AD trial. My name is Michelle, I will be the operator for today's call. During today's event, you may enter a question using the question and answer panel on the lower left side of your screen. Please note that this conference is being recorded. I'll now turn the call over to Alex Braun, Head of Investor Relations. Alex, you may begin. Thank you. Welcome to the Acumen conference call to discuss the top line results from our first-in-human phase I INTERCEPT-AD trial, investigating ACU193 in early Alzheimer's disease. The majority of these data were presented yesterday at the Alzheimer's Association International Conference, or AAIC, in Amsterdam. Please note that during today's call, we'll reference slides that are available on the webcast. If you've not already done so, please go to the Investors section of our website to access the webcast player. A PDF of the slides has been made available on our website as well. During this presentation, we'll be making forward-looking statements based on our current expectations relating to the clinical development of ACU193 and the potential therapeutic value of ACU193. These forward-looking statements are neither promises nor guarantees and are subject to uncertainty and risk. Please see slide two of the investor presentation accompanying this webcast, our press release issued yesterday, and our most recent annual and quarterly reports filed with the SEC for important risk factors that could cause our actual performance and results to differ materially from those expressed or implied in the forward-looking statements. We undertake no obligation to update or revise the statements provided on this call as a result of new information or future results or developments. The data presented today may not be indicative of future data or results of future clinical trials or real-world results. We'll begin with a presentation of the top-line results, followed by a moderated Q&A, and finally, we'll take questions from our analysts and the audience. Now, I'll turn the call over to Dan O'Connell, Chief Executive Officer of Acumen. Thank you, Alex. Good morning to those of you back in the States, and thank you for joining us. Our team has been at the Alzheimer's Association International Conference in Amsterdam all weekend and had the distinct privilege of presenting our top-line results from our INTERCEPT-AD clinical trial to the medical community here yesterday morning. Today, we're pleased to be discussing those results with you. With me today from Acumen are Dr. Eric Siemers, our Chief Medical Officer, who will take you through the data, and Matt Zuga, our Chief Financial and Business Officer. We're delighted that following the data presentation, we'll be joined by special guests, Dr. Steven DeKosky and Dr. Lawrence Honig, for a discussion related to the data set. DeKosky is Deputy Director of the McKnight Brain Institute at the University of Florida and is a member of Acumen Scientific Advisory Board. Dr. Honig is the Director of the New York State Center of Excellence for Alzheimer's Disease at Columbia University and was also an INTERCEPT-AD trial investigator. I'd like to thank both of them for taking the time to be with us today and look forward to hearing their clinical perspectives on ACU193 INTERCEPT-AD data set. I'd like to start off the call with a brief review of Acumen's antibody, ACU193, and a high-level summary of our phase I results. Acumen was founded on the scientific premise that Aβ oligomers are distinct and important triggers for the initiation and propagation of Alzheimer's disease. Scientific consensus asserts that Aβ oligomers are the most toxic form of Aβ, and once oligomers bind to neurons, they inhibit synaptic function and induce neurodegeneration. Our product candidate, ACU193, an affinity-matured, humanized monoclonal antibody, is differentiated from other monoclonal antibodies studied in Alzheimer's disease based on its high selectivity for Aβ oligomers. More than 500-fold selective for oligomers over Aβ monomers, and more than 85-fold selective for oligomers over fibrils, which has been theorized to lead to greater efficacy. ACU193 was also designed with reduced effector function, which is theorized to produce lower rates of ARIA-E compared to plaque-targeting antibodies. Notably, our asset was developed was originally discovered in partnership with Merck & Co., Inc., and which completed extensive preclinical studies to confirm the attributes of the antibody, and at present, ACU193 is being developed by Acumen team, several members of which spent many years doing early-phase and late-phase global Alzheimer's clinical trials at Eli Lilly. Yesterday, we reported positive results from a first-in-human study of ACU193 INTERCEPT-AD. Before I turn to our convincing proof of mechanism results, we were highly encouraged by the rapid dose-related, statistically significant amyloid plaque reduction observed at the higher doses studied, 60 milligrams per kilogram every 4 weeks and 25 milligrams per kilogram every 2 weeks. Although plaque is not ACU193's intended target, it appears 193 reduces amyloid at a rate and level comparable to currently approved monoclonal antibodies at similar time point, in this case, around 3 months. Eric will speak to the possible mechanistic explanations for this finding, but we believe it demonstrates further evidence of 193's activity in the brain and is a promising development, given the established correlation between plaque reduction and reduction in cognitive decline. You'll see in the data we present that 193 also demonstrated robust dose-dependent target engagement of Aβ oligomers, as measured by a novel assay developed by Acumen, and which exceeded our expectations. In fact, we observed our higher doses approaching maximal target engagement. This finding we're particularly excited about, given this is the first time an oligomeric targeted antibody has demonstrated direct target engagement. ACU193 was well tolerated, with no drug-related SAEs and low rates of ARIA-E. Based on the pharmacokinetic profile observed, monthly dosing is supported. To dig into the plaque reduction observed, we plotted the mean reduction in amyloid plaque and Centiloids for our higher doses, 60 milligrams per kilogram dosed every 4 weeks, and 25 milligrams per kilogram dosed every 2 weeks, for a total of 3 doses in each cohort. Against the 3-month plaque reduction observed in lecanemab's phase III Clarity AD study. We chose to compare to lecanemab because the design of this antibody is most closely aligned to ACU193, in that they both target soluble toxic amyloid aggregates but also reduce plaque. The graph on the left indexes the baseline values to 0, while the graph on the right shows the absolute values. As you can see, at a similar time point, ACU193 reduced plaque to a comparable level as lecanemab. Our 60 mg/kg dose once every 4 weeks and our 25 mg/kg dose every 2 weeks, both demonstrated statistically significant reductions within each cohort. It is worth noting that our ACU193 cohorts did have lower baseline levels of plaque. However, the slopes do appear comparable despite this fact. We did not show them here, but earlier-generation antibodies, which have failed to show cognitive benefit in phase III trials, were not able to achieve this rate or level of plaque reduction at this early time point. Typically, with faster and larger reduction in plaque, the rate of ARIA tends to increase as well. Lecanemab, however, exhibited approximately half the amount of ARIA in their phase III trials compared with plaque-targeting antibodies. ACU193 also exhibited low rates of ARIA-E in our phase I study, even at elevated doses. As seen here, when comparing after a single dose, aducanumab saw 100% of patients experience symptomatic ARIA-E at 60 milligrams per kilogram dose in their phase I study. Donanemab saw 50% of participants exhibit ARIA-E at their 40 milligram per kilogram dose, while ACU193 maintained a low rate of ARIA at 60 milligrams per kilogram. In this table, we wanted to compare only ARIA-E after single dose. Due to the timing of the MRIs in our study, we're showing 6 patients from the SAD who received 25 milligrams per kilogram because the MRIs for that cohort were taken after 2 administrations of drug. I'll