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

Day of the Citi Biopharma Back to School Conference. I'm Geoff Meacham. I'm thrilled today to have Acumen. So welcome, guys. The -- there's been a lot of discussion in the Alzheimer's space from a commercial perspective. But maybe, Dan, do you want to give, kind of, a background to where we are in the life cycle, and then we can obviously talk in great detail about the Phase IIb data coming up.

Yes, sure. Thanks, Geoff. Thanks to you and your colleagues for including us in this year's meeting. We're glad to be here. Yes, it's an exciting time for us in the Alzheimer's space, principally as the market continues to develop and reflect the broad and large unmet need of the growing Alzheimer's population. We at Acumen have a pipeline that includes Phase II assets, sabirnetug that will read out later this year. We'll talk more in detail on that in a minute as well as a preclinical or nonclinical program working towards an IND in 2027 that involves some transferrin-directed transport to the brain. So very excited about our portfolio and pipeline to position new and better treatment options for people impacted by Alzheimer's disease. And I think it is important to recognize we are still in the early innings from a commercial market development standpoint. We have 2 approved agents that have been shown in studies to slow the disease, its progression relative to placebo. Those 2 agents have now achieved annual sales run rates exceeding $1 billion and are expected to be north of $2 billion by 2028 and $3 billion to $4 billion in 2030. So it's a growing market in demand of better treatment options, and that's really where Acumen is positioned. We're sort of -- we are now at a point where I think there's clinical, commercial regulatory validation of amyloid targeting strategies as sort of a cornerstone to disease modification. And we at Acumen have a unique riff or scientific hypothesis associated with a species of amyloid or A-beta that is potently toxic and one that we think by neutralizing A-beta oligomers, we have the ability to potentially unlock greater efficacy and safety for patients in this population.

And maybe just talk about the science behind the idea of oligomers being the more toxic species. That's -- you guys have some clinical data, Phase I, prior data, Phase II that sort of underpins that. But maybe just for the audience here just to give us a bit of more background or context.

Of course. And just because I'm joined here by my colleague, Jim Doherty, our Chief Development Officer and President, I invite Jim to comment as the neuroscientist in the room and someone that has been tracking this field for a couple of decades.

Yes, happy to do so, Dan. Good morning, Geoff. Yes. So, it's a really good question. And as Dan said, beta amyloid is now a validated target for the treatment of Alzheimer's disease, and that's a huge step forward in any endeavor to find new therapies. But really, when you look at the biology of amyloid beta, look, the protein has a normal function, and it normally exists as monomer single units. But then something happens, and it's not entirely clear yet what that core thing is, but it leads to misfolding and misaggregation of that protein. So now instead of doing its normal job, it's gumming up the works. And I say it that way intentionally because there's all the things known about the larger things like amyloid plaques, it really the best evidence for true toxicity causing damage to synapses, causing damage to cells, preventing plasticity in the brain and ultimately progressing, interfering with cognitive function is really associated with the small soluble oligomers, at least when it comes to the in vitro and preclinical settings. So a lot of evidence that these small aggregates of amyloid protein are actually interfering with key synaptic function, so messing up signaling. It's an early element in disease. We all know that Alzheimer's is a progressive disorder. And so this dysfunction associated with oligomers occurs early in the course of disease, and it's persistent. So that's a really interesting place to go from a neurobiological point of view. And given that targeting of soluble oligomers with sabirnetug, we're really excited to be testing the oligomer hypothesis really for the first time by getting cognitive data in the ALTITUDE trial.

Yes. So there's really -- go ahead.

I was just going to say that, yes, as Jim is suggesting, I mean, there's a couple of decades of evidence in support of these A-beta oligomers as being a primary toxin. And of course, the origins of our lead program, sabirnetug. Sabirnetug was designed to neutralize and selectively target these species. So it has a high selectivity for oligomers versus monomer and versus plaques. And based on that mechanism and based on some successful Phase I data, we do think sabirnetug is positioned for success and differentiation through this robust 542-patient Phase II study that reads out later this year.

Great. Yes, let's get into the study. So data is expected later this year, year-end. Maybe just given -- could you walk us through maybe the trial design and what we could expect later this year from ALTITUDE-AD?

Yes. So ALTITUDE-AD is a double-blind, placebo-controlled study, 18-month double-blind period followed by a 12-month open-label extension. There are 3 arms in the study, 2 active arms at 35 and 50 milligrams per kilogram IV, once monthly IV administration relative to a placebo arm. Primary endpoint is the iADRS scale, which is a combined scale of ADAS-Cog, which is a cognitive function scale as well as another scale for activities of daily living. So it really is that combination of cognitive impairment as well as impact that has on daily living. We have a number of other cognitive scales also in the study, including CDR Sum of Boxes and a variety of others. As I was just saying, this is -- we see the critical test for the oligomer hypothesis. And given that, we really want to as closely as we can, be measuring cognitive performance. In addition to that, we're also looking at a number of different biomarkers, and I think that's a really interesting area to be talking about these days for Alzheimer's therapies. So we are certainly well represented when it comes to biomarker analysis. So that includes imaging biomarkers like PET scans. We'll be doing amyloid PET as well as a small tau-PET substudy, MR imaging from a safety perspective and a number of biochemical plasma-based biomarkers. So that's the overall design, 542 subjects enrolled in the study, about 180 per arm then. And we are rapidly approaching the conclusion of the study. So we're very excited.

