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

My name is Jason Zemansky. I'm one of the SMID cap analysts here at the bank. And this morning, I'm very pleased to have join me, Dan O'Connell from Acumen Pharmaceuticals. Dan, thank you so much for coming.

Jason, thanks for having us.

Well, excellent. Maybe just to start broadly, especially for those newer to the story, can you briefly describe sabirnetug and why preferentially targeting amyloid beta oligomers might be a more effective approach than focusing on other species like monomers and soluble forms?

Sure. So Acumen is a company dedicated to advancing new treatment options for people living with Alzheimer's disease. Our main program, sabirnetug, is a monoclonal antibody that is highly selective for what we view as the most toxic species of amyloid, principally a-beta oligomers or amyloid beta oligomers. There's a host of data to inform and support the notion that soluble aggregates, these a-beta oligomers are the principal pathogens in Alzheimer's pathology that they have a propensity to bind to neurons and synapses and lead to deleterious effects such as circuit disruption, neuronal dysfunction, tau hyperphosphorylation, calcium influx. So sabirnetug was really directed to neutralize the consequences of oligomer toxicity, we think is principally different than broadly amyloid-lowering approaches or monomer-directed approaches, which are other routes that people have pursued for improving patient lives.

Got it. Well, maybe let's just dive into the data. You recently completed Phase I INTERCEPT-AD. What do you think are the key takeaways at this point given the study outputs?

So INTERCEPT-AD was a first-in-human study that was conducted exclusively in early Alzheimer's patients, and it was designed really to give us really important information about the safety profile, pharmacokinetics, target engagement and general tolerability of sabirnetug. It was a single ascending dose and then multiple ascending dose study conducted here in the U.S. And the results were uniformly successful. I mean we had -- we established a safety profile consistent with the mechanism of targeting a-beta oligomers, which holds that there should be a lower rate of ARIA or a low rate of ARIA relative to plaque-directed antibodies. We had robust target engagement. We employed a novel assay to quantify the complex of sabirnetug bound to oligomers in the cerebrospinal fluid of patients. And we saw sort of a dose response in terms of the target engagement concentrations or signal relative to the exposure of drug in those patients. Really important finding in a -- first time the native oligomer engagement had been demonstrated in a Phase I study. The other element that we were looking for in the study were biomarker effects. And so we did both imaging and fluid biomarker assessments. And on the imaging side, at the higher-dose levels, we actually saw a reduction in the amyloid PET signal pretty much to the rate and magnitude of agents like LEQEMBI, the Eisai-Biogen product. So with 3 administrations of the drug in the high-dose cohorts, there was about a 20% to 25% reduction in the centiloid value on the PET scans. Almost more intriguing was we looked at both plasma and CSF biomarkers, looking at the standard elements of the a-beta 40/42 ratio, phosphorylated-tau, and then we also looked at some synaptic markers, so neurogranin and VAMP2 being 2 that are associated with synaptic well-being or health or just normal function. And across all of those biomarkers in CSF and, to a lesser degree, in plasma, we saw a really robust signal, which gives us confidence that we've got a product in sabirnetug that sees its target, and as a consequence of engaging with that target, you're seeing these downstream effects in this patient-based trial. So that was really what gave us confidence. We sort of first read out those results in '23 and then have moved into a fairly sizable Phase II study, where the information coming out of INTERCEPT really helped inform the dosing strategy and set the expectations for what we expect to read out in -- with the Phase II.

Got it. Well, before we move to the Phase II, obviously, INTERCEPT couldn't focus much on the cognitive impact. But were you able to garner any anecdotal feedback from the trial? And would this be insightful?

Yes. So we did look at clinical measures in that study, which is really kind of a safety measure, first and foremost. I mean the study was not powered for clinical effects. And there were no -- it was really sort of, I would say, call it, noisy to no obvious signal or secondary assumption that we could make about cognitive benefits. Recall, these are -- the maximum -- there were only 3 doses in the multiple dose cohorts. So it really wasn't expected to see a clinical effect. And what I think becomes the basis for the probability of success in the ALTITUDE-AD study, the Phase II, is the effects on biomarkers and then a longer-duration study where we have a primary outcome at 18 months.

Yes. You kind of touched on this, but let's return to the subject of ARIA, which has been a big issue for some of your competitors who are currently commercial. But why do you think rates of ARIA in INTERCEPT were much lower?

Yes. So in INTERCEPT, the incidence of ARIA was confined to 5 cases, 3 at the high-dose cohorts and then 2 at the lower-dose cohorts. Interestingly, we have no observations of ARIA-E in the APOE4 homozygotes, which are the population that is at greatest risk for ARIA and the one that really on the current agents are -- some physicians are not treating the homozygotes as a consequence of that risk profile. So the principal mechanism to explain the ARIA safety with an agent like sabirnetug is that it's really hitting the soluble aggregates that are diffusible and have a propensity, as I mentioned, to sort of bind and do harmful things to brain cells, whereas plaque-directed antibodies are really likely to see vessel-bound amyloid plaques and induce essentially an inflammatory response that leads to the ARIA-E observations. So we do think it's on mechanism for sabirnetug to have a better safety profile in respect of ARIA-E.

Got it. Maybe we can delve into the ALTITUDE-AD study, which we're just referring to. I guess fundamentally, maybe taking a step back, there have been several recent discoveries suggesting that the development of Alzheimer's is a -- could be -- it's likely a decades-long process. Are we going early enough to have a disease-modifying effect?