also note that these are not direct comparisons, as no head-to-head trials have been run between these products. As you'll hear from Eric in more detail, our overall rate of ARIA-E in the INTERCEPT-AD trial was 10.4%, with 2.1%, or one patient, being symptomatic. We highlight this to make the point that ACU193 has the ability to dose quite high on comparable basis to other monoclonal antibodies while maintaining a low rate of ARIA-E, and by doing so, appears to be engaging more of the toxic oligomeric target in the brain, as seen with our near maximal target engagement. This leads us to believe that ACU193 could have a broad therapeutic index. Here's a full view of how we think about 193's proof of mechanism, as demonstrated in the INTERCEPT-AD trial, incorporating low levels of ARIA-E dose-related pharmacokinetics that demonstrated concentrations of 193 orders of magnitude higher than reported Aβ oligomers in CSF and dose-related statistically significant target engagement. Taken together with the observed rapid plaque reduction, all of these elements will guide dose selection for our next study. Taking a step back, I'm very pleased with the positive results of INTERCEPT-AD, and I'd like to thank our team, the patients, their families, and our investigators for all of their hard work that made this such a well-run trial. The success of our novel target engagement assay, robust study design, and committed execution allowed us to demonstrate proof of mechanism for ACU193 and establish dosing optionality for our next phase of development, given the broad therapeutic index. With that, I'd like to turn the call over to Eric to present the INTERCEPT-AD data. A diagram outlining the design of the trial, in some respects, it's a fairly typical SAD/MAD first-in-human study. There are a few differences, mainly that we did not wait to complete all the SAD cohorts before starting the MAD cohorts. Now, there were numerous safety measures that were built into this trial. It was, again, a first-in-humans trial, and so sentinel dosing was used for the SAD cohorts. After each cohort completed, there was a safety review before the next cohorts were started. Again, in this design that we have to look at cohort two, after that cohort was finished and had a safety review, that actually triggered the initiation of cohort three, and also the initiation of cohort five, which was also at 10 milligrams per kilogram. In many respects, a fairly typical SAD/MAD study, which was done in patients with early Alzheimer's disease, in other words, MCI or mild dementia, with evidence of being amyloid positive. If you go to the next slide. These are the baseline characteristics of the patients that we had in the study. I think these are fairly typical for what you would see in a population of early AD, again, MCI or mild dementia. We'll talk about some of the specifics in here, but overall, these are generally similar to other trials using similar patient populations. If you go to the next slide. To go to the safety, which again, is always the primary that actually occurred in just two patients. One of the patients had the lower 2 SAEs. Generally, as you can see here, there's nothing that would suggest that it's related to the drug, and nothing that was problematic in terms of administration of the drug. If you want to go to the next slide. Here's a little bit more detail. These are the treatment-emergent AEs, and these are ones that are greater than 3% and also have ACU193 with a greater number than placebo. Again, this is a relatively small phase I study, as they always are. The numbers are small. We did have 3 cases of COVID in the ACU193 group, compared to 0 in placebo. A couple cases of bronchitis in the ACU group, compared to 0 in placebo. G enerally, not anything there that in a phase I study would raise significant concerns. The ARIA-E, as you can see, we'll talk about that more extensively. That obviously does have some relationship to treatment group as well as ARIA-H. If you want to go to the next slide. This slide is a little complicated, but I think it's worth taking a minute to walk you through it. At the top of the slide are the SAD cohorts, the single ascending dose cohorts, and you can see the various dose groups. At the bottom of the slide are the MAD cohorts, with these arranged by the actual doses. The color coding here is green is no ARIA, yellow is asymptomatic, and red is our single case of symptomatic. We went ahead and left in the placebo-treated patients here because people on a placebo or no treatment can rare- and we didn't see it in this study. We also have included here their APOE status, and I'll come back to that in just a second. Occurred after 3 of the doses. In the MAD cohorts, each person had 3 doses. This occurred after the 3rd dose, was asymptomatic, and radiographically was actually very mild. It was actually missed on the local read, picked up on our central read, and then resolved at the end of the study. At the 25 mg/kg dose group, we did have one person, again, in the MAD cohort, that developed ARIA-E. That was actually, first picked up on the day 70 MRI after the second dose. The day 28 MRI was reread, which was after the first dose, and actually, in hindsight, there were some very subtle, ARIA-E that was graphically is improving. It hasn't quite resolved yet, and we're continuing to follow that patient. Then at 60 mg/kg, we had three cases of ARIA. In the SAD cohort, this is 21 days then after a single administration of 60 mg/kg, we did have a ARIA. This case actually occurred after the first dose, and the patient wasn't dosed again, so this really occurred after a single dose. It was picked up on the scheduled MRI, then the person was brought back in for further clinical evaluation. The reason why we call this symptomatic is that the person complained of their right leg, quote, "giving out" without really focal findings on their exam, but the ARIA was in the left parietal region of the brain, quickly. Then the other case was in the MAD cohort, was asymptomatic. That was day 63, picked up after the third scheduled dose on the scheduled MRI, and again, had resolved by the end of the study. The one other thing that's, I think important to point out on this slide is that we had a total of 6 people who were APOE4 homozygotes who were treated with ACU193. Of those 6 APOE4 homozygotes, none of them had ARIA. Which is quite different than other antibodies, where you see rates of 30%-40% of people who are E4 homozygotes having ARIA. In a small study like this, it could be due to chance. We will continue to watch this very carefully because that could certainly be a differentiating factor compared to other antibodies. If you want to go to the next slide. This is just a bit more detail about the ARIA cases that we had. We were only very recently unblinded, and we're continuing to dig through the details of this data, especially at the individual patient level. Just to give you an example, the third line there was our patient with symptomatic ARIA. That person had the biggest decline to analyze data based on beginning plaque load, the reduction in plaque load, that sort of thing. The other interesting thing, and this is something for that, again, it could just be by chance. That's something that we'll continue to watch quite carefully. If you want to go to the next slide. Here are the changes in plaque load based on florbetapir PET. On the left-hand side of the slide, you can see this is from the SAD cohorts. The red dotted line are the pooled placebo patients, and you can see that they are really quite flat. T here's no change, as you would expect, in their plaque load between baseline and endpoint. Then in the treated groups, you can see with the various doses, there's no consistent change. Again, in with the single administration of drug, not surprising that we don't see any appreciable change in plaque load. On the right-hand side of the slide, this is in the MAD cohort. The situation's a little bit more interesting. At 10 mgs per kg, we don't see any difference between baseline and endpoint in plaque load. At the higher doses, both 25 mgs per kg and 60 mgs per kg, we do see a decrease in plaque load. That actually, if you look at just the difference between baseline and endpoint