But either of those doses, we think, could be competitively safe and efficacious. So we're very excited to see that study progressing at the rate it is and it will be certainly impactful to the field when we're able to read out ALTITUDE-AD in the future.

Excellent. And we're all looking very much forward to that data. I might be jumping the gun here, but perhaps, can you talk about the Phase III, could you incorporate subcu dosing to that study when we see the data from the subcu top line soon. And then I was just wondering, is Phase III something Acumen is capable of doing alone? Or should we expect a partnership here?

Yes. Well, so on the subcu, we're focused in the moment of reading out the top line results in Q1 here. So that's going to be the first next piece of information to inform the go-forward on subcu. I think there's -- we are -- there are a variety of different sort of observations or other approaches people would put forward. We'll factor some of those in as to whether or not -- when and how we pursue the subcu based on the data readout in Q1. And in terms of the next step for sabirnetug, I mean our focus is trying to expedite the advancement of this program for the benefit of patients. So however that comes about and is most beneficial to the pace and probability of success for sabirnetug, I think that's really where we're going to end up for Phase III and later-stage development.

Okay. Excellent. And then the next set of catalysts that you have on the horizon for the year. Last time I spoke to you, there's -- you're keeping very busy this year. We have some conferences in Vienna, Toronto, San Diego. Just what's the -- what should we expect from some of these conferences from you guys?

Yes. We'll be present at -- AD/PD is the upcoming meeting in the first week of April in Vienna. And then the AAN will be in San Diego later in April as well. And then we have AAIC this year in Toronto. So we'll use those conferences -- and then CTAD towards the end of the year. We'll use each of those venues and those opportunities to continue to draw attention to a-beta oligomer as a distinct target and the profile and data in support of sabirnetug as a next-generation asset in the pursuit of better treatments for Alzheimer's patients. So you'll see additional some profiling data, some nonclinical data, maybe more analysis around some of the biomarker effects in Phase I as well as some of the innovation that we've brought to bear in Phase II principally around using these fluid biomarkers as a way to streamline drug development and make it more efficient from a cost and convenience standpoint for study participants.

Could we see any of the detailed subcu data being presented this year?

I can't comment on that today. I think we've got this readout in this quarter, and it will be interesting to see how that comes together and what opportunities we have to present in the future.

Okay. Excellent...

And I guess I should comment that subcu would be an important and interesting format for an agent such as sabirnetug that there's obviously aspects of access and convenience in the right subcu format. So we're very committed to exploring that option for sabirnetug. I think we do believe that IV and subcu are complementary formats and that having the agent available in both of those formats offers prescribers and patients choice, which really is helpful, I think, in terms of what is going to be the right option in a given circumstance for either a prescriber or patient.

Okay. Understood. And perhaps following on slightly from the partnership question I asked, have you any thoughts on dealmaking in this space? It continues to seem quite active to me. We saw AbbVie buy a leader last year. Just any thoughts on people's appetite for CNS and Alzheimer's disease?

Yes. So I would say, Trung, the CNS space, given sort of the early stage risk that the industry has sort of shied away from, does afford opportunities where later-stage, derisked assets command a lot of attention and interest from the established big pharmas that are still encouraged or curious to know what -- how to play some of these larger neurodegenerative indications. So we think there's a healthy partnering environment. I think it just speaks to the unmet need and the promise of if you have something that is distinct and not readily otherwise available, there's lots of partnering interest in the CNS space generally.

Excellent. And we're just heading into the last few minutes here. Do you have any final comments from your side or what message you want to get out to anyone that's listening here today?

No, look, we're really excited to be able to meet the milestone or the guidance of reading out subcu in Q1. So that's -- we're within the zone on that one. And then it would be even more exciting for us to communicate on the enrollment milestone. I think that is a significant undertaking to -- for a relatively small company such as Acumen to go out and enroll 540 patients in multinational type Phase II study is a pretty big lift, and I'm encouraged that the progress we're making and just thankful that we've got great study partners, sites and a team that has been up to the task of that effort.

Okay. Excellent. Well, thank you so much for your time, Dan. In the next few minutes, we're going to have [ Metacell ] present at 1:00 p.m. But again, thanks for your time, and I hope anyone that listened found that enjoyable. Thanks so much.

Thank you, Trung. Take care.

Thank you, guys. Bye.