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

Ladies and gentlemen, the program is about to begin. At this time, it's my pleasure to turn the program over to Jason.

Good morning, and thank you, everyone, for joining us. My name is Jason Zemansky, and I'm one of the SMID cap analysts here at BofA. This morning, it's my distinct pleasure to kick off our annual virtual CNS symposium with the first panel of the day, fireside chat with Acumen Pharmaceuticals. So let me say a quick thank you to Jason Gerberry and his team for allowing us the slot. I'm really pleased to have join me on camera, CEO, Dan O'Connell, and Chief Development Officer, Dr. Jim Doherty. Alzheimer's has been a very exciting space for a lot of reasons. So this should be a very entertaining and vibrant 45-minute or so discussion. We do have several topics to go over. However, if you have a question for the Acumen team or myself, please use the Veracast system, it will flag a question to us and we can ask accordingly. So with that, gentlemen, thank you so much for joining us.

Jason, thanks for having us. Delighted to be here.

Happy to be here, Jason.

Perfect. Well, let's start somewhat broadly. There have been a number of recent discoveries in the Alzheimer's space, many of which suggest that biomarkers start to appear far in advance of symptoms, especially for APOE4 carriers as well as some of the underlying pathology. So I'm curious, how do these updates kind of inform your scientific approach and assumptions about the disease?

Sure. Thanks, Jason. Maybe I'll lead out and Jim welcome your input as well. So [Technical Difficulty] which is this population of mild cognitive impairment and mild dementia due to Alzheimer's disease. And these are folks that have confirmed amyloid pathology and a subjective memory deficit of some form or another. What the field is now, I think, established is, as you Jason, that there are multiple biomarkers or various different protein aggregates that are occurring over decades in these populations. So the present focus on early AD is justified given the clinical symptomology and the likelihood of progression, I do think we would envision a future where use of fluid biomarkers even moving beyond imaging biomarkers would help to identify patients that would be potentially on track for developing clinical symptoms and be amenable to one form of intervention or another. So I think the good news is we're a couple of decades into attempts to produce disease-modifying treatments for all the clinically diagnosed Alzheimer's patients. We're in a really fortuitous moment where I think we have a couple of approved products, and we have next-gen opportunities such as sabirnetug. And that, I think, will continue to afford better understanding of the biology and other treatment regimens that allow us to treat early AD as well as looking into that clinical -- preclinical population as well.

Yes. Maybe, Jim, If you could follow up on this one. But are there any concerns here that you may need or we as a society may need to intervene much earlier than kind of current thinking before maybe even we have prodromal or mild symptoms?

Yes, happy to, Jason. And let me start by repeating something that Dan was just saying, it is a tremendous time in the pursuit of treatments for Alzheimer's disease. Obviously, a devastating disorder that affects millions of people, not only the people suffering with disease, but also their families in a very fundamental way. So we're very motivated as many are to develop these new therapies. And I think although there have been decades of effort into this identifying treatments for Alzheimer's disease. What's happened in the recent past is we've seen approvals in the U.S. for the very first time for disease-modifying approaches with lecanemab and donanemab. And I think that is not to be underestimated. I mean, what we've been able to do is move from a question of, can you impact the progression of this terrible disorder to what is the best way to impact the progression of this terrible disorder? And so we think about the opportunity to generate the next generation of therapies that really is building off of all the work that you're referring to, and by that, I mean all of the fundamental understanding into not only different biomarkers that are involved in the pathophysiology of disease but also increasingly, the timing of when those markers are starting to show dysfunction in relation to when people are starting to feel sick. I think, the main thing we're learning is that there is this long period of time where things are starting to become a problem in the brain of Alzheimer's patients, and it's happening even before they're starting to perceive symptoms. I don't think that changes that the time that we're treating in early Alzheimer's disease is an impactful time to treat the disorder, but it may create additional opportunities in the future to go earlier and earlier because as is often said, time is brain, right? So the more time that you have to be able to intervene, you potentially have an even more beneficial effect...

