And potentially would have more profound effect on cognitive and clinical effects, behavioral effects. With the research, the founding science and research around Acumen was really predicated on finding selective agents that could neutralize the toxicity of A-beta oligomers, in particular. And so we've, you know, recently, the thirty-six-month data, I mean, this is kind of getting into the weeds early, but it looks like chronic treatment with an agent that does have some preference for soluble aggregates, such as protofibrils, continues to offer benefit to patients.
Sure.
So we're really interested in seeing how sabirnetug, our product, reads out in phase II, and would believe that it would be a chronic-type treatment to continue to address and neutralize these toxic species that I should mention are particularly toxic to synapses, right?
Mm.
So the part of the fundamental science is that these aggregates have a propensity to bind to neurons at synapses and cause deleterious effects, essentially circuit disruption, induced tau phosphorylation, and kick off really a neurodegenerative process. So, neutralizing those particular targets, in contrast to A-beta monomer or A-beta plaque in a primary way, could offer and really unlock greater safety and efficacy for patients.
Got it. Yeah. You know, as for the safety, since you spoke about safety, for the INTERCEPT-AD, you know, we thought that the data is also unique with respect to the ARIA, right? Can you touch upon the safety tolerability aspect of the trial and what it means concerning therapeutic index?
Sure. So the phase I design was actually fit for purpose for sabirnetug. So we did this study exclusively in Alzheimer's patients, and it was intended to help us establish the safety profile, target engagement, and observed biomarker effects. And what we in this first-in-human study, which was in patients, we established a wide dosing range, including going upwards of 60 mg per kilogram, to understand whether there would be a dose-limiting.
Mm
... issue. And so the primary issue with any of these A-beta agents generally is ARIA-E, which is an observed effect on brain swelling and edema. And in our phase I study, we had of the total 48 patients that were exposed to sabirnetug, we did have five cases of ARIA-E, and three of those occurred at the high-dose level of 60 mg per kilogram, and then two, one each at 25 and 10 mg per kilogram. But that wide dosing range is important, and I think if you look at some of the historical agents, such as aducanumab, I mean, they had a phase I that went upwards of 60 mg per kilogram , and all three of the subjects exposed at that dose level experienced symptomatic ARIA.
Mm
Which is really the what is of greatest concern for clinicians, is the symptomatic ARIA. We've, you know, on the basis of the phase I, we've also established target engagement, and we saw a dose response.
Yeah
In target engagement. And so for that, what we have learned, it was really important, was that sabirnetug does see oligomers in the brains of Alzheimer's patients. It binds them, and the complex itself can be measured in cerebrospinal fluid. So that has been really instructive as to how we would choose doses for phase II, and we think also de-risk the program substantially, given that we're getting a nice dose response on target engagement of these, you know, potent toxins in a patient-based phase I study.
Right. And that kind of brings me to the next question on target engagement, which I thought was, you know, particularly, kind of a milestone in INTERCEPT, especially with you developing your as... You know, it's kind of tricky to develop that assay, but I think Acumen kind of nailed it down with developing that assay and also showing target engagement. So if you can elaborate on the target engagement assay and the significance of the binding data, that would be probably.
Yeah.
Sure.
It's interesting. I mean, and I'll reference a little bit of history. I mean, the program, Acumen had a partnership with Merck for a number of years, and Merck did some of the primary Acumen sort of initiated the innovation around oligomer toxicity and some of the fundamental science about the target. And then Merck ran a discovery campaign in pursuit of a best-in-class monoclonal that would be highly selective and navigate sort of this safety, efficacy window. What Merck did in their preclinical work in the transgenic mice was establish an ELISA-based assay to measure the complex of 19.3, which was their preclinical candidate.
Now, 19.3 or sabirnetug, and look at the dose response of the complex of 19.3 bound to oligomers in these Tg2576 mice. The Acumen team picked up sort of that assay design, and using anti-idiotype antibodies to sabirnetug, established ELISA plate-based method of pulling down the drug, sabirnetug, and confirming the presence of oligomers as part of that complex.
Mm.
And so even with the single administration, it was sort of two mg per kg was below the level of detection, but even at 10, 25, and 60 in single administration, we see in CSF of patients this complex is present. And then in the multiple ascending dose cohorts across 10, 25, and 60 mg per kilogram, where three administrations of drug were given to these patients, we see significance across those dose levels. So it was really interesting to see that the sensitivity of the assay worked. I mean, we really... It was a fit for purpose, first-time use, but it actually did perform quite well for us and helped.
You know, there's an element of the target engagement that was interesting to observe, whereas we pushed the dose, we were not seeing more signal in terms of target engagement. So there's a bit of a plateauing effect.
Mm.
When we went into the study, we weren't quite sure whether we would see any target engagement or whether we would see target engagement continue to rise with exposure and thus not really have sort of a ceiling or understand.
Mm
What our top target dose should be. But the INTERCEPT-AD results really informed that we don't need to go higher than 60, and in fact, as a consequence of some dose modeling and other considerations, we've taken forward 50 mg per kilogram dosing every two weeks, and then 35 mg per kilogram as the two active arms in the phase II study.
Got it. Thank you. Let's talk about the plaque-lowering aspect of the, you know, the data from the INTERCEPT and the, you know, with respect to plaque lowering, sabirnetug has been compared to lecanemab. Can you elaborate on that or the aspect of the plaque-lowering ability of the.