in both of those cohorts, that change was statistically significant with p-value of 0.01. There did appear to be a change in plaque load in those cohorts at those higher doses. If you want to go to the next slide. Here's the individual patients. Again, we're still analyzing these data but wanted to show them to you today. On the left-hand side is the 60 mgs per kg group, and you can see there's... Most of the people in that group did seem to have some decline in their plaque load. Not all the patients. The patient with the blue triangle towards the bottom was relatively flat, but most had some degree of decline. The green triangle was the patient who had symptomatic ARIA. You can see that the endpoint plaque load wasn't particularly low, but that was the biggest decline. It's this kind of data analysis that we're continuing to do. If you look at the right-hand side of that slide, this is the 25 mg per kg dose group, and there are certainly some patients there who have some decline. Not all of them. I think, to my eye, it looks like there's a little bit more stability, even though some of them do drop. I think that's an important thing that we'll look at further because there is this question of Cmax and whether or not some of the ARIA is driven by Cmax and maybe also the plaque reduction. We're going to continue to analyze these data to try to understand it better. You can see that there's one patient in this cohort that had ARIA, which was asymptomatic. It's kind of buried in the middle there, but there was a decrease in plaque load, but not anything that was really different than other patients in that cohort. We'll continue to analyze these data and to understand it better because this question about ARIA, what's the risk factors? Does Cmax make a difference? That's not just a question for us, it's a question for the field. If you go to the next slide. This gets into the PK data. This is just serum PK. This is fairly well-behaved, actually. I t looks good. On the left-hand side, you can see after a single dose, it's very nice, dose-dependent effect in the PK. On the right-hand side, those are the multiple-dose cohorts. You can see with multiple doses, you don't have any accumulation of drug, which is always a good thing. The serum PK looked really quite good. If you wanna go to the next slide. For immunogenicity, those data are still coming in. We have a handful of cases, and in each of those cases, thus far, the titers are quite low. There doesn't seem to be a relationship with PK, and so we're continuing to follow that. At this early stage of our analysis, we don't see any evidence of immunogenicity that would be problematic. If you wanna go to the next slide. Here's the CSF PK, which I think, is really actually of more interest. On the left-hand side of the slide, you can see for the single-dose cohorts, there's this very nice dose-dependent increase in CSF concentration of drug, 21 days after the single administration. On the right-hand side of this slide, you can see in the multiple-dose cohorts, there's also a very nice dose-dependent increase in CSF drug concentrations. The dotted blue line there is just to bring your attention to the fact that the Y-axis on the two plots is not the same, after multiple doses, you do have substantially higher concentrations of drug in spinal fluid than after a single dose, which obviously is what you would expect. The CSF exposure data looks actually quite good. If you wanna go to the next slide. Target engagement for us means showing that you have antibody bound to an oligomer. If you have an antibody that targets plaque, you can just get a PET scan looking at plaque load and show target engagement. We don't target plaque, so that wasn't our target engagement. We did have some changes in PET, which we just talked about, but that's not our target. This very interesting assay was developed that's not been done before, and so our group at Acumen developed this assay. It's an immunoassay. The capture was with an anti-idiotype antibody. The detection antibody binds to oligomers. The point is that the assay only gives you a signal when you have ACU193 bound to an oligomer. It's actually very technically difficult to do. If you wanna go to the next slide. What we found in the study is that on the left-hand side, for the single-dose cohorts, at 2 mgs per kg, it was below the sensitivity of the assay. At 10, at 25 and 60 mg per kg, you see this very nice dose-dependent increase of the complex of ACU193 bound to oligomers. Then, in the multiple-dose cohorts on the right-hand side, you see the same thing. You see this very nice dose-dependent increase in the complex of ACU193 bound to oligomers. In fact, even in this very small phase I study, we reached statistical significance on some of these differences, as you can see on this slide. The, the assay actually performed very well in this study. If you wanna go to the next slide. This is a slide that was really, at least in my view, very important in terms of our drug development program. What you see here is on the X-axis, this is concentrations of antibody of ACU193 in CSF, so drug concentration in CSF, and on the Y-axis, what you see is the complex of ACU193 bound to oligomers. These are individual patients in the various cohorts that you see plotted here. What you can see is that the lower doses, you have the amounts coming up, you start to reach a plateau. When you start looking at the 60 mg/kg every 4 weeks dose group and the 25 mg/kg every 2 weeks dose group, you're really on the flat part of the curve. The reason why that's so important is that tells you that you're at the point of diminishing returns in terms of target engagement. That means that there's no reason to think that you would want to look at doses above 60 milligrams per kilogram. Whenever you're designing a phase I first-in-humans study, dose selection is very difficult. In this case, the doses that we selected actually bracketed exactly what you would want, and so the beginning of target engagement and then getting to the point where you were near Emax or at the point of diminishing return. We have a little bit more work to do to pick the doses for the next study. One of the things we'll need to do is model what we think the CSF concentration of drug would be with 25 milligrams every four weeks. That can be pretty easily done from these data. We haven't made any final decisions in terms of the doses for the next study, but based on these data, we clearly we'll be able to make those choices and we'll be able to choose doses for the next study, and we know it doesn't have to be above 60 milligrams per kilogram. If you go to the next slide. I guess, and with this, I'll just turn it back over to Dan to kinda summarize for us. Thank you, Eric. As you've just heard in detail from Eric, the results from our phase I studies reduction in our high-dose cohorts is a welcome development, further supporting the convincing proof of mechanism data we've generated. ACU193 was well tolerated in patients with early AD, and near maximal target engagement was demonstrated, establishing broad therapeutic index and path to monthly dosing. We did include exploratory analyses in INTERCEPT-AD, including computerized cognitive testing and MRI, arterial spin labeling, pulse sequencing. That did not show effects due to the short duration of the study and the small N, which was expected. Fluid biomarker data is expected late Q3, which will help further inform the design and dosing strategy for our next trial moving forward. I'll round up today's call with a preview of our future strategic plans. We anticipate an end of phase II meeting with the FDA in the Q4 to guide our proposed phase II, III study design. This includes starting as a phase II and following an interim analysis, expanding to a phase III study, should it be warranted. We also are actively investigating the development of a subcutaneous administration of 193, which now has the benefit to be better informed based on our phase I results. Evaluation of potential next-generation product opportunities and exploration of advantageous partnerships are additional initiatives we are pursuing with the best interest of shareholders in mind. With that, I'd like to welcome Dr. DeKosky and Honig to discuss