So yes, just -- so I think that's -- the point is we're now in a moment where we can intervene in this early AD population and yield clinical benefit. And we think we're at a moment where we can build upon that. But in the future, we may choose and be able to intervene earlier in the broader sense of having preserving more brain and averting some of the early clinical symptomology of the disease.

Yes. Well, it brings up an interesting point and I kind of touched on this earlier, but can you envision the time when a patient goes in, sees their doctor, in their 40s and there's some concern and they start -- they're prescribed daily sabirnetug, weekly sabirnetug, subcu as sort of a prophylactic measure to kind of make sure that, that curve really never gets to the point where the symptomology does start?

I mean I can envision that absolutely, Jason. I think the other element is we have 7 million people in the U.S. that qualify as early AD patients, and that's a pretty significant unmet need and disease burden. And so sort of starting there and then ultimately migrating towards that preclinical population, absolutely. And I think you'll see as we get more experience with these different agents that the treatment regimens, whether it's once monthly or every 3 or 6 months, I mean there will be, I think, a better ability to monitor fluid biomarkers in anticipation of disease, presence and advancement. And then looking to use the tools that will be available in the future to mitigate and otherwise avert primary disease progression.

Makes sense. Well, maybe shifting to sabirnetug and especially for investors somewhat newer to the story. Dan, maybe can you discuss why targeting the a-beta oligomers in contrast to the monomers and plaques is kind of the right strategy here?

Yes. Sure, Jason. Thank you. I think -- so there's a couple of decades of research that have helped to establish the various species of a-beta and a-beta aggregates in the pathophysiology of Alzheimer's disease. And we, at Acumen, have been focused on neutralizing or stopping the primary synaptotoxicity associated with a-beta oligomers. So the fundamental research would support the concept that oligomers -- and the evidence supports that oligomers have a propensity to bind the neurons, particularly at synapses and cause deleterious effects. They basically are an early instigator of the disease and they perpetuate the disease progression, having effects on hyperphosphorylation and inflammatory responses. So we think the a-beta oligomers or, what I would call, a low abundance, yet highly potent target to really have produce potentially a much better clinical benefit and avert some of the safety limitations associated with direct plaque clearance, for instance.

Got it. And then Jim, how much more specific for the oligomers is sabirnetug? And I guess what gives you confidence that not only is this the right target, but the molecule, the antibody is selective enough?

Absolutely. It's a very good question, Jason. The answer is that sabirnetug is quite selective for the oligomers. We've just shown some data from an assay that we've looked at head-to-head binding of sabirnetug to the soluble oligomers versus other forms of a-beta. And we're seeing about an 8,000-fold selectivity for sabirnetug for those soluble oligomers. Not surprising given that sabirnetug was targeting those oligomers, but an important effect. And partially because the oligomers, as Dan was saying, low abundant target. Part of what that means is, the amyloid protein had the normal form of amyloid protein, which has a physiological job in the brain is produced at relatively high abundance. And so if your antibody is not selective or not selective enough and binds to a lot of that monomeric forms of a-beta you're going to have a much lower functional selectivity, even if you are also selective for the pathophysiological oligomers form, if you've got a lot of binding to the monomeric form, given that it's in such high abundance, most of your antibody is going to go to binding that form. So it's really important, and this is the profile of sabirnetug that not only do you have high affinity for the pathophysiological form, the oligomers, but you're also not very potent at binding the normal form. So it's that functional selectivity that we think is really very important in the case of sabirnetug.

Got it. I realize it's somewhat early, but at least based on your models, I mean, how much more efficacy do you think that sabirnetug is likely to have versus targeting the monomers or the plaques? And if not efficacy, I mean, how much do you think it could realistically shift the curve?

