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

Well, good morning, everyone. My name is Jason Zemansky. I'm one of the SMID cap biotech analysts here at BofA. Thank you for joining us on this, our second day of the 2024 Health Care Conference here in Las Vegas. I'm pleased right now to introduce Acumen Pharmaceuticals, Dan O'Connell, Chief Executive Officer; and Matt Zuga, Chief Financial Officer. Gentlemen, thank you so much for joining us.

Jason, thanks for having us.

Well, perfect. Maybe just to start broadly. You're an Alzheimer-focused company and there have been a number of discoveries in this space recently, most of which suggest that biomarkers are starting to appear far in advance of symptoms, especially for the APOE4 carriers, as well as some of the underlying pathology as well. How do these updates inform your scientific approach and assumptions about the disease?

Sure, so I think it's important, Jason, to reflect on the couple decades' of work that's gone in this space that have advanced our understanding of the biology generally and stratification of patients. I think biomarkers at present are an important part of the development program that we're pursuing with sabirnetug. And I think in the future, biomarkers are likely to help sort of usher in a period of personalized medicine, where there's a better ability to identify patients eligible for a variety of different interventions and monitor the disease and presumably optimize patient outcomes. So I think the biomarker piece is really important. We had some interesting biomarker results in our INTERCEPT-AD Phase I study, which we can talk about. And then we'll be looking again at our Phase II study that's ongoing right now.

Definitely. And definitely want to touch on those. I'm just curious, you know, are you concerned that we may need to intervene much earlier than I think kind of the field right now is anticipating, you know, as far as seeing, you know, what the disease progression looks like?

Well, I think there's a huge population of patients that have advancing pathology in the disease and that are going to be eligible and benefit from the modalities such as sabirnetug. So I think that's a -- certainly a huge area of unmet need that will persist for some period of time. I think the field will continue to involve such that opportunities to intervene earlier in the disease, maybe even pre-clinical, will emerge in time. And again, those are pre-clinical patients that may benefit from an earlier intervention. I think it's going to be just this progression of the early AD population that we're looking at right now is substantial and then as we get better tools, diagnostics, biomarkers and others, other agents and treatments can be brought to bear for that population.

Absolutely. Well, I think that's a great segue into your approach. You're targeting a-beta oligomers. Why not focus on the monomers or plaques, both which I think are frequently done by your competitors? Why might this not be the right approach?

Yes, thanks, Jason. I think that's what's unique and distinct about the sabirnetug program. I mean this is a monoclonal antibody that was raised and directed towards soluble a-beta oligomers, which a couple of decades of research have called out as primary pathogenic species of a-beta, basically the toxic species. And a-beta oligomers are implicated in the disruption of LTP and circuit function between neurons and synapses. They've induced tau hyperphosphorylation and calcium influx. So we think that oligomers in a directed fashion, such as with our agent sabirnetug, are an important therapeutic target that may unlock better safety and efficacy for patients. So if you look back over time, I think it's been established that monomers are not directly toxic or a primary form of pathology for the disease. Plaques are sort of the end state of the aggregation that occurs over an extended period of time and we think oligomers really are a distinct and unique and attractive target that can be preferentially addressed with an agent like sabirnetug.

Great. Can you remind us how much more selective is sabirnetug for the oligomers and what gives you confidence that this is selective enough?

Yes, so we are -- on the numbers, sabirnetug has about a 5 -- at least a 500-fold selectivity for oligomers over monomer and about an 80-, 90-fold selectivity for oligomers over fibrils. And these are in vitro, pre-clinical assays that are employed to assess the selective properties. I think what's kind of interesting about our program is in the INTERCEPT-AD, the Phase I study, we had a novel target engagement assay that we used to actually quantify sabirnetug bound to oligomers in patients' cerebral spinal fluid. It was a fit-for-purpose assay, hadn't been used and no one previously in the field had demonstrated oligomer target engagement. And what the study showed us was that with sabirnetug, we can establish target engagement, even at single doses. And then in the multiple-ascending dose cohorts, we saw significance across the dose levels. So that, I think it's really that selectivity, as is evidenced by the target engagement, suggests to us that sabirnetug does have this differentiated mechanism of action and we're hopeful it's going to yield better efficacy and safety for patients. And that's really the objective for the ALTITUDE-AD study, our Phase II study, which really will be that efficacy proof-of-concept type of study.