Just a follow up on that. If you think about the differentiation. So, is it reasonable to assume that the efficacy could be sort of directionally maybe better than the current -- if that -- if oligomers are the toxic species, could you see numerically better on obviously, cross-trial comparisons considerations? But then also on the -- talk a little bit about ARIA and the drug and the differentiation from that perspective.

Absolutely.

Yes. And so we do think that there are opportunities to differentiate from existing therapies when it comes to either efficacy and/or safety. And so I think different arguments for both, as you rightly point out. From an efficacy point of view, it's our hope that given the mechanism we've been talking about, we do have that additional benefit by directly targeting oligomers. And so we're expecting to see significant benefit. We're also going to be looking at timing to see if perhaps we see effects at a different time course than what's been demonstrated so far. But our target for what we'd like to see in the study is what we've been saying is about a 30% slowing in cognitive decline. And if you look at the studies that have been conducted to date, the range is somewhere between 27% to 32% slowing depending on the study, depending on the endpoint. So we feel that anything 30% or better is a really good outcome sabirnetug. Of course, we're hopeful to see even more than that, but that's why you run the study. So we'll wait and see what the numbers look like. But timing is also a relevant thing that we're going to be looking at the rate of any potential improvement. On the safety side, as you point out, ARIA is a key risk with the class of molecules. And so something to pay close attention to. We've, of course, been looking at safety even in our Phase I studies. And what we saw there was an overall ARIA rate at about 10%, which is at least numerically a little bit of an improvement on what's been seen in much larger studies to date. So I always talk about the numbers from the Phase I study with the appropriate caveats. It's a small study, but those are the data we have. What we see there is a total of 5 cases out of about 50, so about a 10% ARIA rate. Four out of 5 of those events were nonsymptomatic. So we had one that was mildly symptomatic. And 3 of those 5 were at 60 milligrams per kilogram, which is a dose that we have not taken forward into the Phase II study. So we're hopeful to see an attractive profile when it comes to risk benefit, both on the efficacy side as well as on the safety side.

I guess could we talk a little bit about how discussions are going with regulators as you are approaching later-stage development readouts?

Yes. So we have interacted with U.S. regulatory, with the FDA at the end of the INTERCEPT study, a so-called end of Phase II meeting. And so a very good interaction. There's obviously a lot of activity in the Alzheimer's space. And so there's a lot of good feedback from the agency. We -- one of the critical pieces of that was the understanding that with a well-controlled and robust ALTITUDE study, the one we're running now, that coupled with a single confirmatory Phase III study could support a regulatory submission. So that is the strategy that we've been following is that we would conduct the ALTITUDE study and if successful, conduct a single confirmatory Phase III study to provide a package to support an approval in the early Alzheimer's space.

And I wonder if I could visit a little bit on the Phase I data, just while we're talking about ALTITUDE and probability of success and what we saw in Phase I and how that translate into Phase II. We used a novel target engagement assay in Phase I that confirmed sabirnetug's ability to bind to and essentially sequester oligomers in a dose-dependent fashion, which was first-in-use novel, but really robust. And what we saw there was really as we pushed the dose a little bit higher, plateauing of the target engagement signal, which said in the context of 60 milligrams per kilogram having 3 cases of ARIA, let's -- we don't need to go that high in Phase II. And so with Phase II, we have the 2 doses that Jim mentioned, 35 mgs per kg and 50 mgs per kg. And what we did see in addition to target engagement in Phase I were biomarker effects, both on imaging as well as fluid and CSF and plasma. And so with a short duration Phase I with 3 doses of sabirnetug, we're moving multiple biomarkers, imaging and fluid in the right direction. So our expectation, our hope is that chronic dosing over an 18-month placebo-controlled period, we're going to replicate and expand on those biomarker effects and as a consequence, really deliver an efficacy signal on a cognitive functional scale that's meaningful to patients and regulators. So I think that we have a lot of ways to win in ALTITUDE with the 2 doses we have in that study and the way we've enrolled study and conducted the study as a registration quality study.

Jim or Dan, when you think about the baseline of the ALTITUDE study, how would you say, you can compare with either the Lilly or the Biogen/Eisai. Those are more contemporary kind of trials. I think we've learned a lot over the years on how to run an Alzheimer's study. So in terms of who we exclude. So maybe do that compare and contrast with those two?