Sure. So we have -- so if you think about the current agents, they produce about a 30% slowing in clinical symptoms over an 18-month period. And I think that, if you look at the sabirnetug Phase I study, the INTERCEPT-AD study with 3 administrations of drug and the multiple ascending dose cohorts, the antibody produced a pronounced effect on Amyloid PET in the 2 high-dose cohorts as well as consistent results or effects on fluid biomarkers, both in CSF and plasma. So we do think that the fact that you're seeing early pharmacodynamic effects of sabirnetug with limited exposure that in a longer duration study, given the selectivity for toxic oligomers, we should have a more pronounced clinical benefit than some of these current agents.

Interesting. Do you have a sense of how sabirnetug would be used in practice? I mean is the idea that a patient at high risk or the start of symptoms would go on therapy? And then for how long is there a fixed duration? Or do you see this as more of a chronically administered assay?

People are routinely now referring to induction and maintenance kind of treatment paradigms. And we think sabirnetug, quite frankly, has the possibility of being both induction and maintenance, and/or maintenance. I think we're running an important Phase II study, a fairly sizable study that's going to help inform precisely where sabirnetug is best used. I think if we have the safety profile that demonstrates that it's perhaps safer in certain populations. There's really no -- and it has, all of the clinical benefit associated with other agents, it certainly would be an attractive treatment choice, given whether it had a lower rate of follow-up monitoring and/or didn't have a higher rate of, for instance, ARIA, amyloid-related imaging abnormalities in the E4 population, whether that's homozygotes or heterozygotes. So we think there's tons of optionality for sabirnetug based on, again, its propensity to neutralize oligomers and potentially yield a better clinical benefit either by efficacy and/or safety.

Yes. Jason, maybe just to amplify a little bit on that. I think it's that optionality that I think of as being probably the critical piece for sabirnetug. The hypothesis is that the soluble oligomers that sabirnetug is targeting are an impactful part of the disorder that you've got this progressive disease where you've got a progressive production of these proteins that are causing acute toxicities, and that's exactly what the oligomers are doing. So as you think about being able to take some of those oligomers out of the equation, you're going to have beneficial effects in a couple of different ways when it comes to efficacy, either in that initial induction phase, as Dan was talking about. But even once you've lowered overall amyloid levels, and you'll hear a lot us talking about the currently approved therapies in reducing overall plaque burden. And of course, we can talk about that plaques are an important marker of ongoing disease and reducing this plaques has been correlated with beneficial effects. But we think that in substantial part, some of those benefits are reducing the levels of these toxic oligomers that are floating around in the brain, either associated directly with neurons or even associated around the plaques. So we do think that there's -- by clearing those, there's potential benefit in a number of different ways, either in the induction phase of disease or in this prolonged phase where you're trying to maintain your current level of function and keep from sliding further into disease in this maintenance phase. And I think that's part of what's going to be interesting is as the data come in, it's going to help guide us to understanding where sabirnetug will be most impactful for patients.

I think also, Jason, in this early AD population in a maintenance mode, the future state of treatment probably incorporates the use of fluid biomarkers, right, to help sort of identify early reversion or sort of figure out the treatment regimen based on some biological observation in a patient. So again, this -- we're still -- it's still sort of in the early days, but given the success we observed elsewhere, we think sabirnetug has a very high probability of success in Phase II and has all of that optionality in the future state.

Got it. Dan, you brought up an interesting point in your answer. I wanted to circle back on, and that was the safety profile of sabirnetug. Why do you think the ARIA burden has been less thus far with sabirnetug? And I guess, the reason I'm asking or driving at here is, how much improved does it really need to be if you consider sort of bringing greater comfort to a community physician who is interested in administering the drug, but is a little concerned about the side effect profile?

