Hi everyone, welcome to the next session of the Stifel CNS Days. I'm James, I'm Paul's associate, and I'm happy to be joined with Dan O'Connell, the CEO of Acumen Pharmaceuticals, and Eric Siemers, the Chief Medical Officer. Looking forward to the discussion. I have a number of questions, but feel free to jump in. Feel free to shoot me any questions in the chat box. Maybe just to get started, we can just have maybe Dan, you can just kind of give a quick overview of some of the data you presented last year and any recent data that you've shared or analyses, and just kind of where things stand with next steps and what lies ahead.
Sounds good. Thanks, James, and thanks to you and your colleagues for inviting us to be here today. Sure. So for those listening in who may be new to our story, Acumen set out to develop an antibody with high selectivity for amyloid beta oligomers. A- beta oligomers are neurotoxic amyloid species that are in the brains of Alzheimer's patients. By targeting them, our foundational theory is that sabirnetug, our highly selective A- beta oligomer antibody, may offer greater efficacy and reduce side effects like ARIA-E as compared to currently marketed treatments. So our phase I positive results last year were announced in July at the AAIC meeting and showed that sabirnetug bound its intended target oligomers, A- beta oligomers, in the brain. It also improved downstream fluid biomarkers with only three doses, having an effect on amyloid levels, tau levels, as well as synaptic biomarkers.
We'll go into some of that detail. In addition, it generated an observed safety profile that we found to be compelling relative to other options. So the takeaway for us really is that the phase I results give us enhanced confidence that the next study, the 201 study we'll discuss today, has the possibility of sabirnetug differentiating on safety and/or efficacy or potentially both, which we think would be fundamentally attractive to providers and patients. We plan to initiate the phase II study in the first half of this year. A lot of activity is underway right now to stand up the study and start enrollment. We also plan to initiate a subcutaneous study, a phase I study, bioavailability study in the middle part of this year, which is also an important workstream for us.
And then I think the key for us is to really highlight the differentiated mechanism and the path towards differentiation for sabirnetug as a highly oligomer selective agent and kind of a first in its class in many respects.
Great. Great. Yeah, definitely want to dive into some of the data and next steps in the study. But maybe kind of first just taking a step back as we kind of think about the Alzheimer's space, the lecanemab launch has been pretty slow and even slower than skeptics were originally expecting. So I guess, one, are you surprised with that? And two, I guess, in your research and discussions, I guess, what are you hearing from the community in terms of what's kind of driving that slow launch? Is it demand, the ARIA monitoring, et cetera? And just kind of curious what you think it's going to take to really get the enthusiasm back to kind of get these launches going.
Sure. Thanks, James. I'll give you an initial take and invite Dr. Siemers to comment as he's the neurologist and one with kind of firsthand knowledge. I'm not surprised. I mean, it's a first-in-class, no precedent treatments are available. And so the infrastructure is in the early phase of getting built out. Our observation is the demand is there. And I think by this time next year, some of these questions about launch and traction will be resolved.
Yeah. So I think that's really it. And it's not unexpected because really for years now, there's been discussions, particularly among KOLs, that the infrastructure just wasn't there for infusions like this. Now, and it's more than just the infusion clinic. So you have to have the availability of PET scans or LPs and people who know how to do those. You do have to have infusion clinics. And then you have to have MRIs to do the surveillance for ARIA-E. Now, there's plenty of MRIs around, but what's lacking at this point is actually even neuroradiologists who really have the expertise to identify a subtle ARIA-E. So all those things we knew would be a problem once there was a drug that was available and lecanemab became that drug. So the fact that the start has been relatively slow based on a number of prescriptions isn't a surprise.
I think the other important point here is that it's not a question of demand or enthusiasm, at least in my view. I think there are plenty of patients who, when you're in this early AD stage, will want to take this kind of disease-modifying therapy. I think even though there is some controversy in the field, I think the majority, certainly of KOLs, feel that the 27% slowing in rate of disease progression, and there's a lot of ways you can frame that, but it's clinically meaningful and worthwhile. I don't think it's a matter of demand. I think it's just a matter of infrastructure. We'll get there. It'll be a little slow at the beginning, but we will get there.
Makes sense. Makes sense. Great. So yeah, just kind of diving into some of the data you've generated yourselves, and I know you shared some additional analyses relatively recently. I guess just how has your thinking evolved around how you think about the differentiation with oligomers? Is it just on efficacy and driving more with oligomers having an additive effect beyond just what we've seen with the plaque targeting and antibodies, or is it better safety? Just kind of curious what the hook you think should be for investors who are looking at Acumen and ACU193 in terms of what can be the differentiator.