Yes. So it's a really good question. And you're absolutely right. That has been a robust learning in the space, right? So as we've talked about, it's a progressive disorder. And so finding those patients who are most likely to benefit is a critical issue. And I would say, first up, and this was a key learning from earlier trials, we put a lot of emphasis on really confirming amyloid positivity. So that meant that what we were able to do is use a p-tau217 prescreen. Now at the time when we were launching the ALTITUDE study, it was sort of early days. So that Eric and the team did a great job of recognizing the potential there. What turned out to be true was that we could significantly reduce the number of failures of amyloid positivity by doing a rapid, relatively inexpensive plasma-based screen to select patients for ultimate confirmation either by amyloid PET or by CSF lumbar puncture. So it really led to a more efficient entry criteria design and really getting what we think are the right patients. Now the other thing that's critically important is aligning the entry criteria to get patients in the right phase of disease to really maximize your chances to see beneficial effects. And this is where we've sort of taken our cue from those trials that you had mentioned. So we're targeting the -- what's conventionally called the early Alzheimer's population. So that's MCI as well as mild dementia. And then within that, if you use those 2 donanemab and lecanemab programs as a bit of a benchmark, they're not exactly the same by design, the Lilly program used a tau entry criterion as well, and that resulted in a slightly more severe patient population relative to the lecanemab trials, which was an active choice. In our case, we are not using a tau requirement. And so our study population is probably closest to the lecanemab population when you really come down to it. And in fact, when we were publishing our entry criteria, they're going to look pretty similar to what people have seen previously with the lecanemab study. So a truly early Alzheimer's population, really with a lot of MCI in that sort of balance between MCI and early dementia.

And so even if it's less severe population over the 18-month endpoint, though, you'll have more than enough time to see progression. I think that's the biggest risk, right?

And that's the balance point, right? Because consistently, studies have been showing that the earlier you intervene, the larger the benefit to patients. But that really -- that's, of course, kind of a population argument. So you -- at the same time, you don't want to go so early that you haven't had enough time to see a decline in your placebo group or your untreated group. So it is a balance between early enough to really maximize benefit to patients, but late enough so that you can run a reasonably sized and reasonably powered 18-month trial. And we think we've hit that balance point, but that's really the approach.

Great. Could we talk a little bit about some of the KOL feedback you've been receiving around the trial design and maybe the potential usage of sabirnetug in the future? I guess also with the endpoints you've mentioned, you have more functional endpoints along with biomarkers. Kind of, what are the KOLs looking for here?

So I think we've had great reception from the KOL community on the program. And the program, this is -- I mean, we had first reception on INTERCEPT data, Phase I data, which was encouraging. And now people are sort of on the edge of their seats, knowing we've got a big data readout later this year. I think the biomarker observations in Phase I have been encouraging to KOLs. I think there's a recognition that having more treatment options is desirable in the space. Most of the KOLs that we've talked with are experienced with both agents that are approved today and are finding those to be suitable for a certain number of their patients. But then I think there's a clear interest in more and better options. The study design is -- has been very well received. I mean I think that we can comment quickly on the overall conduct of the study has been very robust. I mean we enrolled 540 patients in 10 months as a small biopharma swimming in with the big fish in the Alzheimer's space. So really proud of that execution on the part of the team and the study partners. And the overall metrics within the study have been robust. We've had retention in the study that's exceeded our expectations. So we haven't seen high dropout rates due to safety or other considerations that would have been problematic from a powering and statistical standpoint. And we've had really -- so we have an open-label extension. So after the 18-month placebo-controlled period, patients are eligible to roll into an open-label extension for 12 months. And we've had better than 95% of people eligible to roll into the OLE go into that -- take that next step. And of course, all of this is being occurring in the presence of approved agents. So you can -- it sort of gives you a sense that patients and participants in the study are eager to see other options available to them and have committed their time beyond that to be in ALTITUDE in a fairly encouraging way from where we sit.

Yes. And maybe just to echo what Dan is saying. Obviously, testing a key hypothesis for the field is critically important. This is a key program for Acumen's future. And it's -- but it's not just the science or the ideas, it's about execution. And we are very proud of the team, and it's been exciting to see some of the metrics that Dan was talking about. In addition to that, at the AAIC meeting a couple of months ago in London, we had the opportunity to sit down with a number of the PIs from the study. And in general, the feedback was very solid. People liked participating in the study. They enjoyed the study design, the protocol. And these things really do matter. And that -- so we're glad to see that kind of feedback from the KOLs associated with the study.

I think on the other KOL feedback, I mean, the A-beta oligomer hypothesis has existed for 20-plus years, right? It's been out there. It's been a little bit elusive. I think there have been prior claims and attempts to sort of provide the clinical validation. And I think when the clinicians and KOLs that are active in research in the space recognize that ALTITUDE really is an at-scale robust test of that hypothesis. So we are -- we're hopeful for the result and our confidence is predicated on the success in Phase I, but it's an exciting time for us, which really with a successful altitude, I think it ushers in a new discussion within the A-beta space as to what targets are priority and how best to deliver a better risk-benefit profile to patients.

Definitely. You mentioned this, but could we talk a little bit more about the OLE ongoing? Just how is it progressing? And maybe what could we learn from that trial?