Yes, sure. Thanks, Jason. Great question. So I think we -- in the Phase I study for sabirnetug, INTERCEPT-AD, we had a total of five cases of ARIA-E across the 48 patients, and this was all in patients. So it was important that we understand the ARIA profile in that Phase I study. Those -- three of those cases came at the high dose cohorts of 60 milligrams per kilogram. One of those three was symptomatic, was really mildly symptomatic. And then we have one case each at 25 mgs per kg, and 10 mgs per kg. What -- I don't think that establishes a particular rate. It's an observation. It's a sort of a -- we had a low incidence of ARIA, but the ALTITUDE-AD study that we're running now is likely to inform precisely what the general rate of ARIA is and in particular, whether we have a lower rate of ARIA in the E4 carriers or E4 homozygotes. One of the observations in INTERCEPT-AD was that we had no cases of ARIA in the six E4 homozygotes that were exposed to drug. And even if you look at some of the other approved agents, they have a much higher rate of ARIA in that genetically predisposed population. So we think if, in fact, as a consequence of the ALTITUDE-AD, the Phase II study, sabirnetug as a consequence of its primary targeting of oligomers has a lower of ARIA and maybe doesn't interact with CAA and other forms of plaque that are potentially inducing the ARIA rates in the E4 carriers. I mean that alone would be a significant advantage in innovation for the space.

Got it. Maybe we could switch gears to the Phase I, INTERCEPT data. I appreciate it didn't include any cognitive output, but multiple biomarkers were analyzed. And can you speak to some of the more critical ones. And what do you think the key lessons overall here are?

Yes, Jason, I'm happy to take that one. As you say, given that INTERCEPT was a Phase I study, a relatively small study and designed as Phase I studies are to be focused on safety and tolerability of the drug from moving forward, just not a large enough study or a long enough study to expect to see meaningful differences on the measures of cognition. But I do think, as you say, it's very important that part of INTERCEPT was looking at a variety of these different biomarkers, both imaging and biochemical biomarkers. And I think I'll give you the take-home message upfront, and then I'll go into more detail. What's exciting to us about the results from INTERCEPT is that we're seeing movements on some of -- on all of these markers, really both the imaging markers when it comes to PET scanning for plaque, but also for the biochemical biomarkers looking at both markers that are closely associated with disease like a-beta 42/40 ratios or tau pathophysiology measures like phospho-tau181 or phospho-tau217, but also in what we would call downstream markers that are a little more associated with the hypothesis that by removing oligomers, you're benefiting synaptic function and thereby improving brain health. And so markers like neurogranin or VAMP2, which are not directly markers of the disease pathophysiology itself, but would be consequences of modifying the disease pathophysiology. We're seeing, a, the changes in Alzheimer's patients that you would have predicted with these markers either up or down depending on the marker. But crucially, evidence for normalization of those biomarker levels during the 3-month dosing period in the study. And in some cases, as we can talk about if you're interested, we're even seeing nominal statistical significance from this relatively small sample set. It's pretty amazing. That was not the intent in the study. The intent of the study was really to just be able to get some experience with measuring these biomarkers in anticipation of including them in a larger Phase II study. But even in that small study, a number of these markers are moving in the direction that one would predict. So that's what we're really excited about. The diversity of responses that we're seeing, they're all pretty consistent with the hypothesis, but also the consistency in the changes that you're seeing, whether it comes to PET imaging, whether it comes to amyloid pathophysiology, a-beta 42/40 ratios or measures of, call it, synaptic health or synaptic function, normalization of neurogranin and VAMP2. So that's what we're really excited about is that you're seeing several signals that are all moving in the same direction and all suggesting an effect that's pretty consistent with the hypothesis to benefit patients.

Thanks, Jim. I'm curious, how much of an impact on both amyloid and how pathology do you think is necessary to see an actual clinical benefit on top of the biomarker?

