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

Good morning, and welcome to the UBS Biopharma Conference. I'm Colin Bristow, one of the biotech analysts. My pleasure to have Acumen Pharmaceuticals with us here today. On behalf of the company, we have Dan O'Connell, President and CEO. Dan, thanks for being with us today.

Thanks, Colin.

So it's great to have you here sort of right after CTAD and some really interesting developments in the overall Alzheimer's space. Obviously, you guys had a presence at CTAD, some interesting updates. Before we sort of dig into 193, just what were some of the sort of most interesting takeaways for the field that you walked away with?

Sure. Thanks, Colin. Yes, CTAD was an exciting event this year, just generally for the field, there were interesting updates and data to suggest the field is really moving forward and that advancements in terms of patient treatment and options are on the horizon. So in terms of the key elements, I mean, it was interesting to see both Eisai, Biogen and Lilly really highlight the fact that early treatment is advantageous. That basically people with less pathology do better on these A-beta treatments. And so I think that paradigm will continue to evolve. And I think the pursuit of identifying patients that have early signs of pathology and intervening earlier is ultimately going to be kind of the future of therapy in this space. The other development was -- of interest was the subcutaneous administration of LEQEMBI, which I think resolved the question about whether ARIA was mediated based on Cmax versus AUC. And it's really -- at least in the data from the CLARITY cohort, it's really an AUC-driven event. So exposure drives ARIA, it also drives plaque reduction, if that's your intended objective. So it removes sort of the prospect that subcu is a safer mode of A-beta treatment. It certainly advances on the basis of equivalents in terms of overall safety and efficacy at this plaque clearance, if that's your definition of efficacy and then convenience. And then I think -- I mean, those are the big findings. I mean for us, we had a late breaker symposium on Friday morning with 3 talks, 1 around the dosing strategy for the 201 study, the 23 study, which we can talk about in greater detail. And then further analysis and interrogation on the plaque clearance -- plaque reduction, I should say, that was observed in the higher dose cohorts in the INTERCEPT-AD study. And then lastly, Dr. Steve Salloway from Brown highlighted -- reviewed the 5 cases of ARIA that we had in that Phase I study and talked a little bit about the individual case series as well as he noted the absence of any ARIA in the E4 homozygous population, which is a small end, but kind of an interesting observation, given that even like LEQEMBI has a 30% rate of ARIA-E in the homozygous population.

Going back to the sort of the updates we had around subcu administration, how does that -- as you look forward to 193 being on the market and commercialized and you're obviously thinking about subcu now as well, but what is your late -- did that data set make you more or less enthused about the potential of subcu modality?

So I think it kind of -- we have maintained an active play about subcu, to be honest. And now we have established a partnership with Halozyme, which does give us a route to a potential subcu formulation for 193. But I think it really -- we're in the early stages of the infrastructure build. This is in Alzheimer's treatment. And we heard a little bit of that earlier this week from Eisai and Biogen in terms of the rollout. And I think it's happening. I think there's a tremendous demand on the part of patients and families to access an intervention for this devastating disease. So I think as we foresee the future for 193, years out when we are nearing launch, you're sort of in a mode where people are accustomed to going either IV or subcu. We think these will exist in some balance and that will serve us as choices for patients. And having that infrastructure in place gives us a distinct advantage, if, in fact, we can demonstrate the unique value proposition of 193 in terms of its overall safety and efficacy.

And last question before we sort of really dig into the 193 specifics. But on your point about Eisai, Biogen and -- I guess, for want of a better term, somewhat underwhelming launch initially despite Biogen, I think an inside telegraphing it would be. And your comments around there's just a ton of demand, what are you hearing as to why that's not translating right now? Is it just infrastructure right now is not there?

Yes. My perception is it's infrastructure. There is a backlog of demand and interest, the lines of communication. The patient sort of funnel is not in an efficient or directed kind of configuration. And I think it will take time. And I think that's good in some respects for us as a fast follower, if you will. But it will take time. And I think these products will be successful. They'll be large. There are so many patients interested in doing something about the disease. We think -- I don't think that -- this is not a brand line extension. This is truly first-in-class products for a modality that hasn't had this type of option available. So I don't think we should be underwhelmed, disappointed with the launch. I think we should be a bit patient about getting the system. And given the safety monitoring, all of that, I mean this is -- it's a pretty significant lift for the field.