Well, maybe let's start with the data that you do have for INTERCEPT here. I think Cameron from the team had a few questions.

Yes, I was just curious if you could maybe give us a high-level overview of what you think the key takes or learnings are at this point? And of the readouts, what gives you most confidence about moving forward?

Yes, thanks. So I think for INTERCEPT-AD, this was a Phase I single-ascending dose, multiple-ascending dose, 7 cohorts across the SAD and the MAD. It was exclusively done in patients -- so all of the participants in the study had a-beta pathology and so that was important for us, not only to establish the safety profile for an early phase study, but also the target engagement. So the key takeaway really are -- I mean for me, it's -- the foundational piece is the target engagement that was demonstrated, the dose response with target engagement. And more recently, we read out, not only have we got an imaging biomarker signal, so there was a reduction in the Amyloid PET signal at the high-dose cohorts after only 3 administrations of drug, and that was sort of consistent with the magnitude and rate of reduction observed with agents like LEQEMBI, the currently approved treatment. And then a little surprising to us, the biomarker effects with just 3 administrations in cerebral spinal fluid, we had a shift in the right direction between the a-beta 42/40 ratio, which is a suggestion of an effect on amyloid reduction. And then also, phospho-tau181, which is kind of the historical standard for phospho-tau. And then importantly, synaptic markers, so neurogranin, which is a post-synaptic marker, and VAMP2, a pre-synaptic marker. So for me, that sort of ties together the target selectivity of oligomers, oligomers which have been implicated in tau hyperphosphorylation and synaptic loss. And again, short duration study, but it's the confluence of those effects that give us confidence in the ALTITUDE-AD study that sabirnetug can yield and produce this differentiated therapeutic profile.

Yes, I think the neuronal and synaptic injury biomarkers were very encouraging, but just wanted to follow up here. Is -- what threshold do you think is necessary to sort of demonstrate that you're going to have a downward effect or downstream effect on cognition and overall disease progression?

Well, I think amyloid reduction is generally clinically validated as a target with -- there's a correlation between amyloid reduction and clinical benefit. I think that's sort of the current standard state of play. I think the fact that with 3 administrations, we're seeing these downstream effects on suspects of interest, these major biomarkers that are non-amyloid related, gives us confidence that over an 18-month study with a primary cognitive outcome, we will be successful with sabirnetug in that population.

Great. And then specifically with regards to the plaque reduction, very robust, but how does the oligomer hypothesis play into this? Are you reducing plaque but also the damage caused by the oligomers?

Yes, so I think the plaque reduction was noticeable and you're right, it was robust, consistent with LEQEMBI. And LEQEMBI is probably an agent that's as close to sabirnetug in that it was raised against protofibrils, which are soluble aggregates that are also toxic to neurons. So we view the plaque clearance as sort of a secondary effect on -- and as a consequence of shifting the equilibrium by reducing oligomer -- the oligomers present, that there's a secondary effect that plaques are essentially addressable and reduced at those elevated dose levels. I think we're going to see in this next study, so ALTITUDE-AD is a Phase II study with 2 active arms versus placebo. We've used the Phase I data, target engagement information and the PK data, to select doses for the Phase II, each of which we think may be therapeutically beneficial, so efficacious and safe. And I think it will be interesting to see whether the plaque reduction at the high dose level is consistent with some of these other agents that are more directed towards plaque. I think we view that the oligomer target as the primary means of opening up and sort of unlocking better clinical benefit.

Got it. Well, maybe let's dive a little bit deeper on the trial design and study objectives for the Phase II ALTITUDE. You just started dosing, but how derisking or potentially validating are the results going to be? And then I'm curious why the iADRS is the primary versus some of the other measures of cognition?