Yes. Well, I think that's the big question. And of course, that's why we're running the ALTITUDE study is to directly answer that question. Obviously, given the challenges associated with measuring cognitive performance, in individuals. And over time, you really want to have a substantial sample set to be able to measure that. And so that's what we're doing in ALTITUDE-AD. But I think what we can say is that there seems to be a reasonable correlation between the beneficial effects that we're seeing in modulating function and the ultimate performance. I think there's more data that's going to need to be collected. The biomarkers that the field is measuring. The good news, we're all kind of landing around the same biomarkers. And so there's a tremendous amount of clinical data that's starting to be generated on these biomarkers over time in various patient populations at various APOE genotypes, all sorts of things are being addressed. And I think broadly, the message is that these biomarkers are going to be tremendously important in being able to sort of study disease and identify the best treatment for the best patient that kind of thing. But I think we're still very much in the early days of understanding the direct relationship of individual biomarkers and measures of clinical efficacy.

Yes. Well, again, great segue here. Can you walk us through the design of the Phase II ALTITUDE-AD study, what are its design and objectives here? And what ultimately should investors expect to see from the study?

Yes, happy to do it. Yes. So Jason, the Phase II ALTITUDE-AD study is a 3-arm study, placebo-controlled designed to measure the rate of decline in cognitive performance in early Alzheimer's disease. So it is intended as a 540 subject study, 3 arms, randomization, 1:1:1 into those arms, 2 doses of sabirnetug, 35 and 50 milligrams per kilogram once a week and the placebo group. The control period for the study is 18 months. And then there is a follow-up -- a 12-month open-label follow-up extension, which we think is very important because that does mean that anyone who enters the study will ultimately have access to drug, even if they're randomized to the placebo group during the control period. Primary endpoint is the iADRS at 18 months. Of course, we will be looking at a number of measures of cognition in addition to iADRS, including CDR sum of boxes, ADAS-Cog and the variety of other things as well as some of the imaging biomarkers, PET scans for the extent of plaques as well as some of the biochemical biomarkers that we are talking about and that we measured in the INTERCEPT study. So that's the design of the study. And we think that given the pace that we've been enrolling in the study, we're very happy with the progress in the study, and we've actually just recently announced that we intend to complete enrollment in the ALTITUDE-AD study by the end of the first half of 2025.

And Jim, you said dosing IV every 4 -- Q4W, once a month?

Yes.

Yes. Maybe Dan, again, can you talk about the pace of enrollment here? I mean what has feedback been like at these sites? And do they match your expectations as well as any read-throughs especially given that there are two available commercial agents for Alzheimer's.

Yes. Thanks, Jason. Yes, I mean, look, we weren't sure how the study was going to enroll, right? We had a great Phase I result. We have good interaction with the FDA late last year, subsequent interactions with -- in Europe with regulatory bodies. And then embarked on what was a sizable Phase II study even in the presence of approved -- at least the first approved product with LEQEMBI and then a second more recently with donanemab. So the good news is we were out of the gates quickly. I think the team had done a great job preparing sites and laying the groundwork for a quick start in the early part of this year. So we had our first patient dosed in May of '24. And as Jim has just noted, we're going to complete -- we expect to complete enrollment by the first half of next year, which is pretty fast for a Phase II study, particularly in light of the fact that there are approved agents available. I think it's a testament to, I think, the team and the ability to execute is a big piece of it. I think the Phase I data is put in the context that there are options, research options that -- things that can be done for if you have a diagnosis of early AD. And the protocol itself with the two active doses and then the OLE, all of that, I think, is amenable to people being excited about a next-generation opportunity and particularly one that might be safer and more -- potentially more efficacious, right? Like I think all of those elements have contributed to investigator and site enthusiasm for the study as well as participant enrollment and participation.

Got it. And maybe one more follow-up on this line, Jim, why you use iADRS as the primary versus something a little bit more established, like you mentioned CDR-SB, particularly given some of the earlier Alzheimer's studies kind of focused on these, and it would provide a clear way to differentiate yourself some of these earlier studies here?