ACU193, and I'll turn the call back over to Alex. Thanks, Dan. Before we open the call more broadly for Q&A, I'd like to invite Dr. DeKosky and Dr. Honig to share their overall impression of the phase I results presented today. Eric should also be included here, in case there are any questions, regarding the results. Dr. DeKosky, if I can start with you. Given your experience in Alzheimer's disease, what are your overall impressions of this phase I data? Do you believe the safety profile and the PK and the demonstrated target engagement, suitably address proof of mechanism for ACU-193? Dr. DeKosky, I think you might be muted. There you go. Okay. I certainly believe it presents proof of the mechanism, the... especially some of the serial dilutions and serial changes with increasing dose speak to that issue. I was also very encouraged 'cause this is primarily initially at least for safety, that although there are one or two cases that have shown, at least in my view, that the drug is working because of the nature of the side effects, that side effect profile is benign in my view, very benign. No specific Adverse Events, Serious Adverse Events that can be directly traced to the medication itself. Overall, I'm very encouraged by this. I've seen a lot of these kinds of preliminary studies over the past several decades, As has Dr. Honig and Dr. Siemers has seen probably 10 times what both of us have seen. This is as positive an early one study as I can hope for. We know a great deal about how the brain responds to these various antibodies. There's an article this morning, came out in the New England Journal talking about solanezumab, which unfortunately did not hit its targets. We have an immense amount of antibody data in Alzheimer's disease. Some of these have never made it into phase II trials because their phase I safety was not anywhere near what it should have been. Overall, I'm very encouraged by this. Too soon, I think, to make much of the changes in cognition, but certainly, I prefer to see stability to slight declines in rate of change than worsening of cognition, which we have seen in a couple of other trials. Great. Dr. Honig, any, Do you agree, I suppose, and any other feedback? I certainly concur that with Steve, as an investigator, the overall results in this 60-plus patients concur with my personal experience with the patients we had enrolled in my site. Seems like a safe drug to administer without much in the way of side effects other than a low rate of ARIA. I think the safety, which is clearly the major concern in the phase I study, was well demonstrated, the other would be the target engagement and and preliminary efficacy measures. I would, concur that certainly the antibody is getting into the CSF, but the antibody is binding oligomers.... There is, I think, reasonably, clear evidence that at the higher doses, there is some removal of plaque, as we expect for most of these antibodies that interact with forms of amyloid that are larger than monomer, that is oligomeric or fibrillar or plaque. I don't think it's surprising that the oligomeric, that antibody, that binds oligomers would remove plaque. I think, in fact, rather, it's an encouraging indication that, in addition to clearly interacting with oligomers, does remove plaque from the brain, at the higher doses. Safe and meeting its target. That amyloid PET was reduced in those higher doses, in the 60 mgs per kg every 4 weeks, and the 25 mgs per kg every 2 weeks. Despite this not being an objective of the study. Well, one of the things that we do know is that things that happen in the brain aren't necessarily. I've been very focused on the issues of equilibrium, and I think to the extent that it targets predominantly oligomers, the oligomers were going to do. Either dysfunction or disruption, or they're available for adding to the plaque. To the extent that you remove concentration of AβOs from the oligomers, from the extracellular space, equilibrium suggests that you may well get things that come off the. Removed by the fact that it's attached to the beta, which lowers the amount, the concentration in extracellular space. It wouldn't surprise me if any of the things that we have attacking anything that disrupts. A beneficial thing, in my view, since we know the plaque removal does correlate with cognitive changes. Great. Anything to add, Dr. Honig? No, I think the, as we all understand, it's hard to know for certain what the mechanism of the plaque reduction is, whether it's additional binding to plaque or whether it's as Steve mentioned, oligomers, and there's clearly evidence at the highest doses of decrement in plaque in plaque load. I think both of those are encouraging, that the presumed primary method of action is the binding the oligomers. To the extent that we have data on a variety of other agents. To that extent, it's certainly encouraging that there's also a demonstrated plaque removal at the higher doses. In just a few doses. We're talking about a very small number of doses, short period of treatment, yet nonetheless, we're already seeing plaque reduction. Great. I'd like to talk about the target engagement assay, given it was novel. If you think that assay and the results, along with the PK and clinician's point of view, if you think monthly dosing is compelling from a product profile point of view for this product? Either one can start. C ertainly I would say that, monthly dosing, certainly is more favorable for our patients and for that matter, for our practitioners. We certainly would prefer to see the lower burden of monthly dosing. In this case, of course, the actual dose per month between 25 milligrams biweekly and 60 milligrams monthly does not differ by that much. It seems like both were reasonably equivalent, and certainly is promising the idea of having possibly a monthly dosing schedule rather than a biweekly schedule. T here's both convenience for the patient, and family, and there's also a large cost difference for whoever will have to bear it if you drop the infusion, by 50%, of a total like an expected total. It certainly is easier in a month, if it gets to subcutaneous, which we're exploring now. It will be even better, even if it has to be at one-month intervals. We certainly have people give small doses of various medications to themselves. Diabetes, getting insulin, and now pretty much everyone getting Ozempic for weight control, and that has to be injected. I think it is much easier to do it once a month than twice a month, and any of our patients and their families certainly would tell us that because they don't all come from right near the clinic where it's being done. Yes. Quickly turning to the ARIA-E, I know you both mentioned that you were satisfied with what you saw with the rate of ARIA-E in this study. Related to that, should clinicians be focused on symptomatic or asymptomatic ARIA-E rates, in your opinion? I think it's often a hard question. T here's even different forms of symptomatic in the sense that there are people who report symptoms, then you notice they have ARIA. The people who you notice they have ARIA, and you ask them, you question them deeply about whether they have any symptoms, and, oh, yeah, maybe there's some little symptom that may or may not relate to the ARIA. I think we would all agree that asymptomatic ARIA is less scary than symptomatic ARIA. Symptomatic ARIA is less scary than serious symptomatic ARIA. Clearly, in this phase I, we did not have any serious ARIA, but there was a little bit of symptomatic ARIA and a little bit more ARIA as a whole. ARIA, in a way, might almost be now viewed kind of like plaque reduction as an evidence of target engagement in some sense. I think the neurologic community as a whole and the dementia specialist community is less finds ARIA less fearsome than they did initially. The idea of having brain edema or brain swelling certainly wasn't something that people looked as a favorable event. On the other hand, I think we've realized that it isn't quite as scary as it might seem, and that in particular, if 90% of it or so is asymptomatic, that makes one less feared of the side effect. I'd just like to add that it's kind of like if a tree falls in the forest, does it make a noise? We would not have found the vast