You're obviously going to be the beneficiaries of sort of other's work to build the infrastructure. So it's a good thing for 193. And as we think about 193 now and positioning and differentiation, I mean, we have LEQEMBI and it feels like donanemab is going to be on the market with some reasonable certainty. The -- just talk about positioning and differentiation of 193.

Sure. So we think there's a path to differentiation both in terms of safety and ultimately on efficacy. And I think the INTERCEPT-AD, the Phase I study has given us kind of the building blocks for that path in terms of we had a low overall rate of -- well, a good safety profile overall. I think we have reported these 5 cases of ARIA in the totality of 48 subjects exposed to 193, 3 cases at the higher dose level. So all of that has kind of shaped our thinking in the 201 study and guided us towards the dosing strategy. And ultimately, what we really want to do is show not only an improved safety profile, but more significant efficacy. And the 193 is differentiated based on the selectivity for AB oligomer, which are different than amyloid plaque and that are acknowledged to be potent toxins to neurons, due to their propensity to bind the neurons and induce phosphorylation. So we think by overweighting or directing your treatment towards these toxic species, such as we do with 193, there is a path to a same and more efficacious product.

So 193 is 85-fold selectivity for oligomers over fibril forms of amyloid beta. Did you suspect that the dose levels being tested in Phase I would also bind and remove plaque to the extent you saw?

We didn't know, which is why we ran the experiment, and why we included the PET scans on post last-dose basis. And I think we, at the company, acknowledged we were a little surprised in taking it back at the level of and rate of plaque or reduction in those high dose cohorts. The mechanism around that, I think, is still TBD in some respects. And I think there are 2 sort of simple explanations to that, whether it's essentially at the elevated dose level, you have exposure interaction with plaque in a direct fashion. So there's sort of that direct -- 193 hitting plaque in a directed fashion. Or on the other end, and these are not mutually exclusive, there's more of an equilibrium shift. And at the elevated dose levels, we know we're getting very robust target engagement. We are -- I think we have one of the first that we delivered on in the INTERCEPT-AD study was using this CSF A-beta oligomer 193 complex assays. So we actually have direct target engagement and showed a dose response to the signal of that complex in the study. So at the elevated dose levels, we have very robust oligomer target engagement. And we are also seeing a corresponding effect on reduction of amyloid PET. So these are -- I think we would probably view, and I think others, so LEQEMBI as protofibril targeting antibody. Eisai and BioArtic have sort of called that an equilibrium shift even on their plaque clearance, which is kind of interesting here. So I think it's likely more towards the equilibrium shift and less towards direct plaque interaction. But it's an exciting full dynamic effect. I mean the drug is having -- seeking its target, it's having an effect on some of these imaging biomarkers. We'll be reporting on fluid biomarkers in the near term. And it would be interesting to see how any of this holds together in terms of other downstream effects as a consequence of dosing with 193.

Based on some of the updates we've seen recently, do you -- has your opinion shifted in terms of how critical it is for an anti-amyloid antibody to bind and remove plaque?

Yes. I mean that remains a controversial subject even internally to Acumen. I mean the genesis of the company, the fundamental science at Acumen was all predicated on neutralizing the toxicity of a AB oligomers, these soluble aggregates that are distinct from plaques. And I think there's decades of research in support of oligomer pathology and toxicity, and there's not as much evidence to support that plaques are directly neurotoxic. They're clearly the pathological hallmark of the disease, and it's the primary mode of diagnosis. So I think we are still very much in pursuit of the optimal target. The field is accurate on plaque clearance. And I think that's a consequence of the convenience of amyloid path and the corresponding clinical slowing that's been observed in a couple of these studies. But I think the field continues to push ahead, and we have more to learn, undoubtedly.

And with regards to your CTAD presentation specifically, what are the sort of 2 to 3 main points that you want us and investors to take away from that?

Yes. So I think the robustness of the INTERCEPT-AD data set is, first and foremost, like we got really interesting dosing information. We confirm the safety profile and the target engagement and plaque reduction. Those are kind of first in the field sort of outcomes for an antibody at that early stage of testing. But I think that's the sort of the takeaway from the primary talk. The other element is that all of the -- these results have informed our PK/PD model and our dosing strategy for the 201 study. So we are moving forward with two dose -- two active doses and placebo and we'll dose at 50 mg per kg every 4 weeks and then 35 mg per kg every 4 weeks.

