Quick update on the company. 2026 is a huge year for you guys with some schizophrenia data, and then we'll get into more questions. Take it away. Thank you. Great. Thanks, Paul, and thanks everybody for joining. Just to start as a quick overview of MapLight. We're a CNS company really focused on developing targeted circuit-specific therapeutics. Founded the company in 2018 with Rob Malenka and Karl Deisseroth out of Stanford, two real luminaries in the CNS space. We built a platform to be able to identify and develop these therapies against circuit-specific targets comprised of three main elements. One is optogenetics, which is a tool that allows us to turn circuits on and off in living animals. That really allows us to establish a causal link between circuit function and disease. We use two other tools, STARmap, which is a three-dimensional transcriptomic technology that allows us to spatially locate those targets within the circuits of interest, and single-cell transcriptomic data. The combination of those three elements has been incredibly productive for us. We've got a robust pipeline of product candidates, ML-007, which is our muscarinic program. I'll come back to that, and we'll spend most of the time today talking about that. In addition to that, we have ML-004, which is a 5-HT1B, 1D agonist we're developing for social communication deficit and irritability in autism spectrum disorder. We expect top-line data from that phase II in Q3 of this year. We've got a couple of earlier-stage programs, ML-009, which is a GPR52 PAM we're developing for hyperactivity and impulsivity, and 021, which is an M4 antagonist we're developing for the motor symptoms of Parkinson's disease. Both of those will likely be entering the clinic next year. To come back to 007, we are developing 007, which is an M1, M4 muscarinic agonist combined with a peripheral antagonist very similar to COBENFY. Very early on in the development of this program, we saw the potential for the muscarinic class exemplified by COBENFY's data, but also noticed the very significant challenges that were being seen there with respect to tolerability. Ultimately, we discerned that the tolerability challenges were largely a consequence of mismatch of exposures in the periphery of the pro and anticholinergic components. With a muscarinic, you want the procholinergic, the M1, M4 activity in the brain, but hitting those receptors in the periphery causes significant side effects. You pair it with an anticholinergic. The problem we identified with COBENFY was that the match was not great, that's primarily a consequence of the very high inter-patient variability for both of the components of their drug. We really set out from the beginning, we chose two components for our drug, 007 and fesoterodine, which is our peripheral anticholinergic with really attractive physical and chemical properties that would allow us to precisely match the PK exposures. Two drugs with very low inter-patient variability in terms of exposure. Through a very methodical and deliberate phase I program, we did four phase I studies, 275 patients, so were 1,500 exposures. We really deliberately worked through the process to be able to precisely match these two components in the periphery and establish a really tight window of the ratios of the exposure of the two components, which ultimately led to a really attractive safety and tolerability profile. I think we ultimately have the potential to be differentiated not only on safety and tolerability, but also importantly on several facets of ease of use. First, on frequency. Most of the side effects with these drugs are Cmax related. Because we can give the drug to such high Cmaxes, because of this precise matching of the two peripheral components, we can give the drug less frequently. We think we'll ultimately be once a day in schizophrenia, compared to twice a day for COBENFY. We think we'll be twice a day in Alzheimer's disease psychosis, compared to three times a day for COBENFY. We have the potential to be once a day there. We also won't have a fasting requirement, which is really cumbersome with COBENFY. We have very short titrations. Their titrations are one week in schizophrenia, five weeks in ADP, will be a single pill, a one-dose titration in schizophrenia, and a one-week titration in ADP. Really, I think multiple potential ways to differentiate on terms of safety and ease of use. Lastly, we think we have the potential to differentiate on symptom improvement as well. In particular with cognition, we're a much stronger agonist at M1 and M4, but importantly at M1 than is COBENFY. We have preclinical head-to-head data showing superiority on cognition, we think we may ultimately be able to show a robust improvement in cognition in the clinic. Yeah. Okay. Great. Good. Great overview, Chris. Maybe, do you want to set the stage and talk about the design of your phase II schizophrenia study and just how enrollment's been going and when we might get data? Yeah. Sure. Phase II study is a 3-arm study. We're testing once a day, twice a day, and placebo. 