majority of the cases of ARIA in any of the clinical trials that have been done so far if we were not doing scheduled MR scans. Then to our, I wouldn't say to our surprise, but one of the reasons for doing them was to see what happens, and in fact, what we noticed was a great many asymptomatic, mild, for the most part, evidences of cerebral edema. Therefore, if these studies had been done without such frequent data, we'd be talking about the below 10% incidence of symptomatic abnormalities. Now, I noticed that the FDA, wants them at certain points if you look at the instructions for giving other antibodies. I think Larry's point is emphasized by the fact that we wouldn't even know about this if we had not scheduled regular findings, sorry, regular scans to note that things were quietly going on beneath the surface. If they don't cause any symptoms and they go away vastly by three months, that's acceptable to me. We have a lot worse side effects of our medications than this. Great. Last question before we open it up to the analysts to pepper us all with questions. From an investigator's point of view, Dr. Honig, what were your impressions of ACU193 in the clinic? Was there enthusiasm around the trial and the prospects for 193 by patients and caregivers? Well, I think, seeing as the current therapeutic spectrum for Alzheimer's disease is confined to in terms of efficacy signals, to agents that remove beta amyloid from the brain. There was a fair bit of enthusiasm about this trial as another antibody that might have a more specialized mechanism, but that would remove amyloid from the brain. I think there's a wide appreciation in patients and their caregivers that amyloid is the principal evildoer, if you will, in the Alzheimer's cascade, and that removing amyloid seems like a good thing. It's sort of something that intrinsically appeals to patients. Certainly the evidence from this agent and other agents, this agent, now that we know, so far is looking very encouraging, and patients perceive it that way, as a useful thing to do to remove something that's causing injury to the brain. I ntravenous treatments are never quite as eagerly anticipated as subcutaneous or oral, but on the other hand, or other methods of administration, but there doesn't seem to be a large burden with this intravenous treatment, relatively painless and relatively acute side effect-free treatment. Excellent. Thank you both so much for providing your time and your perspectives on ACU193 and the results from this study. At this point, I'd like to invite the Acumen executives back and open the call for Q&A from the queue, the audio queue. It also, if we do have time at the end, we'll take some questions if from the chat box, if you have submitted any. With that, I'll turn it over to the operator to open up that queue. As a reminder, to ask a question, please press star 1 1 on your telephone and wait for your name to be announced. To withdraw your question, please press star. Please stand by while we compile the Q&A roster. The first question comes from Paul Matteis with Stifel. Your line is now open. Great. Thanks so much, and congratulations on the data. I appreciate you taking my questions. I have three, if you don't mind. I guess as you sort of take a step back now, what do you see as the clearest opportunity for differentiation? Is it on efficacy because you're lowering plaques and also lowering oligomers, and there may be an additive effect. Is it on safety, dosing, or something else? Second, I know you still have to do some work on modeling for once monthly, but I think, Eric, you've talked about some CSF data from the SAD that has underlined your optimism, that once monthly for 25 is viable. Can you speak to that, and what would you say your level of confidence is now? Then lastly, where are you on a sub-Q, and I guess, what else needs to be done to get that ready, to enter the clinic? Thanks so much. Thanks, Paul. C an I take the first and last part of that question, maybe, Eric, you can. It's like a sandwich, you can pick up the middle. I think firstly, we are still very much in pursuit of a best-in-class efficacy signal with our mechanism with this agent. T his was a phase I first-in-human study, so we're very interested in seeing what the next study can produce in terms of efficacy and, proof of concept, potentially on the way to a potential registration. I think it is interesting. I think the safety profile is encouraging but still needs, more chronic dosing and exposures over time to sort of see where that settles in. As we've noted on this, in this discussion, I think we've got sort of this duality of a high dose that clearly can clear plaque at rates similar to the first approved product, a mid dose that looks like it's in that zone, but may be a bit safer and ultimately may be more efficacious. That's just we don't have that evidence just yet. We do think that a robust phase II,III study should bring some clarity into that risk benefit and the efficacy potential of ACU193. On the sub-Q, I... T his is, all this data is just fresh off the presses. I think we still have some time to look at, PK modeling and other elements as to how we get to a subcutaneous formulation. We had initiated some assessment of those options just on a technology basis earlier this year. I think those will now be more informed on the basis of the study PK. I think probably we'll have an update by the end of the year as to what the next steps really need to be for sub-Q. Okay. Dan, just on the next clinical steps, you've talked about a phase II, III. I think you've also talked about the possibility of some sort of concurrent biomarker study. Is that still on the table, or how are you thinking about the different possibilities? Thanks, Paul. I think that is apparently now on the table, just given the biomarker effects observed in this study, that one possibility would be to explore some sort of parallel study for the purposes of a biomarker. That is not... That's you're hearing that from me. I think the team has barely had a chance to digest this data, and we've got a lot more information to think about as to what are the broader development plan should be going forward. Certainly, with these data, it would appear that option exists. You'll have to stay tuned. Maybe, Eric, do you want to comment on the? The data that we do have from the SAD, so this is after 1 administration of 25 mgs per kg. The spinal fluid was obtained 21 days later, and the concentrations were well in excess of reported oligomer concentrations in spinal fluid. What some of our data are showing us now, especially that target engagement curve, is that the antibody apparently is picking up oligomers in brain interstitial fluid, where the concentrations of oligomers are higher, and then we're measuring it, of course, in CSF. I think what's really gonna be important about that 25 mg/kg every 4 weeks dose is we'll plot out where our 3-week data are, and then we'll also have our modeled every 4-week data, but we wanna know where we fall on that curve. Maybe just 1 quick comment about biomarker studies. I've, I've also seen that, there's the suggestion of, well, do you do a sort of a separate phase II before you do a phase II, III? T hat would be sort of a traditional sort of drug development approach. I think we have ways in our phase II, III that we don't have to create an extra study in between, but the team will need, a lot of time to talk about that. Again, partly getting back to the dose. W hen we started the study, we didn't know whether we would have any plaque reduction, and we had some people say, "Well, why do you bother getting a PET scan after the baseline since you don't target plaque?" T he answer is, well, that's the theory. Let's see what happens in the clinic. Now we have our answer. W e've got both. We've got target engagement in terms of oligomers, and we also have this effect on plaque. The effect on plaque was sort of less certain, but now we know we've got it. Thank you. Can I ask one last quick follow-up? I'm sorry. I forgot to ask this, and I think it's important. Just on the clinical endpoints, I know you said they're not powered, but just can you just offer any insight? Was anything trending in favor of the drug, given that I do think, at least