And at those levels, have you done any modeling work in terms of how you think the level of -- the sort of level of plaque clearance will be versus 10 mg per kg?

Well, not on a comparative basis. I think what we've done is really -- I mean, I think what you see in the INTERCEPT-AD data set and what we've presented is at the CLARITY-AD, the LEQEMBI Phase III study had a 3-month PET scan. So we're in our higher dose cohorts in the INTERCEPT-AD study at 60 and 71 days. Both the cohort 6 and 7, all approximated the level and rate of plaque clearance observed with LEQEMBI. So we're pretty confident that we will replicate those results in the next study. I think what we've done from a PK/PD modeling standpoint is to really leverage the target engagement evidence to suggest that not only -- try to make sure that we have near maximum target engagement at both dose levels, both in terms of peak and trough. And that with an accumulation of drug over time, we'll continue to extend and expand on that target engagement. So that's really how we ended up at 50 and 35 mg per kg. I think that either of those could have plaque clearance presumably more, we'll do more, but we have not compared it on a model basis with LEQEMBI.

And what levels of CSF oligomer target engagement you're expecting at those doses?

So on average, there's variability even in the Phase I data set, and that will continue in 201. But we're in the 85 to 90-plus percent range on a snapshot basis. And we think that with chronic dosing, you continue to sort of pick up and mop up the native oligomers. So we think that will be sufficient to drive an efficacy signal in -- at a minimum, the Phase II portion of the study.

In terms of your expectations around the instance of ARIA for these 2 doses, looking at the high dose, we've seen data from the 25 milligrams per kg Q2 weekly and from 60 milligrams per kg Q4 weekly, which one of these would you consider to be more predictive of the 50 mg per kg at Q4 weekly? Or is it purely a sort of modeling triangulation exercise?

Yes, I think it's probably premature to try to predict. I think that we've -- 60 struck us as more than we needed to do. And going a little bit lower based on the model suggests that we'll have a lower rate of ARIA than we would at 60. And I think we know this from other programs, just the more drug exposure, the more likely you are to have ARIA. I think that -- it was interesting in our Phase I study, there were 3 cases of ARIA at 60 mg per kg dosed every 4 weeks, and the 25 mg per kg dosed cohort was at every 2 weeks, and we will have one case. So the Cmax/AUC question, at least in our experience, would say yes that the Cmax might be driving ARIA. But I think that's now less likely the case given what we've observed with like LEQEMBI.

We're almost halfway into 4Q, which is unbelievable. But have you -- can you confirm if you've had your FDA meeting yet?

So I can confirm that we're going to update on our FDA status on our earnings call on Monday. And I think time is limited in the quarter. And one might presume that we've had that meeting, but perhaps haven't had all the finality of minutes and the rest of it. But I think Monday will be an instructive point in time to sort of give some color on where things stand with the FDA. And of course, just -- I mean, the key elements of that we had guided to an end of Phase II meeting with the FDA to explore the possibility of running the next study, has a potential Phase II/III pivotal study. And we also explore primary end points, dosing, all of that. But I think it will be interesting to see if there is alignment with the agency on the prospect of running the 201 as a seamless 2/3 study.

Great. And then we're also expecting some more biomarker data from you. Can you give any granularity sort of one on timing and two, what we're going to get from you?

Sure, Colin. And the biomarker stuff, for reasons that have to do with accessing kits and turnaround times with vendors, I mean, it's just taking some time to get samples ran and analyzed and so forth. So we are -- we've done -- we have both CSF and plasma biomarkers under review. I think we will be providing an incremental update Monday as to the precisely where we are with those assays. I think we're going to be really interested to see what happens on the beta 2:40 ratio, the plasma p-tau181, plasma p-tau217, GSAF, neurogram. These are all kind of analytes of interest. And both whether they be in CSF or plasma, we'll have those -- we definitely have them by the end of the year. And certainly, we'll have an update, I think, on some aspects of that come Monday.

Fantastic. Getting back to CTAD, we saw some data on Roche's trontinemab. Just any thoughts there in terms of the sort of index of concern from a competitive perspective for 193?