300-patient study, 100 patients in each arm. The endpoint there is change in PANSS score at 5 weeks. The study is enrolling very robustly, and that pace of enrollment has been really consistent throughout the study. We're now targeting top-line results from that study in Q3 of this year. Right. We talked about the different avenues for potential differentiation. I was just talking to you offline about hearing from some KOLs about how big of a deal QD could be. I guess, how would you think about the probability or the likelihood of hitting these different differentiation thresholds? Starting with QD, the one thing I've asked you regularly throughout our dialogue is how did you select these doses? There's no PET ligand, is that easy? In the context of that, I don't think the half-life of your molecule is all that long. Maybe talk about the dose selection work you did and then your confidence that even with a shorter half-life, you can still get there on QD. Yeah, sure. We did, I think, some very robust and detailed work on selecting the doses. There are a lot of ways you can go about this. You can look at in vitro data, receptor occupancy, et cetera, which is I think largely more relevant for antagonists than agonists. Ultimately, what we determined was that if we really just focused on concentrations in the CSF, we did all the work in preclinical animal models to say, what's a concentration in the CSF that results in efficacy? Then let's target that concentration in human beings in the CSF. We found through all of our preclinical work that we had a very consistent concentration range that led to efficacy, 14-27 nanograms per mil, and that was really across a whole bunch of different animal models. Amphetamine-induced hyperlocomotion, PCP-induced hyperlocomotion, conditioned avoidance, as well as cognition, tardive dyskinesia models, and dyskinesia models in non-human primates. Across all of those models, very consistent exposures led to efficacy. Basically what we said is we're going to take those ED50 concentrations and make sure that we're above those ED50s in the CSF in humans. We were able to achieve that for both the twice-a-day dose, which is 210, and the once-a-day dose, which is 330. We were able to achieve that. We're well above the ED50 throughout with the BID 210 dose. We're above the ED50 for 21-23 hours with the once-a-day dose. Just to put that in context, if you look at the Cavg for COBENFY's relative exposure compared to animal exposure, they achieve a Cavg of the ED30. Our trough concentration is above the ED50. Very conservative concentrations targets for our doses ultimately taken into humans. You'd asked about the half-life. While the half-life of the drug itself is relatively short, it's the half-life in formulation. Remember, this is a gastroretentive formulation, is about 5-6 hours. We have a much longer half-life with the formulation that we're taking into the clinic, and we've tested specifically looking at CSF concentrations throughout the day. In totality, I'd say we're highly confident that we have the exposures that we need with our once-a-day dose to achieve efficacy. Yeah. Okay. As it relates to tolerability, maybe talk a little bit about the side effects where you think you have the best chance to differentiate. Is the probability of differentiating on tolerability the same for the BID and the QD dose, or is the BID better set up with a lower Cmax? I can see it both ways. The BID has the lower Cmax, but it also hits Cmax twice. How do you think about that? In terms of differentiation on the side effects, first put it broadly in context. I think the important side effects to focus on relative to COBENFY is really the GI side effects on the procholinergic side, so high rates of nausea and vomiting, both in their phase II and phase III studies, but importantly, in the real-world experience with COBENFY, even higher rates of nausea and vomiting. On the anticholinergic side, really avoiding urinary retention and severe constipation. I think if we look at the BID versus once a day, most of these muscarinic adverse events are Cmax related. The higher Cmax tends to give you higher rates of adverse events. We certainly saw that in our phase I studies, both in healthy volunteers where the difference was there, but not as robust. More significant in healthy elderly patients where the once-a-day dose wasn't tolerated, and that was very much the same for COBENFY. They were twice a day and schizophrenia had to go to three times a day in elderly folks because they don't tolerate the drug as well. I think as we think of broader differentiation with respect to gastrointestinal side effects I think we have a lower rate of effects, but we're less focused on the actual total number of AEs per patient, than we are on the severity of those adverse events. Really what that points to is the clinical significance of those adverse events. The preponderance of our AEs are mild, which just means if you're having nausea that's mild, it's not affecting your activities of daily living, and it's not requiring therapy. Whereas if you get to moderate, it means it is affecting your daily activity and may require intervention. The rates of moderate AEs for KarXT in their phase III trials was in the 25%-37% range. We've had much lower rates of adverse events through our phase I program. That nausea and vomiting has contributed significantly, I think, to the challenges that we've seen with the uptake of COBENFY during its launch. Yeah. Could that show up in a difference in the discontinuation rate in your trial? Yeah, for sure. I think, it's always a little bit ambiguous about what's the etiology of the D/C. A lot of