Yes. Jason, so a lot of work has gone into developing these scales, and not only the iADRS scale, but a fair amount of work has gone into developing the iADRS scale. It was used extensively in a number of different studies, including for the donanemab approval process. And I think what we see as the opportunity in the iADRS is it's measuring many of the same domains as CDR sum of boxes or other more established tests, but there's an opportunity around sensitivity in iADRS that we think is attractive in at least these early initial studies with sabirnetug. But we think that this is the right measure. We think it's likely to measure exactly the same potential effects that you'll see with some of the other cognitive measures. We'll also include those other additional cognitive measures as secondary endpoints, but it's really that sensitivity profile for the iADRS that we think is attractive.

Dan, you mentioned there are two approved agents available on the market, both of which are anti-amyloid beta therapies. Given your proximity to what's going on, what do you think about the pace of commercial uptake? I mean what are the lessons learned at this point?

So I think the lessons learned for the broader stakeholder universe that maybe was -- didn't fully appreciate the absence of system readiness for delivery of these treatments has kind of caught people, I think, a little bit off guard. From our perspective, I think we knew that care pathways and other ways to identify, diagnose direct patients to treatment and then have adequate protocols in place for safety monitoring and the like, has just been a -- it's a greenfield build kind of effort on the part of the first commercial marketers of these drugs. I think we're seeing progress and uptick. I think the numbers in terms of patients going on drug, I think the fact that the system readiness is improving. I think that infrastructure will continue to be built out over the next several years. And for us, we see that as an opportunity. As these things ultimately become relative standard of care, they afford a great sort of infrastructure for treatment delivery and awareness and demand for better options in the future. So it's, I think, a little bit of -- not a surprise to us, but we recognize some that maybe had heightened expectations that this would be easily deployed and readily adopted -- more readily adopted in the broader population.

Well, what are your expectations as far as the market evolution over the next 2 years? I mean, in terms of access, how easy is it going to be for a patient to get on an anti a-beta monoclonal antibody?

I think it will continue to grow and access will continue to expand and broaden. I think there are multiple elements that will enable that opportunity to sort of materialize. They'll have to do with understanding the treatment and care models that justify establishing the infrastructure for these patients, I think it will also come down to other tools for diagnosis and readily identifying the patients that are most amenable to an intervention. So I think all of that is likely to kind of continue to see the opportunity and awareness and demand for better options.

When you think about all of the infrastructure build that has been kind of necessary to put in place on the prescriber side of things, from the payer side of things, distribution. What do you think the rate limiting step here is? And what do you think kind of is going to be most likely to support sabirnetug's potential launch in the future?

Well, I think for the first agents, it's been multifactorial, right? Like it's been across the board. It's system readiness in the clinical and institutional settings. It's been payer resistance just given the magnitude of sort of the economic burden and getting a better familiarity with the benefit of these interventions and the justification for their use. I think we'll see many of those hurdles and barriers addressed. I think it's happening now. I think it will continue to happen and set up an environment where clearly an agent such as sabirnetug, should it show clear superior efficacy and/or safety becomes a treatment of choice for that broad population of early AD patients that are now aware and more easily access based on the infrastructure being in place.

Yes. Makes sense. And I think...

Jason, I just want to follow -- I think, I missed a dimension to your prior question, too, in terms of this is not going to be -- this is not a single agent, single bullet type of paradigm. I think the anti a-beta approaches are going to seed the market and build the infrastructure. I think there will be a strong interest in looking at combination strategies. I think those combinations are likely to target other elements of the pathophysiology of Alzheimer's disease and also benefit from the diagnostic and/or biomarker tools that will help sort of identify -- I wouldn't call it quite personalized medicine yet, but I think we're going to have a much better ability in the future to segment or stratify or identify patients that are justified and amenable to sort of a combination interventions.

Got it. Maybe just one more on this topic. Why do you think it's been such a contentious sort of field? And how is that being resolved moving forward?