on the curves for some of the other drugs like lecanemab, at an early time point, there may be some numerical separation? Like, what did you see on CDR, or is it just too small of a sample to really speak to this? Well, let me without getting too much into the weeds of drug development. For, like, in the Clarity study, you can start to see things on some of the clinical measures, like the CDR, fairly early, but that's a study of 1,800 patients. We have a study of 8 or 10 people per cohort, and two of those were on placebo. The sample sizes are so small that I think you really do have to be careful about not trying to read the tea leaves too carefully, and Steve and Larry may want to comment on that, too. What I will say is that with this computerized cognitive testing that we did, in collaboration with Cogstate, we were looking for kind of a symptomatic bump, an improvement with only 2 or 3 doses of drug. W e didn't find any convincing evidence of that. The other thing to keep in mind is we also didn't see any indication that people became worse, and there have been drugs developed for Alzheimer's disease that actually made things go the wrong direction, and we didn't see any evidence of that at all. T his is a little bit of a cautious answer to your question because I could pull out data to say, "This looks good," or, "That looks good." The reality is, in a study like this, you have to be kinda humble in terms of not trying to overread the data on things like the CDR sum of boxes. F air enough. Thank you. Please stand by for our next question. Our next question comes from Tom Shrader with BTIG. Your line is now open. Congratulations. Really a remarkably rich phase I study. A couple of dosing questions for Eric, and then maybe a mechanistic follow-up. Eric, you've talked about titration dosing, it's reduced already in the past. Are you still thinking about that, given that it looks like you have to go to quite high antibody doses to really see plaque removal at all, or does that make less sense? A follow-up to the last question that I think you talked to, is modeling good enough now that you would launch into a 25 mg monthly cohort in a bigger trial, or do you think you'd do some sort of smaller experiment first? Thanks. As far as the titration question, as you know, that strategy was used with aducanumab, for me, maybe a little surprisingly, but it seemed to work. Again, we haven't finalized any of these decisions yet, but there's, I don't think there's a lot to lose to do that, and it would be something like, 25 mgs per kg for 3 times and then jump to 60 mgs per kg. Yeah, again, we haven't finalized any of these decisions yet, but there's, I don't think there's a lot to lose to do that, unless you would do a very prolonged titration period when you're kind of underdosing for a long time. I don't think we would do that either. That's one of the things that we would do. In terms of your question about just, launching into a study using model data, again, you could do a more traditional sort of phase II at this point, but the way our phase II, III study is being designed is that you will get to an interim analysis, and the interim analysis will look at a number of things. It'll look at clinical measures, it'll look at biomarkers, and a number of things to make a decision whether to scale up to a full-size phase III or to just let the study complete as a phase II, which we may end up doing. The DSMB, who will be looking at those data, may also recommend dropping a dose. If it turns out that, at the lower dose, whatever it ends up being, you don't really see anything in biomarkers or clinical, maybe you drop that. On the other hand, maybe at the lower dose, you'd have really good efficacy, but a lot better safety, and maybe you'd drop the higher dose. The way that adaptive design is being done is it allows you to do some of the things you would do with a standalone phase II study, but at the same time, not do that standalone phase II study and create that extra white space and basically delay the antibody becoming available to patients. Got it. If I can ask a quick mechanistic follow-up. The patients that had the maximum plaque removal, did that patient essentially clear the plaque? Oh, do you have a sense of the% plaque reduction, or, it looks like it's probably just that one patient that's relevant? Thank you for asking that. I should have clarified that. None of these patients had their plaque lowered where we would consider them amyloid negative. Again, this is a short study and whatnot, but generally, somewhere between 25 and 30 Centiloids, if you get below that, you would be considered amyloid negative, and none of our patients dropped below 25 or 30 Centiloids. Again, remember, that's with 3 administrations of drug in 3 months. What might happen after 18 months, we'll have to find out. At least in this short study, we didn't see anybody, even though they declined, they didn't decline to the point where we would consider them amyloid negative. Great. Thank you, and congratulations again. Please stand by for our next question. The next question comes from Colin Bristow with UBS. Your line is open. G ood morning, congrats again on the data. Maybe just a follow-on on phase II dose selection. Y our Emax curve suggests maximal target engagement from the, from really the 25 mg and at 2 weeks and the 60 mg at 4 weeks. I'm just curious, what is your thinking around evaluating a potential intermediate dose, and I'm guessing at 4 weeks? Second, can you give us more details on the ARIA-H that you observed in the trial? I think there were 4 cases. Was there any cerebral hemorrhage here? Can you comment on that with regards to APOE4 status? Maybe lastly, can you just remind us if you measured NFL in the trial, and if you did, is there anything you can share at this point? Thanks. A gain, thanks. All good questions. We actually just had this conversation earlier today, is while we're modeling data, say, for 25 mgs per kg every 4 weeks, we could ask the model, what if we did 35 milligrams every 4 weeks or 40 milligrams every 4 weeks? I think that's one of the nice things about modeling data is you can make those kind of estimates in terms of adjusting doses. I think that's one of the advantages we have with this rich data set, that now we have something to model with. In terms of ARIA-H, yeah, we did have 4 cases. These were people who just either went from 0 to 1 or maybe 2 to 3. There was only an increase in 1 ARIA-H. I can't, off the top of my head, tell you what their APOE status was. I'd have to look that up. There wasn't anything remarkable about that, I know. I think the most important thing about ARIA-H is, I think it's becoming kind of apparent that, when you talk about hemorrhage, that sounds like a pretty scary thing to a lot of people. For ARIA-H, the vast majority of those are microhemorrhages. Those microhemorrhages happen in people with Alzheimer's disease as part of the disease course. They're a microhemorrhage is virtually always asymptomatic. If you look at observational studies from a statistical standpoint, if you have more microhemorrhages, you may have a little bit more disease progression, but certainly you don't see anything within an individual patient. The macro hemorrhage, which would really, in the absence of anticoagulants, be a very rare event, that obviously would be worrisome. 