Sure. So the study design, as I said, is 2 active arms versus placebo. This is -- there will be up to 180 subjects per cohort. So a total patient population of 540. The primary outcome for the study is the iADRS, which is a composite of both cognitive and functional measures. And we'll also have secondary outcomes in CDR sum of boxes and obviously, all of the biomarker effects. So I mean that's the primary design. I think we've just kicked off -- we just announced last week, the first patient dosed. We had our investigator meeting late last week in Florida, and there's a lot of enthusiasm for what we're doing. I think the study is designed as a Phase II. So really reading out and having clarity on that differentiated outcome within a reasonable time frame, we view as sort of the definitive proof of the oligomer hypothesis, that we will -- we'll be looking at aspects of safety, tolerability, but really the efficacy piece is going to be important for us.

You mentioned the possibility of potentially doing an interim analysis maybe in terms of thinking about a Phase III. But does that mean a pivotal could initiate before we see overall completion of the Phase II?

So yes, we've -- I think that possibility may exist. I think we are really not contemplating interims for any sort of data assessment or other elements. There is the possibility of using an interim to assess sort of early activities for Phase III. I think what's really important about the ALTITUDE-AD study is maintaining its integrity as a potential registration study, both for European and U.S. regulatory parties. And that's really the work that we undertook last year with a Type B interaction with the FDA and a Phase II meeting and then more recently, feedback with the EMA. So ALTITUDE-AD, if successful, could serve as the first of 2 pivotal studies and at the end of ALTITUDE-AD, we'd be looking at launching a confirmatory Phase III that would be a single global registration study.

Got it. And I want to use my words carefully here, but FDA recently issued new guidelines regarding the development of Alzheimer's treatment, suggested a fundamental shift towards the use of biomarkers like plaque reduction. Again, I want to be careful here, but does this suggest there may be a path towards accelerated approval if ALTITUDE is positive?

So Jason, yes, I want to be careful with my words as well. I think we've noted that guidance. I think it's really encouraging that the agency has kind of put -- opened the door, it really extended the window for biomarker-based accelerated approval. I mean for our purposes and given the fact that we have at least one agent, maybe another coming online, we're primarily focused on a clinical outcome, cognitive benefit. If per chance it becomes more clear and we have the data set to support a filing, certainly, we would want to pursue that. But our primary focus really is on the execution and conduct of ALTITUDE-AD and reading out the Phase II in a wholesome full data set rather than kind of trying to see if we could find our way to some sort of -- let's just leave it at that, I think.

Fair enough. It makes complete sense. Well, in the time we have left, a number of other anti a-beta developers having some challenges, uptake of patients, I think, has disappointed a lot of folks in the community for a variety of reasons. But when you think of sabirnetug's differentiated profile here, what gives you confidence that some of the issues that might have slowed down the uptake of these other agents may not necessarily apply to sabirnetug, hopefully, when it gets on the market?

Sure. So real quickly, I think the launch on LEQEMBI, right, which I think is what you're referring to, has kind of gone as expected for -- I mean the infrastructure is not in place. Our view is that there's a lot of pent-up demand. I think even leading centers haven't implemented sort of the protocols and put sort of the connective tissue between the infusion center and the radiologist and all of this. So I think it's a -- it was a greenfield launch. So some of that infrastructure is now in place. I think that even -- there's been an update on guidance, I think it's going to go -- and it's going to be established mode of treatment, right? And I think that's where sabirnetug, having a differentiated mechanism and presumed outcomes in the ALTITUDE-AD study, sets up for a future choice for patients. I'll also comment at the investigator meeting, there's a lot of enthusiasm for the program. There's an appreciation for our target mechanism and a lot of enthusiasm also for the Phase I data set, but that just really informs why you would want to put a patient into this research study even in the presence of approved and reimbursed products.

Great. Very exciting times for the field and for Acumen. Thank you so much for joining us.

Thanks, Jason, appreciate it.