Good morning, everybody. Thanks so much for joining our, I think, sixth annual virtual CNS conference. We pivoted to virtual in March of 2020, which was pretty crazy, and now it feels like Zoom is a much more normal thing than I think it was audio only back then. Happy to be moderating this first panel with Liz Thompson from ACADIA, who runs research and development. Liz, you want me to just kind a get into questions, or any kind of quick opening remarks you'd like to give? I didn't have any opening remarks, so happy to just jump right in. Okay. Maybe we can, like, switch the order around that I've kinda sent over and maybe talk about Alzheimer's psychosis first. Does that sound good? Absolutely. Okay, great. Yeah, maybe like just set the stage on the program, like the upcoming trial readout, like, you know, the scope, the asset you're studying and how it compares to pimavanserin, and then I'll have some follow-ups if that's cool? Sure. Of course. First off, what we used to refer to as ACP-204 and now call remlifanserin is our next generation 5-HT2A inverse agonist program. Exactly as you say, we built this based on our learnings from pimavanserin. Pimavanserin or NUPLAZID is one of our two marketed medicines. It is the first and only approved medicine for Parkinson's disease psychosis, and really has been a great medicine for patients there and has brought, you know, we think a lot of benefit. That said, there were some things we were looking to improve upon with it, with the next generation molecule, looking for something that had decreased possibility of QT prolongation. NUPLAZID does have that as a signal, not meaningfully at the marketed dose level, but you do need to be careful of this in a frail and elderly population. We were looking to avoid that in and of itself, but also allow for some greater dose ranging, look for faster time to steady state, and with remlifanserin, we think we've done all of those things. Right now, remlifanserin's in two programs, the Alzheimer's disease psychosis program, which I'm sure we'll talk about in more detail, and also a Lewy body dementia psychosis program where it's in phase two. Okay. Okay, great. Awesome overview. I've covered ACADIA since 2014. I followed the development of pimavanserin and how it went through the FDA really closely. I guess my view on pimavanserin was that it was a super safe antipsychotic, the safest, like, in the whole atypical class, but that some of the data in, like, schizophrenia, MDD, and ADP obviously were, like, more mixed. You know, I always sort of wondered, is this mechanism too selective to really have the punch for some of these more challenging diseases? How do you kind of make sense of the totality of the evidence for pimavanserin as it relates to prospects in ADP? And again, I'm just gonna say 204 so I don't mispronounce it, but. Totally. What would be the argument that 204 would have a relatively higher probability of success? Yeah, as you say, we have a very rich data set upon which, from which to draw and upon which to build as we look at what we think this mechanism could do, and where we maybe don't want to keep trying to make it play. You know, I'll say as we looked across the data set, I do agree we have some mixed data in some of these indications. Overall, you know, as I consider it, we need to think about mechanism, molecule, and study design. I think that varying some of those contributed to different levels in some of these indications. In Alzheimer's, as we look at it, we think that there is reason to think that the mechanism has shown some potential utility here. There was the phase ll, which I know you're familiar with, where we did meet the primary endpoint with pimavanserin in Alzheimer's, in an Alzheimer's specific population. If you look at the subpopulation of the HARMONY study, it was not adequately powered, absolutely. There is some indication of an exposure-response relationship with efficacy there, which again we think supports the fact that the mechanism may be relevant, but maybe there's an opportunity to improve on both the molecule and the program from that perspective. I definitely think that there were a couple of things, you know, we could do better the second time around. The first is that there is that indication that higher exposures may get you greater efficacy. With remlifanserin, we do have the opportunity to go to higher exposure levels. There's also, you know, I alluded to the fact that the Alzheimer's population in the HARMONY study, it wasn't powered for that subpopulation. That's one of the other things that we're doing differently, is really focusing in on making sure this is an adequately powered study, such that we have a good likelihood of seeing an effect if there is one to be seen. Yep. Okay. Makes sense. I guess, like, maybe more quantitatively if possible, like how much can you push the degree of 5-HT2A antagonism or inverse agonism? Like, I guess, there's no PET study for pimavanserin to really