99% of what we're talking about here, in the absence of anticoagulants, would be these microhemorrhages, which are really asymptomatic. You see them with the disease. In most patients with Alzheimer's disease, after a period of time, will have microhemorrhages. I think that's created maybe just a little bit of confusion. Recent studies for Alzheimer's disease haven't really shown that NFL is necessarily the best biomarker. We will be sending out fluid biomarkers, both plasma and CSF. We're kind of in the final stages of deciding exactly which biomarkers we'll send out. Certainly, it'll be one of the p-taus, probably GFAP, that sort of thing. The one thing I would caution people on is, this is a small study where people got, at most, 3 administrations of the drug. I would not expect to see any change in those downstream biomarkers. I think our reason for wanting to run those is to get some familiarity with the labs, with the variability, that sort of thing, so that when we really do need to rely on the results, like for our interim analysis in the phase II, III, we'll have a really good understanding of what we get from these labs with these biomarkers. I personally wouldn't really expect to see a change in those in this small, short study. If I can just jump in really quickly, since we have Dr. DeKosky and Dr. Honig on the call, do you agree with Eric and his assessment of ARIA-H, and would you have anything to add to that? I think the major thing I'd add is, having done this for 30 years, you see people who have microhemorrhages, which basically is a spot around a vessel where, in all likelihood, amyloid in the vessel wall has caused weakness and hemorrhages or blood has come through. Those spots are asymptomatic. At the same time, because of the amyloid that builds up in the blood vessels of the vast majority of people with the disease, some more than others, there is a spontaneous hemorrhage, not just a bit of blood around a small blood vessel, but actually a mass hemorrhage that occurs in people with AD who have a significant amount of angiopathy, that is deposition of amyloid in the blood vessels. Those occur spontaneously in people with the disease. If we had been unlucky enough to have a hemorrhage occur in this relatively small state, we'd be debating forever whether this was one of the spontaneous hemorrhages or whether it was caused by the medication. There are these, not unlike the appearance and disappearance of ARIA, there are these things that occur in the brains of AD patients, and when you look at a significant number over a significant amount of time, you see them. This has been, as far as I'm concerned, a pretty clean study so far. There were no big flags here that say something about this drug is not only toxic but will be toxic if you continue these studies. I would, like Eric, minimize the thought that there was a significant meaning to the small hemorrhages. I call them blood dots. As long as they're asymptomatic, I would say it would be perfectly reasonable to continue. Larry, I'm curious about your response to this one as well. I don't want to put you on the spot. No, I think it's widely recognized that microhemorrhages, like Eric and you have mentioned, are asymptomatic in the vast majority of cases. In some cases, there may be brief transient neurological events associated with them that may or may not be associable by the patients or their practitioners. Microhemorrhages are generally asymptomatic. Isolated microhemorrhages, generally, with the drugs that have more extensive data in this class, broad class of anti-amyloid agents, have not been particularly associated with the drug itself, but rather just simply with APOE genotype and time. As Eric alluded to, the major concern and fear, of course, is always the macrohemorrhages or larger hemorrhages, which often can be symptomatic. Again, it's not clear that they're in the drugs, in the other drugs, which they have more extensive data. It's not clear they're drug-related. Again, it does seem like edema or swelling, even though it doesn't sound as bad as bleeding, is the greater concern with drugs of this class. Obviously, in the patient perspective, the idea of bleeding in the brain sounds very fearsome. Great. Thank you both. I, just... I was just, y ep. Sorry. I just wanted to briefly give you an anecdote. I saw a patient on a Thursday, a woman who had fairly obvious, I'd say, moderate Alzheimer's disease. When she came in on Monday of the following week for an MR scan, I got a frantic call from the resident on call because he'd been called to radiology because this lady had a right parietal superficial hemorrhage of some significant size, although she walked in. Resident and senior found all sorts of left-sided abnormalities, including a little bit of neglect, and looked at my scan, my evaluation from three days before and said, "You know, did you miss all this?" I said, "Well, no. She had a hemorrhage over the weekend." Of course, this was totally spontaneous. This was in the days before. She was not in a trial. There wasn't very much going on except the anticholinesterases. These things occur spontaneously. As I said, over the course of, let's say, an 18-month trial, it would not be unexpected to see a few of these spontaneous ones. What you have to hope for is that your drug does not precipitate any, and so far, we look like we're in very good shape in that regard. That's great. Thank you. Thank you both. I'll turn it back over to the operator to continue the queue. Apologies. Please stand by for our next question. The next question comes from Pete Stavropoulos with Cantor Fitzgerald. Your line is open. Hi, Dan and team. Congratulations on the data presentation for ACU193. Thank you for taking my questions. Well, my first question is about next steps and how you're gonna be thinking about the next study. I know the data are fresh, and you're combing through it. Is there a route forward where you can try and tease out, potential therapeutic benefit, not associated with the plaque reduction, but perhaps associated with oligomer removal? Those where there could be no or really low ARIA rates, but close to maximal target engagement, and then a dose you expect there to be a low ARIA and plaque reduction, say, using the lecanemab as a benchmark. O r is your current thinking that, you just go for doses that will likely show plaque reduction since there's an established regulatory path forward for accelerated approval? A great question, Pete. I'll lead up, maybe Eric can provide some comment. I think we've established that 60 mgs per kg every 4 weeks is sort of the highest rational dose, given the target engagement and given the plaque observations. I think that a mid-dose that generally has been described on this call and maybe, Like, a mid-dose at 25 mgs per kg every 4 weeks, presumably is not going to have that rate of ARIA, as may achieve sufficient oligomer target engagement to sort of, demonstrate that unique benefit of that mechanism. As we said, I don't think we have dialed in precisely the doses that get carried forward here, but I do think that with high and mid doses, we should have sufficient target engagement and be able to pursue, clarity on the best risk-benefit profile in terms of safety and efficacy for patients. Maybe just to add a bit to that, and again, I kind of mentioned this before, is that, these clinical measures have a lot of variability and really are very noisy. Y ou can look at, large trials like the Clarity trial or the ENGAGE, well, the EMERGE trial, and look at group differences. When you try to look at individual subjects, having done this for a long time, you can sort of kid yourself and talk yourself into things that, may not really be there. I think what we really rely on is things where there's less variability. Our target engagement assay is one of those things. The PET scan is another thing. You don't get placebo responses and as much, well, the test retest, let's just say, in a PET scan, is much better than something like a CDR sum of boxes. We'll rely on those things to guide our dose selection. Again, for the next studies of phase II, III, when you get up to bigger sample sizes, part of that interim analysis will include those clinical measures. All right, thank you. For Doctors DeKosky and Honig, the symptomatic ARIA that was observed, in your experience or from your discussions with others who treated patients, with anti-amyloid antibodies, is leg dysfunction commonly observed for those experienced in a symptomatic ARIA? In other words, would you be confident that leg dysfunction was a result of ARIA, or would you be on the fence? ARIA is edema of the brain, so typically the symptoms relate to the location of the edema. Sometimes the scenario is just remarkably silent. Sometimes it's just accompanied by nonspecific symptoms, such as headache, sometimes by a electrical irritability, kind of causing a seizure. Certainly, in this case, it was viewed as related because, in fact, the leg dysfunction was anatomically correlated to the area of the brain that was affected by the ARIA. They happened, synchronously. I think the overwhelming odds in this