ABOS - NASDAQ

Good day, and thank you for standing by. Welcome to the Acumen Pharma Q1 2023 Conference Call and Webcast. At this time all participants are in a listen-only mode. After the speaker’s presentation there’ll be a question-and-answer session. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to Alex Braun, Head of Investor Relations.

Thanks, Joe. Good morning, and welcome to the Acumen conference call to discuss our business update and the financial results for the quarter ended March 31, 2023. With me today are Daniel O'Connell, our Chief Executive Officer; Dr. Eric Siemers, our Chief Medical Officer; and Matt

Thanks, Alex. Good morning, and thank you, everyone, for joining us today. The first quarter of 2023 marked the completion of enrollment in our Phase I INTERCEPT-AD trial, evaluating ACU193 in early Alzheimer's patients. The study is near completion with top line results expected in the third quarter. For those of you who may be new to Acumen, our product candidate ACU193, is differentiated from other monoclonal antibodies studied in Alzheimer's disease based on the high selectivity for A-beta oligomers. Scientific consensus asserts that oligomers are the most toxic form of A-Beta. And once they bind to neurons, they inhibit synaptic function and induce neurodegeneration. We are pleased that our top line results are positioned to provide important clinical proof of mechanism data to our monoclonal antibody developed to selectively target toxic A-Beta oligomers in the effort to develop a next-generation therapeutic for Alzheimer's patients. INTERCEPT-AD will provide valuable information required to finalize the design of our next phase for the program, including dose selection. At present, we have growing confidence that every four-week dosing is a viable scenario for ACU193. In addition, as previously disclosed, preliminary CSF PK data from Cohort 3, our 25-milligram per kilogram single ascending dose cohort showed ACU193 concentrations substantially above reported levels of A-Beta oligomers indicating this may be a dosing option to include in our next study. We continue to prepare for Phase II/III activities in anticipation of successful results from our Phase I study, an end of Phase II meeting with the FDA to discuss the design of the next trial is anticipated to be held in the fourth quarter. As previously disclosed, the study design incorporates an interim decision to expand the size of the study from Phase II to a Phase III study, which is the most expeditious route to a BLA registration. We, along with the rest of the field, are encouraged by the positive momentum in the evolving Alzheimer's landscape. We are keen to see upcoming outcomes for lecanemabs Advisory Committee meeting, PDUFA date and any shift in CMS coverage decision, which would increase access and uptake for this therapeutic option for patients. We are also highly interested in digesting the full data set from donanemab's TRAILBLA

Thanks, Dan, and good morning, everyone. We continue to work diligently as we near the finish line of our Phase I trial. As Dan highlighted, the totality of the data from INTERCEPT-AD will be important for choosing doses for subsequent studies of ACU193. This includes data on Safety, CSF PK, and CSF target engagement. As I mentioned on our last call at the end of March, the assay for our target engagement is designed to measure the complex of A-Beta oligomers bound to ACU193, and CSF. We have since run preliminary assay tests using CSF from patients which have increased our confidence that the assay is performing as intended. Recall that oligomer concentrations in CSF are generally reported to be less than 2pM, which means that our target engagement assay must be very sensitive. We also anticipate announcing exploratory data with our topline results from our Phase I study, including Cogstate computerized cognitive testing as well as arterial spin labeling pull sequences on MRI, which will determine if cerebral blood flow has increased after treatment with ACU193. While these analyses are exploratory and may not result in a clear signal in this small study with a short duration of treatment, these techniques maybe employed in the subsequent larger clinical trial using ACU193. As a reminder, we have included typical clinical measures like the CDR sum of boxes and the ADAS-Cog in our Phase I study. However, because this is a small, short study, it is unlikely that those measures will show a drug effect. During the first quarter, our team also presented a poster at AD/PD in Sweden that demonstrated the utility of a human in vitro model of induced pluripotent stem cell-derived excitatory neurons for a better understanding of which forms of A-beta oligomers contribute to the pathogenesis of AD in the human brain. This study found that soluble A-beta size may influence synaptic binding, low molecular weight 5-way beta species such as monomers, dimers and trimers, demonstrated the lowest levels of detectable synaptic binding compared to those of mid and high molecular weight defined as greater than 150 kilodaltons. We believe that these research efforts can contribute to the development of next-generation therapies with higher selectivity for toxic soluble amyloid species that are the most relevant to Alzheimer's type of genesis such as ACU193. Finally, the success of donanemab in the TRAILBLA