kinda index to, but my assumption with pimavanserin was that it's a really low dose, right? I think it's like 30 or 40 mg a day. Like, it should be saturating the target, right? Is that not the right way to think about it? Yeah, I mean, it's one of those things where I don't have the perfect data to show you because the only receptor occupancy information we have is in young healthy volunteers, and there's only so much you can extrapolate that to an elderly and diseased population where we do know there's just a difference in terms of this particular biology. I guess what I do tend to orient to most is that, yes, pimavanserin is a pretty high potency molecule. You know, 34 milligrams is the marketed dose level. But if we look at that exposure-response relationship, it does seem to suggest that you can get higher levels. You have the potential for higher levels of efficacy at an exposure that is beyond what you can get with the- Right You know, sort of median exposure that you see with the 34 milligram dose of NUPLAZID. Suggesting that even with a, you know, pretty high potency molecule, there is the possibility that if we're able to get to higher exposures, higher average exposures, we may be able to push that efficacy a little bit further. Yeah. I'll say that even if we are not able to get, you know, more out of this mechanism than we saw with pimavanserin, I think with an adequately powered trial, there's the potential that we could be seeing something meaningful there in any case. Yeah. Okay. Do you wanna talk about the trial design and how it compares specifically to that phase ll for pimavanserin, which I remember was, like, kind of an atypical study, right? It was done at a network of nursing homes in the U.K. Like, it took a long time to enroll. Like, I certainly wonder too if that was, like, the best study to test this mechanism as well. What's your approach and how does it compare? Yeah. Obviously there are some key similarities in terms of them, we are looking at the same core mechanism at the end of the day. Also, they are both relatively short placebo controlled efficacy assessments, so six weeks looking at sort of a target of how quickly you'd want to get effect in this disease. We're also, in both cases we were targeting hallucinations and delusions as sort of our core clinical manifestations, and where we think we have the greatest likelihood of success. That said, there are a number of distinctions where we think we've been able to learn from that program and some things that may give us a better likelihood the second time around. We talked about some of the improvements to the molecule itself. From a trial design perspective, I would say that one of the biggest things is that we are looking not just in that very focused nursing home population. The phase ll was just patients who are maybe a little bit later in their disease, all in nursing care, all in a nursing home setting. This is more community based. We are looking at making sure that everybody actually has Alzheimer's. This is consistent with what we did the last time around. Now we're actually also biomarker testing them as well to really be confident that that is the patient population that we're looking at. From an endpoint perspective, in that study we used something called the NPI-NH, the NPI Nursing Home Scale. It does focus in on hallucinations and delusions, but it's a nonlinear scale. Its frequency, time, severity, which can make it a little bit more challenging to interpret and can make it a little bit less sensitive to change. We're using SAPS-H+D here, which we have used in other trials. It was a component of the HARMONY trial, for example. We think that it is going to be more sensitive to change and more able to detect an effect if there really is an effect there. Yeah Those are some of the main things that we are looking at that we think is going to improve our likelihood of success here. Yeah. Okay. How do you, as it relates to, like, raters in a study like this, how good are raters at delineating what is delusional thinking versus misremembering or, like, a cognitive issue in a disease like this? Yeah. Yeah, we are pretty selective in the kinds of raters that we have participating in our trial. Certainly there's some pretty rigorous training and assessment of them that's necessary before they're able to qualify. But we also are requiring that they be fairly experienced, that they have been working with this patient population for some time so that we think that they are as able to distinguish between that as possible. Right Recognizing that those are challenging. Right. Okay. For this clinical endpoint you're using, so is it the same endpoint you got approved on in PDP, the SAPS? SAPS H+D, yes, is a component. It was a component of the HARMONY study, and we did use it in the Parkinson's program as well. Okay. Do you wanna talk a little bit about, like, powering and just, you know, a clinically meaningful effect size? Like, what are those