Yeah. So real quickly, James, I think it should be on efficacy and safety. And that possibility remains very strong and I think attractive for sabirnetug, and particularly in light of the phase I evidence where we demonstrated robust target engagement of oligomer and then had observed effects on both PET and fluid biomarkers, which suggests to us we've got an agent that has high selectivity for toxic species. And as a consequence of engaging with that target, we're having downstream pharmacological effects. So for us, it really is about driving increased clinical benefit to patients as a consequence of increased efficacy and ideally improved safety or competitive safety in respect of other agents.
Yeah. Yeah. And maybe just to add a bit to that, we're in our sort of biased view of the world. The phase I study that we ran, INTERCEPT-AD, is really unprecedented. I mean, we did it in patients. These MAD cohorts got three administrations of drug. So we have information on sabirnetug that really hasn't been available for other monoclonal antibodies in their phase I studies. So I think as Dan points out, we have target engagement. The PK looks good. But beyond the target engagement, you see this downstream pharmacology. So you're seeing decreases in pTau 181 and pTau 217. And then in spinal fluid. And then what I think is even more remarkable, actually, is that we're seeing changes in these synaptic biomarkers. So we've seen decreases or improvements in a synaptic biomarker called a VAMP2, which is a presynaptic biomarker.
And then similar findings in a biomarker called neurogranin, which is a postsynaptic biomarker. So we're hitting both sides of the synapse, essentially. So I think what that tells you is not only do we have target engagement, but oligomers appear to be a very good target to hit.
I think that's, I'll just kind of augment that a little bit too because all of the non-clinical, a lot of the evidence over a couple of decades in support of oligomers as a primary toxin are really associated with their ability to bind to neurons at synapses and have deleterious effects on synaptic function and induce downstream neurodegeneration such as tau phosphorylation and so forth. So this is an early phase I study, but in terms of the totality of the data and the notion, like Eric is saying, we're neutralizing toxic oligomers. And as a consequence of that, we're seeing a potential drug effect on these other downstream markers. One of the other and I think we were at AD/PD week before last in Lisbon, and we had an oral presentation on some of the biomarker effects.
One point to note is that it looks like the drug exposure is also it's dose level and dose exposure that sort of has a contributing element to how these biomarkers are being moved in the right direction. So it's sort of a totality of the data, but it also highlights the priority of the target and the unique selectivity of sabirnetug as an oligomer-directed monoclonal.
Great. Yeah, that's a super helpful overview of everything. Kind of looking to your next study and taking the learnings from this phase I b, you're kind of taking forward a mid-dose and a high dose in this next study. So I guess can you kind of just walk through the rationale of selecting those doses? I know they're slightly different than the doses we saw in the phase Ib . Two, kind of just what thesis you're trying to test with both those doses or if there's a different thesis at all. Just kind of curious what the rationale and what you're looking to see across those two doses.
Sure, Eric. Do you want to take that one?
Yeah, sure. So yeah, one of the things that we were really, I think, able to do well based on our phase I results is to pick doses for our next study. So we worked with a company called Certara who does a lot of PKPD modeling work. And so we really have pretty extensive modeling data. And when we look at those data for the 35 mg / kg dose group, even at trough levels of sabirnetug, you still have over 70% of the maximum target engagement, so over 70% of what's maximally possible. For 50 mg/kg, it's higher. It's almost 78%. And then if you look at the peak blood levels and peak target engagement, they're over 85% and 89% of maximum target engagement for the 35 and 50 mg/kg doses.
So when we looked at that kind of target engagement and also looked at the safety data, of course, we thought that that was the dose range that we would be most informative for our next study. So it was based on a lot of data, but the PKPD modeling was really a key part of that.
On mute.
You're on mute.
So yeah, that's super helpful and makes sense. And I guess kind of sticking on the phase II here, I believe you mentioned you're planning to use iADRS as kind of your primary endpoint here. And I guess one, why'd you select this endpoint? And two, just why do you think it gives you kind of the best shot at showing differentiation or having a success in this study?
