Acumen Pharmaceuticals, Inc. ($ABOS)

Last day of Bank of America's Annual Healthcare Conference and a very, very warm Las Vegas. My name is Jason Zemansky. I'm one of the SMID-cap analysts here at BofA. And I'm very pleased to have join me on stage Acu Pharma (sic) [ Acumen Pharmaceuticals ], Dan O'Connell, Chief Executive Officer. Dan, thanks so much for joining us.

Thanks, Jason. Thanks to you and your colleagues for having us to the meeting.

Perfect. Maybe just to start at a higher level for those less familiar with the story. Can you briefly describe sabirnetug and its mechanism of action.

Sure. So just to introduce Acumen, real briefly, Acumen is a clinical stage company that is committed to advancing better treatment options for people living with Alzheimer's disease. Sabirnetug is our lead program. It's a humanized monoclonal antibody that has high selectivity for soluble toxic A-beta oligomers and that mechanism and for sabirnetug is one of the ways we think it has the potential to really differentiate on safety and efficacy measures for patients. That program is in Phase II study that will read out late this year. We can go into more of the details on that. But it's a very exciting time in the field and for Acumen. A second program that we've described in the last 12 months involves using enhanced brain delivery, so taking some of our therapeutic cargoes, sabirnetug and sabirnetug-like antibodies and using receptor-mediated transcytosis to deliver more of that payload into the brain and interstitial space. So that is slated to go to hit an IND milestone mid-'27, but really excited about that part of the portfolio as well.

Maybe if we could go a little bit deeper on the rationale for targeting specifically the oligomers versus other subspecies like the monomers, protofibrils, insoluble plaque.

Sure, Jason. So as our Chief Medical Officer is accustomed saying, amyloid is not monolithic. It has -- it comes in a variety of shapes, forms and aggregated states. So A-beta monomer is a normal physiological peptide that's produced with high rates in the body, accumulating aggregated A-beta has had a pathological consequence. It's really sort of the hallmark of Alzheimer's disease. In terms of therapeutic strategies, we think because these soluble aggregates or oligomers have, over a couple of decades, been shown to be potent toxins to synapses and neurons that they represent a distinct and attractive therapeutic target for slowing down disease progression in Alzheimer's disease. And so some of the hallmarks of oligomer toxicity involve more circuit disruption, synaptic loss tau hyperphosphorylation and induction of calcium into cells and essentially initiating and propagating the neurodegenerative processes in Alzheimer's disease, which is distinct from monomer, which is really not toxic and shown really the strategies that have interacted with or targeted monomer have been ineffective, safe, but ineffective for the most part. And then there's obviously a lot of emphasis right now in the field on plaque reduction as a mode of getting to a clinical benefit. And we think sabirnetug and oligomer-directed approaches really offer a different approach that could yield improved efficacy and safety relative to those plaque-directed approaches that are kind of the current class, if you will, today.

Excellent. So it goes without saying a recent Cochrane review raised questions about the efficacy of the class. When you look at the results, how would you kind of -- what were your takeaways there? And again, kind of thinking about the evidence behind sabirnetug, what's your rebuttal?

Yes. Thanks, Jason. Yes. So for those of you that might not be familiar the Cochrane report was a meta-analysis looking at over a decade of A-beta-directed strategies towards clinical benefit for Alzheimer's patients. And that meta-analysis included a number of agents that have been shown to be failed and essentially shifts the conclusion towards those other programs, which didn't yield the results that -- at least the first 2 approved agents in well-designed controlled Phase III studies have shown clinical benefit of between 25% and 32% slowing on clinical measures and also other biomarker effects. So I think the report itself, the methodology has been called out by many experts in the field. The Alzheimer's Association has sort of highlighted some of the flaws in the approach and the underlying conclusions that the report asserts. So we do think that it's been my own experience to sort of observe how the field has cumulatively learned what not to do in terms of more monomer targeting strategies and other things and has really found a path towards designing studies with the right population and now with agents that are really more prone and designed to target pathological species.