Thank you, Eric. Good morning, everyone. As a reminder, our first quarter 2023 financial results are available in the press release we issued this morning and in our 10-Q that will be filed later today. As of March 31, we had approximately $184 million in cash and marketable securities on the balance sheet and continue to expect that cash to last through 2025. R&D expenses were approximately $8.7 million in the first quarter, increase over the prior year was primarily due to the increased activity in the ongoing INTERCEPT-AD trial. G&A expenses were $4.4 million in the quarter, with the increase over the prior year, primarily the result of increased headcount as we built the company to support INTERCEPT-AD. This led to a loss from operations of $13.1 million in the quarter. We are encouraged to report topline data for INTERCEPT-AD in the third quarter and will remain financially disciplined as we use our capital to advance our clinical program for ACU193, and deliver value to patients and shareholders. And with that, we can open the call for Q&A. Operator?

[Operator Instructions] Our first question -- I believe this is James on the phone for Stifel.

This is James here. Thanks for taking our question. On for Paul Matteis. We were just wondering, how are you thinking about the different scenarios for what your Phase II could look like? And what exactly you'll be able to test. For example, if say 193 were to have a similar effect size as the A-beta antibodies, would this study be powered for stats on these clinical scales? Or would you be looking at something else at the interim and basing your decision to expand the trial? Any color there would be great. Thanks so much.

Let's exchange. I'm going to invite Eric to comment on that question. Good question.

Yes, sure. Thanks. Great question. So the team has been working hard on finalizing the design of that study. It's not completely finalized yet. But to get to the question that you raised, we'll look at a number of different things in order to make the decision whether to continue the study as a Phase II or to increase the size of the study and making a Phase III registration trial. So that interim analysis involves an algorithm that we'll look at a number of different things. So of course, we'll look at things like the IDRs, which will be actually our primary outcome, but also the CDR sum of boxes, the ADAS-cog, that sort of thing. Obviously, if you would have statistical significance on one of those clinical measures at an interim analysis, I think that would be a fairly clear signal to scale up to a Phase III. But we'll look at a variety of other things. And those things may include things like the computerized cognitive testing that we're using in our Phase I study and also a variety of biomarkers. And just to give you one example of that, phosphorylated tau, both in blood and spinal fluid, seems to be a quite good biomarker for effects of drugs on downstream pathology in Alzheimer's disease. So in other words, if your drug affects a mild of COGS or in our case, A-beta oligomers, if you see a change in phosph-tau, that really gives you a sign that you're having an effect on the underlying disease process. So we have an algorithm put together. We'll look at several different things like that. And then that will trigger the decision of do you increase the size of the study to a Phase III? Or do you just continue it out as a Phase II study? So hopefully, that addresses to the question that you brought up.

Yes, very helpful. Thank you.

Our next question comes from Tom Shrader with BTIG. Go ahead with your question.

Good morning. And thanks for taking the question. You're doing all this elegant work with, I think, one of the biggest questions in the field, which is, which oligomers really matter? Is it changing your thoughts on target engagement? I assume you'd like to have antibody levels that only hit the relevant particle. So is it -- are you learning that 2pM is an overestimate? Or do you think you need to get most of the particles in order to be safe? Or is that something you need to read out from clinical data? Thanks.

So maybe I'll take that one, too. So again, I always have to promise this -- another good question, but I always have profit like say, I'm a clinical trial, it's by nature. And so I think the real answers ultimately have to come from the clinic. But as our poster illustrated at AD/PD, there's a lot that we're still learning about what are the most toxic species. We -- thus far, it would appear that the species that ACU193 targets are the ones that are relatively more toxic. I mean the most toxic that we've been able to find, we're going to put it the other way around. We don't see any evidence that ACU193 binds to species that are not toxic. But again, the proof is always in the clinic. The one other point that's some interest and this is a little bit more hypothetical, but the concentrations of oligomers and spinal fluid, as mentioned, are very low, less than 2 picamolar. But no one knows really the concentration of oligomers in interstitial spacing in brain [ph]. So our antibody ACU193, has to exit the arterial system and then enter the interstitial space. And there, the actual concentration of oligomers maybe more -- maybe higher. So again, we've had some positive results regarding our target engagement assay. We think that assay appears to be working well. And we're really looking forward to seeing those results along with all the others in INTERCEPT-AD.