thresholds? Yeah. What we're looking for in the phase ll portion of our overall program, which is a phase ll/phase lll single master protocol, what we're looking at here is we powered for an effect size of 0.4 or a moderate effect size. We've got 80% power on that. Again, we picked this based on an endpoint that we have some experience with and some understanding of, and some sense of how this is gonna behave with this mechanism. We are looking, typical to what you do in a phase ll, at a number of different other endpoints in our trial to make sure we sort of holistically understand what's going on. Although the one in particular that we added in, actually fairly soon after I joined the company, was the NPI-C, which is another, fairly standard way of looking at, neuropsychiatric symptoms and looking at that H+D component there as well. To get approved for dementia psychosis, or I guess Alzheimer's psychosis is a subcomponent of it, do you need to disprove the negative on safety and the black box history? That's a really interesting question. I don't know. Well, I can't specifically tell you what FDA is going to make their decisions on, you know, in the future. What I can say is that, you know, one, we do think we have a better understanding now of the kinds of data that FDA is going to be interested in to make their judgment on whether a black box needs to apply or not. We're collecting very rigorously information about any deaths that might happen, for example. All that said, you know, there's a wide variety of molecules, including NUPLAZID, that did get approved even with that black box. I think that, you know, it's going to be a totality of evidence kind of consideration of benefit risk, as is usually the case. Makes sense. Do we think we should have mechanistically a good case for arguing? Yeah Against the black box? Yes, we do. Right. It is very much gonna depend on the nature of the clinical data that we end up seeing. Right. Okay. Makes sense. From a development perspective, I mean, we've seen this division be open to phase ll studies counting as a pivotal trial, like with CAPLYTA, VRAYLAR, Karuna recently. What do you think in terms of the registrational or the actual regulatory utility of this phase two? Yeah. I mean, our intent all along has been to conduct it in a rigorous way such that it has at least the potential to be considered as an adequate and well-controlled trial. That will probably depend a little bit at the end of the day on a few factors. One of those is I have talked about the fact that we are going to use this phase ll to inform if there are things we might wanna change about our phase lll programs. If we wound up being meaningfully different in terms of how those looked, then its regulatory standing would probably be more confirmatory than others. The other thing is, obviously, we, like the rest of the industry, are keeping a very close eye on FDA as they talk a little bit more about the single study approach and how they're thinking about it and the scenarios in which it could apply. There are a number of different ways that the next few years could play out. Yeah. Yeah I think. What we can control is that we are conducting this in as rigorous of a method as we can, such that we're maintaining as much possibility to utilize this for regulatory purposes. Makes sense. On the single study piece, not to take a diversion, but we were talking about this internally yesterday. Like, you know, I would assume for this molecule, you're gonna need an ICH guideline safety database anyways. Like, how much does the single study really get you? Like, don't you need to do enough clinical work to get to 1,500 exposures? I will say that is still my default expectation. You know. Right At this point, what we've seen is that FDA has put out a couple-page article in the New England Journal. This has not made its way into guidance documents yet. We'll see how they're thinking about it. My default expectation is that given the, you know, given how common this disease is, that it is going to be appropriate and necessary for us to continue to have an ICH level safety database. That's what we're planning for. Yeah. You know. Yeah We'll see how regulatory thinking is evolving. Look, we're always gonna embrace regulatory innovation in ways that could help us bring safe and effective medicines to patients faster. For sure. Makes sense. Are you thinking that if you did two subsequent phase lll, they both would be parallel group studies? The way we designed this program at the beginning is essentially to have three very similar trials under a master protocol, so a phase ll and two phase lll. They are all designed at this point as parallel group studies, and that is what we are continuing to expect to do. Okay. Though obviously, you know, the randomized withdrawal concept does come up, and there is certainly some utility in that, and it provides different evidence. It provides your- Sure ability to maintain a response. Right Rather than