So I don't -- I'm not exactly -- I don't know if I can explain precisely why it's so contentious. It does -- to my view, I think there are some very vocal detractors that are not supportive of the current sort of paradigm of approved products. And they are persistent and kind of dug in and have a voice. But I don't know that, that's -- and we kind of -- in our interactions with clinicians and with the patient population, I think they're more hopeful and optimistic that we are in a moment of success. The progress that's been achieved over the last couple of decades is likely to yield more success and better options going forward. So it is -- you're right, it's been a bit of a consensus run. I think part of that was the first experience with the first approved agent that was sort of, again, a complicated situation that really allowed for confusion and contention given the way that played out.

Got it. Well, I think, a really nice segue into your ongoing work to advance the subcu formulation. Can you talk a little bit about some of the strategic considerations driving this decision? I mean, ultimately, how important is it going to be for both the launch and then thinking ahead to the combinations that you mentioned earlier, is having kind of an easy to administer formulation?

Sure. Yes. So when we first started thinking about subcutaneous sabirnetug or ACU193, it was in advance of the way the field that yielded more information on subcu. So if you go back to early '22, roughly, there was this notion that subcutaneous administration of an anti a-beta agent might have an intrinsic safety advantage, so lower rates of ARIA. And I think what -- so we were -- that was important for us to understand and also have a line of sight to potentially subcutaneous formulation. I think what the field has now shown is that these agents, principally -- particularly ones that have primary interactions with plaque, or the ARIAs exposure driven. So they don't have an intrinsic advantage. And from a safety perspective, they may have advantages in terms of convenience and other considerations. So I think that's where we at Acumen, we entered into a partnership with Halozyme. We're using their technology to co-formulate and administer sabirnetug in a subcutaneous development format. And I think what -- we envision IV and subcu as being complementary forms that are likely to be patient prescriber choice oriented where it may be better to have the IV available for certain patients or possibly for induction phase and then migrating towards subcutaneous in more of a maintenance, maybe even as you suggest, in a combination strategy in some future state. So we're excited about the partnership with Halozyme. We've launched the healthy volunteer Phase I in the third quarter. We've guided to those top line results in the first quarter of next year, and that will help inform precisely what next step or steps we would take with subcu.

Got it. And then maybe, if you could just give us a few details, Jim, on the development pathway? What should we look for from the readout? And what's the next step beyond the healthy volunteer study that you're kind of anticipating for this subcu formulation?

Yes, absolutely, Jason. So as you say, the current study is a Phase I study, this time in healthy volunteers, not in Alzheimer's patients, in part because the key goal here is to understand exposure to the subcutaneous form of the drug. We have the advantage that the data was collected from the INTERCEPT study includes a measure of target engagement, actually binding to soluble oligomers in the brain of Alzheimer's patients. And so we have a good target for the exposure level that we think can add clinical benefit. And so the exercise in the Phase I study then is to measure the PK and, of course, safety associated with subcu sabirnetug, but then take those data and be able to extrapolate what we think the appropriate dose and even dose frequency would be for the subcutaneous form that would generate exposure levels similar to what we're doing with the IV sabirnetug in the ALTITUDE study. So that's the major output in the study. As is the case in Phase I, it's always safety and tolerability, but then it's really understanding the PK profile of the subcu formulation because as Dan was saying, we do think that having the subcu availability can only benefit when it comes to convenience and therefore, expanding the population of patients who are going to benefit from the drug.

Is it feasible that the subcu formulation could be available when you start your Phase III? Or do you think that just given the time lines, it makes sense to move forward with the IV formulation and then kind of a follow-up on maybe a Phase IV?

Yes. So I'd tell you it's still too early to tell. We are moving as quickly as we can forward with the IV formulation, that's ALTITUDE-AD, is our major effort. Of course, we will also be addressing and moving forward with the subcu form as quickly as we can. And I think that this is part of what the teams are looking at right now. It will always be data-driven. So we'll look at the results from the Phase I study and decide where to go next. But we do have different options available to us to how to proceed with the subcu formulation.

Got it. Well, then in the time we have left, maybe you could address, I think, a source of confusion about the Phase II, but can you talk about the potential of an interim? It sounds like it may have been a possibility in the past. But do you think going forward is going to be feasible?