So Jason, yes, I think it is not a controversial concept that Alzheimer's is -- occurs over 10 to 25 years. And the good news is we're getting more reliable tools to help us assess the established pathology, the biological basis of the disease in advance of the symptomology, so the clinical phase of the disease. And I think, we think an agent like sabirnetug is well positioned in the early 80 population, which is a symptomatic population that has both established pathology but also symptomology. But as you think about going earlier, there really is a way to -- and we probably see this with other chronic diseases like cardiovascular disease and others, where getting -- intervening early at the first sign of pathology likely affords a better long-term outcome. And that's certainly the future state of the field. And I think for those that have been paying attention to the Alzheimer's space generally, I think the field has made tremendous progress over the last 2 decades in terms of the -- a couple of first approved disease-modifying drugs, better insights into next-generation candidates such as sabirnetug. And now these fluid-based biomarkers are going to streamline and economize our ability to identify patients at the early stages of disease.

Got it. Along the same lines, as you mentioned earlier, you're looking at an 18-month endpoint. Is that a sufficient amount of time to see a change in cognition? And then maybe can you touch upon your selection of the measure there, especially given pivoting away from more conventional tests like the CDR-SB or the ADAS-Cog-13?

Sure. So ALTITUDE-AD, our Phase II study has 2 active dose cohorts versus placebo. It's 180 patients per cohort roughly. So 542 patients have been enrolled in the study. We completed enrollment in the first quarter of the year, which was phenomenal. The primary outcome will be the iADRS, which is a composite of the ADAS-Cog as well as the ADCS-Activities of Daily Living. So it's a combination of cognitive and functional outcomes. And there's some evidence to support that it's a more sensitive measure in this early AD population. And if you look back at programs like donanemab in their Phase II study, they had the iADRS as the primary, CDR sum of boxes as the secondary. They hit on the primary. They didn't hit on CDR sum of boxes. Subsequently, they hit on both in the Phase III. But I think that for stage and population appropriateness of what we're doing in ALTITUDE-AD, iADRS is the right one. We, of course, will have CDR sum of boxes and other secondary measures. And as I mentioned, we'll be looking at the imaging and fluid biomarkers for sure.

Yes. Makes sense. You completed enrollment in March, which was fairly rapid. Can you talk a little bit about feedback? I mean what are your takes sort of on the broader state of the market in Alzheimer's?

Yes, I think -- so ALTITUDE-AD enrolled 542 patients in roughly 10 months. And so this is a study being conducted at roughly 80 sites across 5 countries. We have small but skillful team. There was a lot of preparation that went into kind of preceding the launch of that study. But I think it's indicative of the awareness that there -- if you have a diagnosis of Alzheimer's, there are things that you can do. And particularly for ALTITUDE-AD, given the data set and the evidence generated in INTERCEPT, we think there was a lot of momentum to -- for some of the best sites and the best candidates to rapidly enroll in the study. So pretty encouraged to see how that -- the pace of adoption and enrollment in the study. And now we'll be looking at adherence and essentially retention through the course of the study.

Got it. Well, I know you've downplayed this possibility, but I'm going to press you on it a little bit. Any possibility of having an early look at the data, especially given overall, there seems to be a very open attitude in terms of regulators on having a -- supporting development here?

Yes. So the -- I think we have consistently said we're not looking early at data or conducting interim or futility analyses. The goal of ALTITUDE-AD is to actually serve as evidence as part of a submission. So we want to maintain the integrity. We're conducting the study in a -- as if it's a pivotal study for that particular reason. So I think we are -- as tempting as it might be, we're not intending to be looking at interim data.

Perfect. Well, maybe in the time we have left, can we talk about the competitive landscape? What's your assessment there? And any modalities you think might eventually pair well with an anti-amyloid beta antibody?

Sure. So it's a very exciting time in the field. As I've mentioned, we've got a couple of approved agents that are sort of making their way into the clinic. Those products have acknowledged limitations. And so there's ample room for improvement. I mean there's 7 million people in the U.S. that have dementia associated with Alzheimer's disease. I think we're seeing -- you mentioned modalities. I think we're seeing ways to improve the delivery of various agents into the brain using brain shuttles or what we refer to as enhanced brain delivery. That's an area that's of great interest to us. And as we think about the profile for sabirnetug reading out in ALTITUDE-AD, putting a carrier, an ABD-type carrier with a sabirnetug-like asset to even further advance the safety and efficacy of our mechanism, we think, could be a really compelling opportunity for the field.

Makes sense. You recently completed a Phase I for a subcutaneous formulation of sabirnetug. How does that read into everything? First, is it possible that you could incorporate that into ALTITUDE? And then I just -- overall, how valuable is it to have that convenience?

Yes. So we are very interested in advancing a subcu formulation of sabirnetug, and we're doing that in parallel with the IV. And I think it's -- the 2 formulations are presumably complementary that having those options as physicians or for patients, I think, is important. We're not yet decided on the precise next step for where subcu goes. We've got ongoing formulation and delivery assessments underway. And there are a couple of obvious options, whether we want to add the subcu to the confirmatory Phase III, either in the primary portion of that study or in the OLE is TBD, or conduct a stand-alone subcu Phase II or Phase II/III type study still is another option that we might consider.

Got it. And then kind of dovetailing back into the previous question. In terms of stacking modalities together, any thoughts on a different sort of mechanism of action that might pair well with an antibody, especially if it were in a subcu formulation?

Yes. So we're starting to see combination strategies, right? So whether it be IV or subcu, I think the state of play is really like can you pair an amyloid-directed approach with either a tau or an inflammatory-related mechanism or maybe an endocrine would be the other modality that might come to play in this space. So all of those possibilities, I think, are worth pursuing. And I'm encouraged to think that we're making enough progress to keep the momentum in the space going forward.

Makes good sense. Dan, thank you so much for joining us.

Jason, thank you so much.