to induce a response. I mean, wouldn't you agree those studies have a higher probability of success, all else equal? I will say that it does seem in these disease. Yeah spaces that they do often. Right They do often prove out more positive. Right. Yeah. Okay. Data's coming soon. Anything else you would add that, you know, people should be considering about this upcoming ADP readout? Again, like, you know, how to think about the bar and success and just, like, what's enough to move forward? Yeah. I guess how I am thinking about it and what I'm looking for is continued data that indicate that remlifanserin is consistent with the target product profile that we've laid out for it. You know, obviously there is an efficacy bar to that. You know, first and foremost, this phase ll needs to show us that there is some effect of this medicine in this population. Really it's about continuing to support that this is something that holistically we think is gonna be important for patients. There are a number of components to that, from things we already feel very confident about to things that this phase ll may give us some directional sense of, but are not gonna answer for sure. It's everything from, you know, is this a molecule that's gonna be relatively easy for this patient population to take and be compliant with? Things like, you know, we're pretty confident once a day dosing. We're confident that it can be done with or without food. We're confident that it has you know, you don't need to worry about DDI with other medicines that these patients are taking for their disease. So things that lend towards patients being able to take it easily and stay compliant with their medicine. I would be very happy to see a safety profile that looked very similar to what we've seen with pimavanserin, aside, of course, from the QT prolongation. That would be in line with what I'm hoping for. some of the things that we don't think this study's gonna be able to definitively answer for us, but can give us some directional senses of things like are we, as we would expect, not seeing deleterious impact on motor function, or are we not seeing deleterious impact on cognition? Those kinds of things that we think are gonna be important in this patient population as well. That's sort of kinds of things I'm gonna be looking for. Right In the data readout and that I think others should be looking for as well. Right. Okay. Is the study long enough to rule out a cognitive impact? I remember phase ll two years ago was a six-week efficacy outcome, but blinded to 12 weeks, I think, for that safety reason, but I don't know if that's, like, objectively the right way to do it. Yeah. This only goes out to six weeks, and that's part of why I'm saying that, you know, it is not going to definitively answer the question. Okay We do have open label extension, which, while not blinded, can give a sense. Sure Some sense of whether things continue to play out in the longer term. That's one of those, it's gonna take a while for us to more definitively answer the question, but we can probably get a sense early on if we're going the wrong way. That's Right Looking for. Right. Okay. Okay, great. Can I ask you a totally, like, loaded question? Ooh- So- I love those. If someone asks me, what's a higher probability of success, ADP or Lewy body dementia? I would say Lewy body dementia, and I feel like it was a missed opportunity to not pursue this with pimavanserin. Like, any history you can provide on why that wasn't done, and how do you think about the relative utility or probability of this mechanism across those two indications? Now, that is painfully close to asking me which of my children I like better. I guess I'll say a few things. Obviously, much of this history did predate me. I think that by the time the company had gotten through the DRP and then the Alzheimer's situation, by that point we were moving along with remlifanserin's development, and we were excited about the potential there in terms of what I've already talked about, with the faster time to steady state, the lessened QT prolongation, the ability to dose range. I think rather than putting in future continued development work with pimavanserin, we made the decision that we were gonna focus on remlifanserin instead. As I think about ADP and Lewy body, I think that there are good reasons to believe in both cases. We have a lot more data in terms of patient numbers in Alzheimer's, though, with the caveats that we've talked about with both the phase ll and the HARMONY. I think that there's good biological reason to believe and good clinical reason to believe with the information we have, we just need a more robust approach to it. I think the strength of the Lewy body data are striking, but it's in a very small number of patients, so it's sort of the flip side. Yeah, yeah To the argument. I'm enthusiastic about both, but I do think that Lewy body is a really nice complement to this program. Right. I will say it was the first