Right. Right. Well, the iADRS, as you probably know, it's a combination of cognitive measures that come from the ADAS-Cog scale and functional measures that come from the ADCS-ADL scale. And they're combined together mathematically. So it's similar in a lot of ways to the CDR, which is the other scale that's commonly used. The CDR has six items, and three are cognitive and three are functional. If you look at published data on this, the powering for the iADRS is always a little bit better than powering for the CDR sum of boxes. And in my opinion, that may be because there's a little bit more of a subjective component to the CDR sum of boxes where the clinician has to sort of make a subjective judgment for these items. And it takes a lot of training to be able to do that, actually.
So the iADRS, it basically gives you the same sort of information, but I think it's actually a more refined scale. Obviously, Lilly's using it in their TRAILBLAZER studies, and of course, we paid attention to that, but we just thought it was the best outcome measure for our study. Now, obviously, we're going to get the CDR in addition, and that'll become a secondary outcome.
Yeah. Okay. And that kind of leads me to my next question of you've talked about potentially doing an interim as part of this phase II and the possibility of expanding it to a phase III. And so I guess, is there any kind of color you can provide around what that interim could look like? And is that something that could involve iADRS or CDR sum of boxes, or is it going to be based on biomarkers? Just kind of curious how you're thinking about that now and after you've already had your discussions with the FDA and everything.
Sure, James. And we can provide a little bit of update and clarity on sort of the interims and the scope of the phase II. So I think as we sit here today, we anticipate amending the 2/3 protocol to run the study as a standalone phase II. It may include interim analyses, but those analyses will not be for the purpose of expanding the study to phase III, but rather potentially inform what steps we might take to either launch at risk a standalone phase III or at least start activities towards a phase III. So I think that's an important distinction to make and a decision. Again, we haven't made that change from a regulatory perspective just yet, but we do anticipate amending at some point probably in the third quarter.
Okay. So it'd be just a standalone phase II.
Yes. I mean, we'll continue to employ the interims, which are permissible in terms of how we might employ interim data to inform essentially a phase III. But the continuity, sort of the adaptive design, I think is something that we're going to move away for a variety of reasons, including practical and regulatory considerations.
Okay. Okay. So yeah, you could potentially still run an interim and run a separate phase III kind of before the full phase II data were to read out.
Correct. And I think it's also important to make clear that the phase II is intended as a registration-eligible study and will be conducted as such. And so that would be an important part of a filing in conjunction with a phase III outcome as well.
Yeah. Okay. Okay. And that was going to be one of my questions around if originally, if it was going to be adaptive, if it could still be considered pivotal. Is the reason to kind of make it more standalone just to ensure that kind of regulatory utility of the study?
I think that's a fair yeah. I think the elements, the simplicity, or at least the clarity of running a standalone phase II with an obvious readout and ensuring that that study is registration-eligible across a variety of different geographies seems to be the right approach for us at this point.
Okay. Okay. Okay. And so then, maybe just thinking about this phase II, if you could maybe just remind kind of the timelines, the size, and kind of what you're powering, if you can share anything around that, just kind of some of more of the details around this phase II in terms of what you're looking to see?
Yeah, sure. So the study has got it to start first half of 2024. Happy to confirm that we're on track for that objective. Got lots of activity underway to stand up the study. What we've found very recently, we engaged with high-quality CRO with a lot of recent experience in the Alzheimer's space. We've come through a series of interactions, even as recently at the AD/PD meeting with site investigators and folks. And there seems to be a tremendous amount of enthusiasm for this ALTITUDE-AD study, the 201 study, given the timeliness of the mechanism and the desire for other treatment options for patients. So all of that bodes well. The Acumen team is working extremely diligently to operationalize the study, and we're hopeful to sort of update on that status in the relative near term.
We haven't guided for timelines in terms of top-line results and so forth. I think it's a bit premature to forecast that publicly until we have dosed a patient and have sites up and running and so forth. So hopefully, we'll have an opportunity to provide more granularity on that element. And I'll invite Eric to describe maybe the study design scope and we talked a little bit about the primary, but just in terms of the size of the study and some of the other observations we'll be looking for in secondary outcomes.
Yeah. Well, thanks, Dan. So just to remind people, this study will be 18 months long. It will be 540 total patients in three arms, one placebo in the two doses that we talked about, 35 and 50 mg/kg. And the primary outcome will be the iADRS. So we are looking at this cognitive functional composite score as a clinical outcome that will be our primary. But we'll build in, or we have built in, lots of the same biomarkers we looked at in the phase I. And the fact that we've seen changes in spinal fluid biomarkers in phase I with just three administrations of drug makes me pretty confident that we're going to see that after 18 months of treatment.
So again, we're going to focus, well, the primary outcome will be the iADRS, but I think all this biomarker data for a phase II study is almost as important.