the discontinuations that you see from reported in COBENFY studies really are a withdrawal of consent. You really don't know what the reason was for that withdrawal. I do think our sense is, certainly from real-world use, that a lot of the patients are not continuing on the drug as a consequence of those GI side effects, nausea and vomiting in particular. Right. Okay. What are your expectations for the COBENFY data later this year? What are the implications for MapLight's efforts in Alzheimer's? Yeah. I think, obviously, they announced earlier this year that they had a number of sites with some data challenges, so they excluded the data from those sites, and they've made the decision following an unblinded DSMB review to continue to enroll that study, just replacing the patients that they lost from those questionable sites. I think that can be interpreted a lot of ways. If it was truly a futility analysis, that's very positive. They chose not to increase the size of the study. It could be any number of other things where maybe they were just tasked with, "Hey, is the data different if you include these patients or exclude these patients? If it's different, we'll just replace them." That really doesn't tell you anything about the probability of success. I think what we have seen is that BMS has taken a very different posture since that time, and they've taken a much more positive or signaled much more positively to the markets with respect to those studies. I think they're now in probably a good position where they'll be reading out three studies, potentially concurrently, in the latter half of this year. They have the two acute ADP studies, and they have a relapse prevention study that will read out. Based on historical precedents, pretty good probability of success for the relapse prevention study. Then in total, having three shots on goal, I think puts them in a good position to have some positive data to talk about. I think we have had concerns just about the design of the study in that because they have a five-week titration and a two-week placebo run-in, their endpoint is at 14 weeks. That really falls right in the window where there's some natural waxing and waning of ADP symptoms. If symptoms are naturally going to get better during the time point where you're choosing to assess the difference, you may have a higher placebo effect. They also have a number of doses where patients can ultimately settle. Lower doses as they move up to the highest dose in the study, and I think it depends on where patients fall out. What we saw from Lilly's data with xanomeline was really the highest dose that showed the biggest difference with respect to improvement in hallucinations and delusions. If they have a modest number of patients achieving that higher dose, that may be a problem for them to show efficacy overall. I think, at a high level, I think we do believe that xanomeline works and will work in ADP. I think some questions about whether the studies that they've performed will show that. I'm expecting we'll see some positive data in ADP, and I think if they're able to show significant responses at the higher doses, but maybe not at the lower doses and had some trouble getting patients up to the higher doses, I think that plays well to the advantages that we present in terms of tolerability. Yeah. From a design perspective, I guess your endpoint in your phase II ADP studies is week seven, right? It's an earlier- That's right endpoint. Otherwise, is it a fairly similar population and- Yeah. Yeah, go ahead. Seven weeks. You're right. Thanks for pointing that out. I should have said that. Ours is seven weeks because we only have a one-week titration, and we don't have the two-week placebo run-in, so six weeks on therapy, seven-week endpoint. We avoid that natural waning period. Otherwise, the studies are largely designed the same. 300-patient study, two arms for us, just the BID arm, and the placebo arm. Yeah. Okay. Makes sense. Great. What else would you want to cover in the last five minutes here, Chris? Yeah. Do you want to maybe just talk a little bit about, we've talked about this a bunch before, the COBENFY launch and maybe how that- Yeah. That was interesting for anyone who was listening to our last session. This came up with the KOLs we had in this panel on why COBENFY hasn't launched as well as people expected. They had a number of reasons, which I'm happy to share. Yeah, Chris, we'd love your perspective on the learnings from that launch and what has that sort of informed for you on your target product profile and the level of differentiation that you think you need. Yeah. I think, first of all, just to put the launch in context, people sort of push on it and say, "Hey, the launch really hasn't been great." I think compared to consensus estimates, that's probably true, but if you look at it in the context of schiz-only launches historically, which is what this is, right? It's not an atypical that people are used to using in other indications. It's only got approval for schiz. If you compare it to other schiz-only launches, it's actually doing quite well. Prescription- Right numbers continue to grow. I think all in all, it's not a terrible launch, but I think lots of ways that it could be better. I think what we've, in talking to docs and in BMS, put out a poster looking at real-world data. Really, I think it was