clinical program I started when I got to Acadia, so I think you can read into that the fact that I think that is a really good place for us to be looking. Right. Makes sense. You talked about doing biomarker testing in the ADP study to confirm Alzheimer's diagnosis. A Lewy body diagnosis is, like, not straightforward. Like, I think a lot of these patients get diagnosed with Parkinson's for a long time, and the path to a correct diagnosis I think is, like, subjective and, again, it's a long road. How do you make sure that that's the homogeneous and the right population? Yeah. That one is trickier, absolutely, in the sense that I think that many things have evolved faster in the Alzheimer's space than the Lewy body space, and the degree to which we understand biomarkers and know how to apply them is absolutely one of those. You know, we are looking within that Lewy body study at sort of two distinct populations, those that have the motor symptoms that emerge first, and those that have the cognitive symptoms that emerge first. I will say we are looking for alpha-synuclein biomarkers in those. That said, again, the biomarker science has just not evolved to the same level. It's not as definitive of a biomarker-confirmed diagnosis, but we think that will give us some interesting information into that subpopulation of patients and whether we ought to focus future efforts on any one of those subgroups, the motor first, the cognitive first, or the alpha-synuclein positive folks. Okay. Because of these overarching questions, would you call this phase ll study you're running as, like, more exploratory at this point? There- I know exploratory has a connotation, but you know what I mean. Yeah. I don't wanna necessarily pull out all the connotations it can have, but I will say I very much consider this to be a learning study. Right. I am very enthused about the potential of this mechanism in this disease, but I did feel that there were several things we needed to better understand before we'd be able to design, say, a phase lll program, and so that's why we are approaching this the way we are. Another way we could have done it is waited for the Alzheimer's phase ll readout and then tried jumping straight into phase lll with Lewy body, but I felt like there were things that we needed to understand better before we could meaningfully do that. Yeah. Okay. Makes sense. Well, maybe in the last couple minutes we can just touch upon one of your other pipeline assets, the 211 compound you have in development. Sure, yeah. Do you wanna just briefly give a quick snapshot of that and the work you're doing in MDD? Yeah, absolutely. ACP-211 is our selectively deuterated R-ketamine, which we are looking at in the context of MDD. Data that we have thus far, and this is preclinical data and some phase l data, suggests that there is the potential to have sort of ketamine-like efficacy. Now, to be clear, that is the preclinical data that are supporting that. But with a lower or, hopefully really negligible level of sedation and dissociation. Right now, you know, SPRAVATO, which is a great drug that is working well for patients, it does have sedation and dissociation associated with it, and that means that patients do need to stay in the doctor's offices to be monitored for, you know, I think it's something like four hours at this point. What we are hoping for is something that can provide a ketamine-like level of efficacy without the patient experience components of the dissociation and sedation, and frankly more importantly, the needing to sit in the doctor's office to make sure you're not having sedation and dissociation. The way that we've looked at our phase ll study is both to inform on efficacy, but also with the intent to try to rule out unacceptable levels of sedation and dissociation and figure out if it's worth taking it forward after that. Okay. It's the R enantiomer? Yes. Is that right? Okay. J&J picked the S enantiomer because at that time they thought that there was, like, all this scientific evidence for why that was the one driving the- Yeah antidepressant effect. Like, what's the counter-evidence that you guys would point people to? Yeah. I would say that there is, you know, preclinical information suggesting that you do have efficacy with the R enantiomer as well. That, I mean, that's the main thing that we have that we can speak to right now from an efficacy perspective, and otherwise I'd say wait and see on the phase ll data, which we are expecting to be seeing in the mid-part of next year. Okay. Great. All right, well, we're at time. Any more specifics on the timing of the 204 readout? Do you wanna give us the week from today? No, I don't. But thank you for asking. I appreciate. Okay the opportunity. Okay. All right. Well, great. Thank you. August through October timeframe. August through October. Okay. Wonderful. All right. Well, thank you so much. Appreciate it, Liz. Good talking with you. All right. Thank you. Have a good one. You too.