Great. Thank you.

And now we have Judah Frommer with Credit Suisse. Go ahead with your call.

Yes. Good morning. Thanks for taking the questions. First, just as we think about potentially having two A-Beta antibodies on the market, any evolved thinking around including a comparator or a combination arm with another A-Beta antibody in any subsequent trials, whether it's for a potential Phase III or beyond that? And how could that affect 193s clinical profile? And then separately, can you just remind us or give us some direction on cash runway and potential to get you through Phase II or how you would deal with moving into the Phase III given the cash position? Thank you.

Yes. Let me maybe take your first question and then turn it over to Matt for your second question. But in terms of comparators, that question has come up a lot, especially since last week with Donanemab announcement. I think there's a pretty broad agreement that -- well, first of all, a head-to-head trial with drugs like that is very difficult to do. You have to do what's called a non-inferiority study, which requires really huge studies. And at least of all the people I've talked to, I don't think anyone really would expect certainly regulatory agencies to require that kind of head-to-head comparison at this point. The other thing that's really of interest is how quickly these things will be taken up in clinical medicine. There was actually at the American Academy of Neurology meeting a couple of weeks ago, they have what they call a fireside chat and someone who is, I think, a lead investigator in the clarity style for lecanemab was talking about all the things that you would have to do to use that in your clinical practice. So these are practicing neurologists. And there was a lot of a bit of angst, I might say, among the clinical neurologist that this is really complicated because the infrastructure for PET scans and MRIs and all that just isn't there yet. I think donanemab actually will be even more complicated because they have this tower requirement. So now you have to get maybe an amyloid pet scan and then a top head scan. So the uptake in the marketplace, I think, is not going to be overnight. The infrastructure needs to be built that actually, to some degree, works to our favor because by the time we would launch with ACU193, that infrastructure should be much more better developed. So yes, stay tuned. But for right now, we do not expect there to be any requirement for a head-to-head trial. And so Matt, I'll turn it over to you.

Thanks, Eric. Judah, with regard to the cash, until we meet with the FDA and know exactly which clinical trial we're going to run next, it's hard for me to tell you exactly when the cash might run out. However, all the forecasting that we've done gives us confidence that our current cash will last through 2025. With that said, as we've disclosed in our filings, any next trial that we do is likely to take us out past 2025. And how far out past 2025 we have to go just simply depends on our interactions with the FDA. So we can get very far down the road. But if we're running a Phase II/III clinical trial, then at some point, we're going to have to finance. And even if we run a very large Phase II clinical trial to be determined, we would have to finance at some point after 2025. I hope that helps.

Yes. Thank you.

Next, we have Colin Bristow with UBS. Colin, go ahead with your question.

Hi, good morning. This is Tina on for Colin. Thanks for taking our question. So at AD/PD Dr. Selkoe for HMI, he presented interesting findings from his lab that previously thought as soluble oligomers from Stipulated monogomers AB, they can actually be replicated and led to the discovery of new species which they call short fibrils. So that somehow raises the question. If the neurotoxicity and bio activity, previously observed with those soluble brain extracts are solely attributable to the oligomers. I think some of the first work will found the same rework on another HMS lab. Would you stop over this finding, and we're just wondering like out of curiosity, besides solubility, how differentiated are this soluble fibril species from oligomers, for example? Thank you.