Maybe this is a good time to pivot to your INTERCEPT results. Can you briefly summarize what those were? And then looking ahead, what gave you confidence to move into the ALTITUDE Phase II?

Sure. So our INTERCEPT-AD study was the first-in-human study, Phase I single ascending dose and multiple ascending dose study in early Alzheimer's patients. And we deliberately included patients in both the SAD and MAD cohorts in order to assess key attributes of sabirnetug, including its safety profile, the ability to engage oligomeric target and to assess any impact on both imaging and fluid biomarkers. And in the study, the results of the study -- it's a short duration study. So the single ascending dose had 4 dose levels escalating over time, single administration of the drug, IV, I should mention. And then the 3 MAD dose cohorts had 3 different dose levels, again, where there were only -- excuse me, there were only 3 doses administered in that MAD portion of the study. And what we found in the study was robust target engagement and sort of dose proportional elements of engaging oligomeric target as measured by a novel assay assessing that complex of sabirnetug bound to oligomers in the cerebrospinal fluid of patients. And corresponding with the target engagement, we also observed effects on imaging biomarkers of the amyloid PET, in particular, at the high dose levels, which moved the PET signal consistent with what's been shown for agents like lecanemab at a 3-month time point. In addition to the imaging biomarkers, we had assessment of CSF and plasma biomarkers. And there, though we hadn't had sort of overzealous expectations to see effects with such a short duration study, we actually moved kind of the standard fluid biomarkers of the AB of 42 to 40 ratio elements of phospho tau, so phospho-tau181 as well as ptau-217 in plasma. And intriguingly, we did actually see also on synaptic markers, neurogranin and VAMP2, again, achieving almost a statistical significance at some of the higher dose levels. So those are -- the totality of those results in Phase I gave us confidence to move into Phase II and kind of underpin our optimism for a successful result later this year in ALTITUDE.

Obviously, a very exciting year. We'll see the results of ALTITUDE at the end of this year. Can you help us frame expectations going in? What do you -- what would you like to see on the primary endpoint, the iADRS?

Sure. So in terms of ALTITUDE-AD, it's a robust Phase II study. We have 2 active doses versus placebo. The 2 dose levels are 35 mg per kg and 50 mg per kg, and this is Q4W dosing IV. There we have designed that with 180 subjects per cohort. So in as short as 10 months, we enrolled 542 patients in that study across 5 countries and with fewer than 80 sites. So there was a robust enrollment in the study. And I think it was attributed to the Phase I results, I think, enthusiasm for our mechanism advancing the field in terms of oligomer-directed approaches. The study is an 18-month placebo-controlled period, and the primary outcome is the iADRS, which is a composite score that includes aspects of the ADAS-Cog as well as the ADCS-ADL measure, so both cognition and function. And what we would -- a clear win for us on the primary would be something in the 30% slowing over 18 months in this particular early Alzheimer's population. It is -- we'll also be looking at the CDR sum of boxes. We also have both imaging and fluid biomarkers. So the totality of the results are going to inform the next step for sabirnetug. But we -- the study conduct has been great. The early terminations have been consistent with our forecast and expectations. And last November, we had the first patient enrolled into an open-label extension. And that open-label extension has attracted high rates of conversion from the placebo into OLE in the upper 90 percentile in terms of people willing to stay in the study and know that they will be on sabirnetug for the open-label portion of the study.

Excellent. Well, I did want to pivot to your developmental -- more development portfolio. Can you tell us a little bit about the enhanced brain delivery system? What made you partner with...

JCR.

JCR. And what the potential sort of added benefit is there?