Yes. I mean -- so it was a really interesting talk from Roche. I think the fact that they have this very dramatic plaque reduction with gantenerumab, with very low dose, the 1.8 mg per kg is kind of interesting. So it's an early study. They'll have more data. There does appear to be some element of a safety signal on anemia. And it's a different modality. I mean it's an exciting thing that the field continues to pursue this other ways of driving patient benefits. So I don't know that we worry about it from a direct competitive piece. But certainly, it reinforces the -- some of these mechanisms in different modalities. And it's great to see that Roche is going to stay in the room and be in the hunt and be an active participant in this field. I mean, they've kind of had to live through a couple of sort of epic Phase III disappointments. And their staying power, I think, is important just in terms of options and capital and expertise in pursuit of better choices for patients.

That's great. So you also announced this week your collaboration with Halozyme for their enhanced technology for subcu 193. Can you give us a bit more details around the plan here, time lines and any broad consideration for dosing?

Sure, Colin. Yes. So we're really excited about the collaboration with Halozyme. They are the leader in -- with their ENHANZE product for subcu coadministration. We're excited. This is a nonexclusive deal. So it was sort of within our budget and allowed us to get sort of market-leading technology and expertise and know-how. So we're really excited about the collaboration as I believe they are. The first step here, I mean this is the good news on with ENHANZE is it's from a regulatory and a clinical standpoint, there's a lot of history and experience. And so the first step for us will likely involve a Phase I PK study in healthy volunteers to establish the bioavailability of the 193 and ENHANZE co-administration. That's a study that we think we think we'll initiate in the middle part of next year and would read out. This is not a chronic study, it's really a safety study, but that would then read out and help inform precisely what a patient-based study would look like. So I think it's too early for us to guide on precisely let's call it a biomarker or and efficacy-type study. But I think in the near term, our work plan is pretty well-constructed and laid out for us.

Have you had any discussions with FDA on this yet?

We have not.

Okay. What would be a reasonable time frame, just ballpark, in terms of when we could see some data from that healthy volunteer population, would it be end of '24?

I don't -- I think that's -- you'd have to sort of look at what other people have done in this space. I think these are not long studies. I would hope that, that time frame would apply in our circumstance, but I don't want to be too specific about this.

Sure. And will the development plan for the subcu formulation, in any way, interrupt the IV 193 time line?

We don't think so. I mean IV, we think, is going to be an established route of treatment. And we have a very clear design for the Phase II 201 study. And so that is very much kind of our primary goal of advancing that as expeditiously as possible. I think where we bring the subcu into the development program and whether that's a stand-alone 1b/2a type study for the subcu or whether, as others have done, adding it into an OLE protocol amendment, those are things that are ahead of us. We have to -- more to learn before we commit to one path or another. But IV is very much our top priority.

And then as we're thinking about the evolution of the treatment of Alzheimer's, there's a lot of discussion around sort of combination therapies. And any early thoughts about mechanisms that would be obvious to pair 193 with?

Yes. So I think even just coming out of CTAD, I think this sort of dynamic between amyloid and tau and amyloid driving tau, and so I think there's probably the first order of combination. And I don't know which precise tau mechanism or modality to choose. But something in and around tau with ideally in oligomer selective agents such as 193, could be a really attractive way to elevate the efficacy for patients. Other immune modulating elements to reducing inflammation might be complementary, if not synergistic. So those are also kind of on the horizon.

And maybe just to summarize because we're right at the end of time, what would be the -- as we look over the next 6 to 12 months, what are the key updates that you would advise us and investors to pay attention to?

Sure. So I think stay tuned to the INTERCEPT-AD data set. It continues to perform and reveal more of the -- confirm the activity and safety of the antibody. And so that fundamentally derisks the next stage of development. And it fundamentally informs our dosing strategy for the 201. I think understanding -- yes, so the data piece is important. The regulatory piece, I think, is also instructive as to kind of what the option is for getting quickly to a BLA. And then subcu, let's see how that progresses, whether Eisai gets approved and whether they have ultimately clinical benefit observed with that modality and it's still a question there, how the payers will react and then presumably we'll be in the clinic with the subcu certainly by this time next year.

Well, I think we're firmly at the end of time. Dan, thank you for your time. And really congrats on all the progress.

Thanks, Colin. Really enjoyed the talk. Thank you.