Sure, Jason. Yes, it sounds like there continues to be some persistent uncertainty or ambiguity about the use of utility of interns in the ALTITUDE-AD study. And I think that really goes back to when the study was contemplated as a Phase II/III study. And as I mentioned, we had good interactions with the FDA and European regulators. And as a consequence of those interactions, we elected to run ALTITUDE-AD as a stand-alone Phase II study, which is essentially registration eligible. So in the interest of preserving the filing status and the utility of ALTITUDE-AD as a pivotal study, we don't anticipate any public interims or utilities or what have you. So I should be real clear on that topic.

To dance around this a little bit delicately, but do you think there's a potential scenario where you may be able to get a sense of how the trial is going in order to move more quickly into a pivotal? I mean is that a possibility?

Look, we're going to be as aggressive as possible to expedite the development of sabirnetug. And I think it is predicated on our desire to advance better treatment options for patients. So if there is a possibility, I'm sure we will look to employ it. I don't think we have a priority plans or intent to do so. But I think it will be interesting, I mean, this is a pretty sizable study, and we're optimistic that the results are going to be irrefutably successful and positive. And I think even that outcome might warrant some further discussion with regulatory bodies as to what the next step should be for development.

Makes sense. Jim, based on the data you've collected thus far, about how long do you think it will take to resolve a clear difference in iADRS for a patient on therapy with sabirnetug?

Yes. Well, I think what I would come back to, Jason, is the study design. The study was designed quite intentionally as an 18-month study. It's a question of both -- well, it's a multifactorial question, right? It's both understanding the patient population you're trying to study as well as the amount of time that you want to give the therapy to work and then the size of the study. And so we think that the design of the study for an 18-month endpoint, 540 subjects, 180-or-so per arm gives us a very good shot of detecting any significant effect of sabirnetug on cognitive performance as measured by iADRS. And I think you can look at some of the earlier first-generation studies with anti-amyloid therapies and see similarities there in size and assumptions. So we're pretty confident that we've got the right time and the right end point.

Got it. Well, we're quickly coming up on time. I just want to remind those of us -- for those who are listening in, if you have a question, please ping us on Veracast. Otherwise, I'd like to kind of maybe circle back on regulators. In March, FDA issued new guidelines regarding the development of Alzheimer's treatment. Can you talk a little bit about what the implications are for this kind of policy shift on your development pathway and ultimately, regulators support for the development of more treatments?

Jim, do you want to comment first?

Yes, happy to comment on that one, Dan. Well, as you said, Jason, the FDA has recently put out some new guidance. They've been very much involved with the field as the work around biomarkers has evolved. And I think they are not only watching with the rest of us, but they're engaging with various sponsors and data packages. And I think they're seeing how much knowledge is emerging around these biomarkers and how they can be used. And it goes beyond the scope of time that we have this morning to talk about all the different ways that can be used. But there's no question that all of these data are going to fundamentally alter the way Alzheimer's disease is diagnosed. And as Dan was saying earlier, I think when it comes to treatment, we're likely to move ultimately into an area that's more personalized where you can use some of this information to really identify what the best treatment is for individual patients. I think we're ways away from that. But I think the agency is already thinking ahead to how these new data are impacting the way patients are diagnosed, and the way treaters will make decisions about which treatments to use. And I think you're starting to see them thinking about how the best way to employ that knowledge will be. And I think we will continue to interact with the regulatory agencies and continue to follow as they put out guidance around how to use this information to be most efficient to move forward. And that's, I think what it comes down to for us is what's the most efficient way to move forward with the development of sabirnetug.

Well, with that, we are actually just at time. Dan, Jim, thank you so much for joining us this morning. Really appreciate your thoughts and insights. Thanks everyone.

Jason, thank you so much. Really enjoyed the discussion.

Thanks, everyone. Thanks, Jason.