Yes, sure. So the field of receptor-mediated transport of larger molecules into the brain is something that's been evolving over the last couple of decades, again, where different targets on the blood-brain barrier have the ability to transport larger molecules, payloads or cargoes are the terminology that we use. JCR Pharma is a Japanese company that's been a pioneer in the field. They have an approved product using a transferrin-directed enzyme replacement therapy for Hunter syndrome. And we -- about 2 years ago, as the proof-of-principle data were coming out on a program that Roche has in Phase III now, it became apparent that these delivery modalities afford the potential sort of supercharge or enhance a product profile. So potentially greater efficacy, lower dose requirements, potentially improved safety and convenience. So those fundamentals were what kind of got our attention about sort of what should our strategy be. And engaging with JCR, we found that their clinically validated approach, for instance, their IZCARGO product has not shown any anemia either in development or clinically. And we think anything that is directed towards the transferrin receptor has a potential vulnerability to inducing reticulocyte count drop and anemia in patients. And that's -- some of that has been observed with some of the ongoing programs. So we really like the validated clinical transparent-directed approach from JCR. And then we're delivering the payload of sabirnetug and another Acumen antibody called 234, which has similar potentially enhanced properties such as sabirnetug, so it had a little bit higher selectivity for oligomers over monomer even than sabirnetug. So we think both -- each of these agents and payloads are part of the candidate portfolio that we are close to designating -- 2 candidates as our -- exercising our option under the JCR agreement and looking to have a single clinical candidate to file an IND in the middle of next year.

If you look at your competitor data, I think a couple of things that we saw certainly better overall efficacy but more intriguing, I think, greater brain penetration. So is the idea that sabirnetug -- is there a potential for an overall synergistic effect going much deeper into the brain? Or is it a chance just to extend more linearly the efficacy?

So what's been shown with other agents, and we're doing work to sort of confirm this. We've already demonstrated in nonhuman primates that we get somewhere between 14 and 40-fold elevated levels of drug in the cortex relative to the unmodified antibody. So there, that's a pretty massive and very competitive enhanced exposure profile. I think the other element is that it's understood that using this transferrin delivery modality, a lot of the transference in delivery is through small capillaries. And so you're actually -- it's not just higher levels, but it's a more broadly distributed delivery of the payload or cargo. And in our case, oligomers have -- it's kind of interesting where oligomers sort of present early in hippocampal and other areas. And so to the extent that we have not only enhanced broader exposure, but also within more diffused and harder to reach large parts of the brain anatomy, we think that could be very synergistic therapeutically. The only other -- another sort of mechanistic thing that I think is of some interest is there are transparent receptors on neurons, and there's also been evidence that there's interneuronal A-beta and whether you could actually get an antibody or a payload into a neuron and address underlying A-beta pathology, oligomer pathology with one of these enhanced brain delivery approaches is of interest to us.

That's great. We have about a minute left, so I'm going to ask probably the most challenging question for you. But you've maintained that anti-amyloid antibodies are likely to be foundational in Alzheimer's. And obviously, we had some news this morning on an anti-tau approach. So just can you give us your overall sort of high-level thoughts here?

Yes. So we do subscribe to the belief that anti-beta strategies are going to be a cornerstone of treatment for Alzheimer's patients for the foreseeable future. And that, that population of patients, not only the early AD population that we're working on right now in ALTITUDE and would anticipate in Phase III, but also the preclinical population. So I think the landscape or the opportunity is expanding. And it's being enabled by novel technologies, diagnostic technologies, plasma-based diagnostics. So that we would anticipate as sort of a cornerstone strategy. That field will continue to adopt new agents with differentiated mechanisms and better enhanced profiles, if you will. And we see that is really where sabirnetug and EBD play into that cornerstone approach. But I don't think anybody believes that Alzheimer's is a disease that is going to be most efficaciously treated with a monotherapy that there will be combination strategies. And the news this morning on the Biogen tau program is -- sounds encouraging potentially. So we'll need to see more of the data. But to think that Biogen would be declaring a willingness to move forward based on what they've seen. And I think they probably do have a high bar internally for why they would continue given the nature of some of the things the company has experienced over the last bit of time. So I guess I'm optimistic that they're seeing something. We haven't had clinical validation of a tau strategy heretofore. So if they really do have evidence that they are on the right path, I do think that's a positive development for the field and something that puts us one step closer towards this combination strategy that ultimately may be the greatest benefit to patients. So hopefully, that was -- a tough question, but I'm optimistic that the future is still bright in the space, and we at Acumen have an important contribution to make.

It was a great answer. Really looking forward to the readout later this year. Dan, thanks so much for joining us.

Thanks, Jason.