Yeah. I think adequately powered for the purposes of a phase II.
Okay. Yeah. That was going to be my question because I think I don't remember exactly the size of donanemab or lecanemab's phase II, but their phase IIIs were obviously thousands of patients.
Yeah. Right.
Okay.
I think we're going to be in the sweet spot between Leqembi and donanemab. I think the Leqembi phase II was 850 patients and five dose arms. Very complicated, kind of really interesting study. Then the donanemab was, I think, just a single dose level at like 140 subjects or something in that order per cohort. With iADRS at 18 months is the primary.
Oh, and maybe just to be clear too, I should point out that we don't have a Tau requirement in our study. We'll measure Tau as one of the secondaries, one of the biomarkers. But for a lot of reasons, we thought through it and decided not to include that as an inclusion/exclusion criteria.
Okay. Okay. That's helpful. But is adequately powered for a typical phase II in this space? Okay.
For a robust phase II. Yeah, exactly.
Yeah. Okay. Great. And then so, yeah, I guess maybe just walk through the kind of decision criteria around doing this interim and potentially starting a phase III based on just an interim. Just kind of curious what that decision tree is going to look like and when you may or may not pull that trigger.
Yeah. So fair question, James. Just given the history around how we talked about some of these interims, I think the current protocol has per protocol these interim assessments at various time points when certain patients have achieved a certain percentage of patients have achieved a certain amount of follow-up. And so I think we'll continue to deploy that algorithm and that methodology. And it really will be only rather than adapting the 201 study, it will be used to assess whether we should take at-risk activities towards moving into a standalone phase III. And again, every effort will be made to ensure that the phase II meets registration sort of eligibility from a data integrity and validation and quality standpoint.
Yeah. Okay. Okay. That makes sense. I know we're coming up on our time, but I do want to ask about the sub-Q. And you've obviously partnered with Halozyme. So just kind of curious, one, where things stand there, and two, what would next steps look like beyond the phase I in terms of would it be incorporated into a potential phase III? Just curious kind of what the options going forward are there.
Yeah, James. So the simple answer to that is we think there are a variety of options available to us, and we haven't set one as the priority over others. I think it's going to be important for us to see the bioavailability data out of the phase I for sub-Q and then assess there will be other both regulatory and commercial developments to sort of set sort of the precedent for sub-Q strategy. And we'll be conducting the 201 study. Then there's the possibility of launching a phase III. So it's still a bit premature for us to predict precisely how we advance the sub-Q, but we do think that there are a variety of options, several of which could be quite attractive to us in the future.
Yeah. I mean, one of the advantages we have is we have this great target engagement assay. So the first study is in volunteers, so that's all just PK. But once we get to patients, then what we really want to do from a target engagement standpoint is mirror what we see at 35 and 50 mg/kg IV every four weeks, but achieve the same goal with the sub-Q administration.
Okay. Great. And maybe just in the last minute, 30 seconds here, I think previously the guidance was that we have cash runway through to fully run through the phase II study. And just kind of curious, one, is that still kind of the guidance? And two, if you were to go to a phase III, just curious how you're thinking about fundraising, etc., and funding?
Yeah. Yeah. So very quickly, and maybe to dissociate sort of the phase II outcome versus cash runway, we have updated as of today our cash runway guidance to first half of 2027. Previously, it had stood at first or second half of 2026. And that's a consequence of getting through the contracting and budgeting and getting a better sense of sort of the actual phase II costs associated with the ALTITUDE-AD study. So we're excited to provide that update today. I think from a data readout standpoint, we haven't publicly guided to that readout, but I think the extended runway is pertinent to people's assessment of how and when that might occur. So yeah, those are important factors. I think from a phase III and a partnering standpoint, there's a lot of interest in this space generally.
I think partners are kind of in a wait-and-watch mode in terms of the commercial development. And I know that our program in particular, on the basis of its differentiation, has a lot of attention from partners that presumably are going to be interested to see a data readout in a timely fashion that underpins the differentiation on potentially superior efficacy and a high level of safety for patients. So at some point, that partnership will be part of our future. I don't know that we anticipate it's an imminent development, but there is a lot of interest in this space right now, and we'll see how things develop in the coming weeks and months.
Great. Awesome. Well, thanks both so much for joining, and thanks everyone for listening in. Looking forward to the next one. We have a full day of panels ahead. So thanks again, Eric and Dan. Appreciate it.
Thanks, James. Appreciate it. Thanks very much.