My name is Jason Zimanski. I'm one of the mid-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.
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 insoluble forms?
Sure. 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 beta oligomers or amyloid beta oligomers. There's a host of data to inform and support the notion that soluble aggregates, these amyloid beta oligomers, are the principal pathogens in Alzheimer's pathology, that they have a propensity to bind to neurons, and lead to deleterious effects such as circuit disruption, neuronal dysfunction, tau hyperphosphorylation, calcium influx. Sabirnetug was really directed to neutralize the consequences of oligomer toxicity, which we think is principally different than broadly amyloid-lowering monomer-directed approaches, which are other routes that people have pursued for improving patient lives.
Got it. Maybe the side data. You recently completed phase I Intercept AD. What do you think are the key takeaways at this point, given the study outputs?
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. We established the safety profile consistent with the mechanism of targeting amyloid 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 concentration signal relative to the exposure of drug in those patients.
Really important finding, and first time 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. On the imaging side, at the high 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. With three administrations of the drug in the high dose cohorts, there was about a 20%-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 Aβ 40/42 ratio, phosphorylated tau, and then we also looked at some synaptic markers, so Neurogranin and BANT2 being two that are associated with synaptic well-being or health or just normal function. 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. That was really what gave us confidence.
We sort of first read out those results in 2023 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 with the phase II.
Got it. Before we move to the phase II, obviously Intercept could not focus much on the cognitive impact, but were you able to garner any anecdotal feedback from the trial, and would this be insightful?
Yeah. 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 maximal, there were only three doses in the multiple dose cohort, so it really was not expected to see a clinical effect. What I think becomes the basis for the probability of success in the Altitude AD study, the phase II, is the effect on biomarkers and then a longer duration study where we have a primary outcome at 18 months.
Yeah. 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. Why do you think rates of ARIA in Intercept were much lower?
Yeah. In Intercept, the incidence of ARIA was confined to five cases, three at the high dose cohorts and two at the lower dose cohorts. Interestingly, we had no observations of ARIA in the ApoE4 homozygotes, which are the population that is at greatest risk for ARIA, and one that really on the current agents, some physicians are not treating the homozygotes as a consequence of that risk profile. The principal mechanism to explain the ARIA safety with an agent like sabirnetug is that it is really hitting the soluble aggregates that are diffusable 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 observations.
We do think it's a mechanism for sabirnetug to have a better safety profile in respect of ARIA.
Got it. Maybe we could 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 could be a, it's likely a decade-long process. Are we going early enough to have a disease-modifying effect?
Jason, yeah, I think it is not a controversial concept that Alzheimer's occurs over 10 to 25 years. 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 stage of the disease. I think we think an agent like sabirnetug is well-positioned in the early AD population, which is a symptomatic population that has both established pathology but also symptomology. 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 intervening early at the first sign of pathology likely affords a better long-term outcome. That's certainly the future state of the field.
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 two decades in terms of a couple 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. On the same lines, as you mentioned earlier, you're looking at an 18-month endpoint. Is that a good amount of time to see a change in cognition? Maybe can you touch upon your selection of the measure there, especially given pivoting away from more conventional tests like CDR-SB or the ADAS-Cog study?
Two active dose cohorts versus placebo. So 180 patients per cohort roughly, so 540 patients have been enrolled in the study. We completed on CDR-SB boxes. Subsequently, they hit on both in the phase III. 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-SB boxes and other secondary measures. As I mentioned, we'll be looking at the imaging fluid biomarkers for sure.
Yeah, makes sense. Now, 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?
Yeah, I think so. Altitude AD enrolled 542 patients in roughly 10 months. This is a study being conducted at roughly 80 sites across five countries. We have a small but skillful team. There was a lot of preparation that went into kind of preceding the launch of that study. I think it's indicative of the awareness that if you have a diagnosis of Alzheimer's, there are things that you can do. Particularly for Altitude AD, given the dataset and the evidence generated in Intercept, we think there was a lot of momentum for some of the best sites and the best candidates to rapidly enroll in the study. Pretty encouraged to see the pace of adoption and enrollment in the study. Now we'll be looking at adherence and essentially retention through the course of the study.
Got it. 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?
Yeah. 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. We want to maintain the integrity. We're conducting the study as if it's a pivotal study for that particular reason. I think we are, as tempting as it might be, we're not intending to be looking at interim data.
Perfect. Maybe in the time we have left, can we talk about the competitive landscape? I mean, what's your assessment there and any modalities you think might eventually pair well with an anti-amyloid beta antibody?
Sure. It's a very exciting time in the field. As I mentioned, we've got a couple 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 are 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 an antibody brain delivery. That's an area that's of great interest to us. As we think about the profile for sabirnetug, we're reading out in Altitude AD, putting a carrier, an EBD-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? I just, overall, how valuable is it to have that convenience?
Yeah. We are very interested in advancing this subQ formulation of sabirnetug, and we're doing that in parallel with the IV. I think the two 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 subQ goes. We've got ongoing formulation and delivery assessments underway. There are a couple of obvious options, whether we want to add the subQ to a confirmatory phase III, either in the primary portion of that study or in the OLE, is TBD, or conduct a standalone subQ phase II or phase II, III type study 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 subQ formulation?
Yeah. So yeah, we're starting to see combination strategies, right? Whether it be IV or subQ, I think the state of play is really 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. 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.