case, although one can never be certain, given that there was unexplained leg dysfunction that related to the area of the brain, was that it was symptomatic. Again, it was entirely reversible, radiographically and, clinically as the vast majority of ARIA is. I, if I remember correctly, Larry, this, her, edema, her ARIA was in the right parietal lobe. If so, if it's posterior enough that it doesn't cause primarily weakness, it might well cause. Isn't as clear as we'd like to have it. Given the fact that it occurred in the region, as you said, that's referable to right leg function, probably was due to... My view would be that it was probably related to the ARIA. On the other hand, she was walking, and she just had an auditory complaint, so it speaks again to the fact that ARIA might be mild and in many cases, never noticed. It takes a lot of ARIA, sometimes, the few we've seen that have been diffused, that is in multiple places in the brain, before people actually are confused or have some kind of cognitive disturbance above that of the dementia itself. In her case, she was describing things, so it obviously did not cause any kind of global problem. All right. Thank you very much for that, congratulations once again. Thanks, Pete. Please stand by for our next question. The next question comes from Judah Frommer with Credit Suisse. Your line is now open. H i. Congrats again on the day, you guys, and thanks for taking the question. Just a couple more from us. Maybe first, just as you continue to think about modeling phase II dose, can you give us a little more detail on the immunogenicity that you saw in this trial, and how that might factor into dosing in the phase II, III? Additionally, can you give us a little more color, potentially, Dan, on what the data, and obviously you're still going through it. Given the ARIA, given the plaque reduction, any evolution in the oligomer hypothesis that you're considering at this point? Or do we kinda need to wait for functional demonstration to start altering that hypothesis? Thank you. Tell you what, Dan, you want me to take the first and the third one, and then I'll let you comment on the sub-Q? Sure. T hanks. R eally interesting questions, actually. The, in terms of the modeling the dose versus immunogenicity, t hat's actually a really good illustration of the fact that, we're early on in analyzing the data. We certainly would want to... If we did, and so far we haven't, but if we did come up with an anti-drug antibody, and then that was neutralizing, and so they had a reduction in drug, yeah, we would figure that into the modeling because you probably wouldn't model in a person who had that. Again, we haven't seen that so far, but we don't have all the data yet. Yeah, we would definitely figure that in. As far as your broader question in terms of sort of the oligomer hypothesis and does the ARIA and the plaque reduction change that? T hat's something that'll probably be discussed for a long time. I think as far as right now, this minute, I would say that our oligomer hypothesis by itself hasn't really changed. O ur feeling about plaque reduction hasn't really changed. I think it is important to note that for the drugs that reduce plaque that have been successful, they do reduce plaque down to essentially zero by the end of 18 months. T his is very analogous to lecanemab, actually, where they target protofibrils, but they get a great deal of plaque reduction to the point where it does get down to essentially zero. What accounts for the efficacy there? Is it the plaque reduction, or is it the targeting protofibrils? I don't know that there's any way to answer that, and I think we could end up in the same situation. We'll see what we have in terms of plaque reduction at 18 months, but, you know, we could end up in a similar sort of situation. I'll just say, you know, I'm a clinical trialist, and so even though these mechanism questions are really interesting, and we talk about them a lot, at the end of the day, what we really need to see is how much does it slow disease progression and what's the safety profile. Those are the two things that will really allow you to make a decision. It'll allow regulators to make a decision to approve it, but I think it'll allow clinicians, like the two folks we have on today, to make a decision: Do I want to treat my patients with this drug? The mechanism questions are really interesting, but at the end of the day, is what does it do for people clinically? Thanks, Eric. Judah, I think in terms of subacute, I would expect by year-end to have kind of the game plan in terms of timelines and, format and, you know, sort of clarity around precisely how we're gonna move forward. Okay, thank you. Please stand by for the next question. The next question comes from Charlie Yang with Bank of America. Your line is open. Great. Thanks for taking the question, congrats on the data. This is Charlie Yang for Geoff Meacham. I have 3 questions. Number 1, mechanistically, can you just maybe provide more clarity on what's the reason for the lack of ARIA-E observed in the homozygous patient? Is there any kind of mechanistic rationale for that? Number 2, in terms of the trial design, I believe Clarity AD for lecanemab, you know, they suspend dosing for patients who experience moderate asymptomatic ARIA-E. I'm wondering if that was done here and perhaps maybe even going forward, what's the intention in terms of the dosing from that perspective? Number 3, based on the computer test results that you're seeing from phase I, do you intend to continue to use the test, in the later stages of study? Are there any kind of modification that you intend to do, you know, based on what you observed? Thank you. As far as the lack of ARIA in the APOE4 homozygotes, you know, I can't tell you today. I really don't have a mechanistic explanation as to that. T he fact that it's the opposite of what's seen with other antibodies. Again, this, you have to preface all this with saying this is a very small trial, and it's very preliminary, and we'll have to see how all this plays out. Since if this does hold up, and it's essentially the opposite of other antibodies, where you have higher rates in homozygotes, then I think maybe we have to sort of consider that in what our theories are of what really causes the ARIA. T hat's not entirely clear exactly how that works. We'll have to think through that, but I have to admit, you know, right now, I can't come up with a really good explanation for that. It's a finding, and we'll continue to follow it. In terms of what we would do in a phase II, III, in terms of dosing, if a person has ARIA, I think that's a really good question, and we haven't made any final decisions about that. I think as the field actually has come to be more comfortable with especially asymptomatic ARIA, we, I think, could consider for people who had asymptomatic ARIA that was radiographically mild, that we would continue to dose those people. It turns out in early studies of bapineuzumab, before this ARIA was very well understood or described, that they dosed through ARIA a lot because they didn't know any better at the time. Actually, it didn't cause big problems. I think we'll need to have some criteria for that. Obviously, if somebody's symptomatic, you would hold the dosing. I think even if they were asymptomatic, if radiographically it was, say, moderate, you would hold the dosing, but we need to make, you know, final decisions about that. As far as the Cogstate testing, yeah, I'm glad you asked that question. That Cogstate battery that we showed the results on, there's actually five different things that go into the battery, and we've only seen the results of the composite of all five of those things. Now, I would guess that some of those pieces of that battery will work better than others. In fact, I had a conversation with someone from Cogstate earlier today, saying one of the next steps that we need to do is to dissect out that battery and see which things seem to be useful, which things are not so useful, and then decide what to incorporate into the phase II, III. T he whole battery is only a half an hour as it is, so it's not particularly burdensome. If you can make it shorter and make it better, then that would be a good thing.