trying to inform folks on how patients are switching or titrating patients off of their atypicals and onto muscarinics. What you see there are very high rates of nausea and vomiting. A third of the patients are having vomiting, more than half the patients have nausea, more than half the patients are on antiemetics. A real challenge for docs is they try to put patients on a muscarinic. It's being used almost exclusively adjunctively. They're adding it to existing therapy and then trying to titrate folks up on their dose, working around not only the challenges of dosing frequency and fasting, but the nausea and vomiting that they're seeing with pretty high frequency. Limited number of patients are actually getting to the 125 dose, which was the dose that had a dedicated arm in their phase III study. A significant proportion of patients, like a quarter of the patients, are stopping at 50, which is purely a titration dose and not an efficacious dose. I think what we're hearing is the primary challenges there are getting patients up to an efficacious dose, challenged both by the frequency of nausea and vomiting and by the frequency of dosing. As a BID pill, I think that's representing a real challenge for adherence and compliance. They put out this poster, which was, I think, the hope was to guide folks on how to switch patients, but they haven't published a formal switch study yet. I think they're enrolling one or may have completed enrollment at this point. I think once they put that data out there, I would expect that that's really going to help give docs a roadmap on how to move patients off of their atypical and onto a muscarinic. The last thing I'll point out is that the guidelines for therapy get revised every couple of years, and they're set to be revised, I think, this year. Presumably. That'd be helpful. With approval of COBENFY, they'll now be included in the guidelines, which I think will do a lot to change docs' prescribing habits. Yeah. All that's to say, I think a big opportunity for us, because we've got a drug we think will be much better tolerated, in particular with respect to nausea and vomiting, potential to be once a day. We don't have the challenges of a long titration. We don't have a requirement for fasting. All of that will make it much easier to use, and I think docs will find that pretty attractive. Yeah. Absolutely. Maybe in the last couple of minutes, Chris, you want to talk about the balance sheet. You have this readout this year in schizophrenia. You've got Alzheimer's next year. How much cushion do you have beyond these studies, and how good of a position are you in right now? Yeah. As of year-end, we've got $450 million in cash, a pretty healthy balance sheet that carries us out through 2027 and beyond, and that includes the initiation of a couple of phase III studies. As you point out, we're expecting top-line data from the phase II in schizophrenia in Q3 of this year. We're also expecting top-line for the autism spectrum disorder study in Q3 of this year, then top-line for Alzheimer's disease psychosis in the second half of 2027. Got cash on hand to get through all of those significant milestones. Yeah. I guess we didn't talk about the autism study. I know it doesn't do it justice, but you want to take one minute and just quickly set that up for people who are not aware that that readout's also coming this year? Yeah, it's a little hard to do in one minute. Sorry circuit-specific data related to that therapy, in particular, 5-HT1B and the nucleus accumbens and its relevance in multiple different animal models of autism. We're looking in that study at both social communication deficit, which is one of the core features of autism. It's really defined by social communication deficit and repetitive and restrictive behaviors. Nothing's ever been approved before for social communication deficits, so it's a little bit of a regulatory unknown. We're using an endpoint that Janssen developed in conjunction with FDA, went through all of the validation steps with FDA to get that endpoint approved. We're using that for social communication deficits. Already have, we think, some buy-in from FDA on the endpoints we're using. Because of the regulatory unknowns there, we're also looking at irritability. Irritability and autism is an indication for which there are already two approved drugs, atypical antipsychotics, interestingly, aripiprazole and risperidone, with all the liabilities of atypicals that we talk about when we talk about schizophrenia, maybe even a little more so here with adolescents, where they tend to experience more significant weight gain. I think real opportunity for a better and differentiated drug just to treat irritability where there is a known regulatory path and for which we have guidance to get to approval. This is unlike our ZEPHYR phase II and our VISTA phase II with 007. This is truly an exploratory phase II study, so it's 150 patients, 60 adults. We had to enroll 60 adults for safety before FDA would allow us to move into adolescence. We got about 100 adolescents in the study, we're really going to look at the totality of the data and then make the strategic decision about which path to pursue going forward in terms of phase III studies. Okay. Awesome. All right. Well, thank you, Chris. Great discussion as always. We appreciate it, and best of luck. Yeah. Thanks very much