Sure, Neena. So we, you know, as part of a first-in-human, first-in-patient study, we employed amyloid PET as baseline and post-last dose to understand whether there were effects on amyloid PET. In fact, as you mentioned, in the high-dose cohorts, the cohort six and seven of the MAD cohort, we observed about a 20-25% reduction from the baseline amyloid PET, which was not entirely anticipated, but to us, also doesn't come as a surprise, given Leqembi has shown similar comparable rates of amyloid PET reduction. So we were encouraged by the pharmacodynamic observation, the biomarker effects, and would anticipate that we'll continue to see amyloid PET signal reduction with chronic administration or extended dosing of sabirnetug. So we'll see.
I mean, the phase II is intended to inform on that basis, but it was an interesting effect. Certainly, the drug is active, you know, against amyloid, and I think when you put the amyloid PET effects observed in the context of the target engagement, you know, there's some real linkage between target engagement and then a corresponding effect on plaque reduction.
Correct. You know, you mentioned-
And I'll just elaborate on that. And to clarify that particular point, that effect, you know, we would view as a shift in the equilibrium, that you've basically saturated oligomeric target.
Mm.
Which are typically in the presence or adjacent to, you know, neuritic.
Neuritic.
Fibrillar plaque.
Sure.
And so you can envision, you know, sabirnetug basically engaging with its intended target, clearance of that species, and then a shift in the equilibrium.
Equilibrium.
Away from plaque, and so forth.
Yes.
Yeah.
Great. Thanks. You know, you mentioned about biomarker analysis. What were the learnings from the intercept biomarker analysis and the significance of the neurogranin data, and how and the durability of the treatment?
Sure. So, the intent for the biomarker... the fluid biomarker.
The fluid.
Analysis now was really to give the team and our group and some of our vendors experience running these assays in anticipation of the phase II, right? That that's really where you're gonna be observing biomarker effects. Again, to our delight and surprise, we actually had effects, observable effects on multiple biofluid biomarkers across the amyloid, total tau, phospho-tau, and then some of these synaptic markers that you mentioned, VAMP2 and neurogranin. And it was interesting to see, you know, observable dose effects, including significance on a couple, such as the VAMP2 synaptic, presynaptic marker, and then high dose levels of phospho-tau 181 and neurogranin.
And so the totality of those results, again, not anticipated to be observed in such a short duration study, suggests to us again that the molecule is active, engaging its target, that the target is actually having downstream effects on other markers of neurodegeneration and Alzheimer's, and take that as a real, you know, a confidence in terms of the probability of success for phase II.
All right.
I'll just say, the synaptic markers, just to link it back to the target, are of great interest to us, given it links back to the oligomeric toxicity associated with neuronal and synaptic binding and pathology. Essentially, induction of pathology. So that for us, you know, again, is sort of this. That's the notion of sabirnetug unlocking greater efficacy and safety for patients relative to some of the other prior agents that were directed at other species or had different mechanisms of action.
All right. Very helpful. Let's talk about the ALTITUDE-AD and the timeline. You know, how has the trial been going with respect to the enrollment and the feedback from the sites?
Yeah, so the ALTITUDE-AD kicked off in the first half of the year. It was conceived of as a, you know, a randomized, double-blind controlled study with two active arms versus placebo. We have 180 subjects intended for each cohort, so roughly 540 patients in total. You know, we thought we would be looking at 125-130 sites globally, North America, Europe, maybe having to go to Europe to find patients, given the launch of a couple products here in the U.S. We recently guided that enrollment is exceeding our expectations. We attribute that to the phase I results, sort of the profile of sabirnetug as being a potentially safer and ultimately more efficacious agent.
That the protocol itself is amenable to investigator sites, that they sort of are familiar doing these studies, that we're within, you know, the operating instructions, if you will, of the protocol, are user-friendly at the site level. And that, you know, that there's greater awareness in the population you know, this is a large population that now has been introduced to the idea that there are things that you can do.
Mm.
If you have a concern about memory loss and Alzheimer's disease, and research such as entering into the ALTITUDE-AD study seems to be a compelling value proposition, given, you know, the two active arms versus placebo, and then we also do have an open-label extension, so everybody gets exposed to the drug, provided, you know, they do well in the study.
Okay.
Operationally, we have like 50 sites now, over 50 sites active, and we don't. I don't think we're gonna need to go, you know, we're kind of done with activating sites.
Okay.
The enrollment is moving quite nicely.
Awesome. And with that, you know, I came to the last question, and so can you briefly discuss the subcutaneous program for sabirnetug, and what are the goals for the ongoing phase I PK study?
Yeah, sure. So we have been working since late last year with Halozyme on developing a subcutaneous formulation that would be amenable to single weekly injection in patients. And we launched in the middle part of this year a phase I in healthy volunteers. So we're doing essentially a PK bioavailability study in those healthy volunteers to establish the exposure equivalence between IV and subQ. And I think that'll be really important information that we'll have Q1 of next year to help guide what the development strategy ought to be for a subcutaneous version of sabirnetug. Yeah, we take the view that IV and subQ are complementary modalities that likely, as we're seeing the initial rollout and establishment of the infrastructure to deliver IV-based treatments.
Mm-hmm.
Subcutaneous could be complementary, either as a maintenance treatment or ultimately as induction. And we're very much committed to, you know, patient access and ensuring that we have all options available to patients. And having both formats is actually, I think, quite attractive to clinicians, because in the early stages of treatment, having, you know, visibility and line of sight on patients that are coming in for infusions and then ultimately migrating them to more of a subcutaneous modality seems like it would be the right treatment paradigm for, you know, cost, convenience, and general access.
Great. Thank you. I think that was very productive. If there are any questions from the audience, then it's open. Otherwise, thanks very much, Eric.