Dr. Selkoe, of course, does some really cutting-edge research. And I think your question is a good example of just where the cutting edge is in the field right now. So one of the things we've talked about before is that ACU193, of course, targets oligomers, lecanemab was designed to target protofibrils. Now partly, this gets into definitions and Dr. Selkoe in the past and currently actually would sort of define anything that's soluble as an oligomer. So protofibril is actually one type of oligomer if you want to use that definition. But he recently presented, and I think this was part of the AD/PD presentation that how you define soluble can vary. So in other words, you -- what happens is the centrifuge things and whatever ends up in the pellet is not soluble and whatever ends up in the supernatant is soluble. But if you centrifuge it faster and harder, you can change what is in the pellet and what's in the supernatant. So all of these things are kind of evolving, including the terminology, just to get back to the protofibrils differentiation with what ACU193 targets, protofibrils are linear structures. The structures that ACU193 targets are globular. So the appearance is different on atomic force microscopy. So they're not exactly the same thing. We think of those as cousins. So they're both soluble by usual definitions. They're both toxic, but they don't have exactly the same structure. And so one of the things that's really unique then about ACU193 is that we're targeting a type of oligomer that's unique. I mean there's no other antibody that targets what we target that's currently in the clinic. I hope that helps, but it's a complicated question.

Yes, that’s really helpful. Thanks so much, Eric. We have a follow-up question. So you mentioned we will use IDRs for that [ph] as a primary endpoint. In [indiscernible] to top line, there seems to be some disconnection on IDRs benefit for the high top [ph] group versus CDR FP we see the CDR FP benefit was more consistent across the subgroups. So what's your thought on the demand data and as well as worse of your primary reasons to use IDRs instead of CRB for the fifth primary endpoint?

Yes, right. So one of the things, just to remind everybody is that we only have a press release from Laurea on the donanemab data. So there's they included quite a bit in their press release, which was great, but they didn't include everything. So questions like that, how about IDRs perform compared to whatever else, the CDR sum of boxes in the high tow group versus the intermediate tow group? Those are things I think we just have to wait for the presentation at AIC to really better evaluate. But our decision -- and again, things can change depending on new data, but our decision to use the IDRs is really based on everything up until this point in time. It actually appears to be a very good scale. And as you know, that's what Lilly has used as their primary outcome. So we'll be looking forward to seeing more of those data from TRAILBLA

Okay. Thank you, Eric. If we may maybe one last set of questions from our side. Will there be additional PK/PD or safety updates ahead of the 3Q update? Thank you.

No, we -- yes, we don't anticipate any new disclosures prior to our topline results in the third quarter. And the study is going well. I mean if there were some new safety information or something, obviously, we'd have to say something about that. But at this point, in any study, even though we're all blinded we're feeling pretty comfortable about the safety profile. And so I wouldn't anticipate any new disclosures before our topline results.

Thank you so much.

And now it looks to be our last question. And this is from Charlie Yang with BofA. Go ahead with your question.

Hi, thanks for taking for question. This is Charlie Yang on for what Geoff Meacham. Can you talk about just given the level data, potentially to kind of include one of the A-Beta drugs in your kind of Phase II, Phase III trial?

I'm sorry, I'm not sure I quite understood the question. Would we include other A-beta drugs in our Phase II/III?

Right, combination therapy given the recent…

Right. Got you. Well, so combination therapy is an important topic, and it's something that we at Acumen have certainly had some discussions about. Now our approach to that would probably be the combination would be a drug that different complementary mechanism rather than another one that's related to A-Beta or amyloid in one way or another. In terms of our Phase II/III study, we don't have any safety data from animal studies based on combinations, say, of lecanemab, donanemab with ACU193. And so I don't think it would make a lot of sense for our Phase II/III study to allow that kind of combination. Obviously, that would make it a lot more complicated study too. But as we've thought through this, as I mentioned previously, I think that the sort of clinical uptake is going to be pretty slow actually for both lecanemab and donanemab. And so I think for us to run a placebo-controlled trial for our Phase II/III is certainly going to be feasible. But looking down the road in terms of combination therapies, which is the future. I think we all agree for Alzheimer's disease. I think it would make more sense to use some complementary mechanisms. So you would use something that's related to Tow, something was related to inflammation, something like that to combine with ACU193, to see whether you get additive or even synergistic effects.

Thank you.

I'd now like to turn the call back over to Dan O'Connell.

Thanks, and thank you, everyone, for joining this morning's call. We are very much looking forward to sharing the INTERCEPT-AD top line data in the third quarter, data that will be informative on ACU193, as a selective agent neutralizing toxic A-beta oligomers. So thanks again for joining. We look forward to speaking with you again soon.