Back, everybody, and good afternoon. I'm Brian Abrahams, Senior Analyst, Biotechnology at RBC Capital Markets. We're really pleased to have our next presenting company, Neumora Therapeutics, represented by Josh Pinto, their President, Nick Brandon, their Chief Scientific Officer, and Jason Duncan, their Chief Administrative Officer. Thanks so much, guys, for being here. Yeah, thanks, Brian, for inviting us. Really appreciate it. Lots to cover 'cause I know there's a lot of programs that have been moving forward very actively. Maybe we can start with navacaprant. in MDD. For those new to the story, the data from the phase III, KOASTAL-2 and KOASTAL-3 studies are very close at hand. Can you maybe just remind us around some of the study amendments and some of the changes that you implemented to KOASTAL-2 and KOASTAL-3 following the KOASTAL-1 results, and maybe how those may be contributing to I guess, how the conduct has been going so far, how the implementation's been going as we kind of near the end and how you think those are contributing to a study population that's more likely to demonstrate and showcase statistical significant effects for navacaprant for the drug. Yeah. Absolutely. Thanks, Brian, for the question. I think as you think about the KOASTAL-2 and KOASTAL-3 studies, which are expected to read out later this quarter, they were part of a broader phase III KOASTAL program that included three phase III studies that we ran. As you mentioned, we got results from the KOASTAL-1 study in early 2025. What we saw in that study was an overly inflated placebo response, particularly in the male population, that led us to dig into that. A couple of things we noted is that we enrolled more male patients than you historically see in MDD clinical trials, and we don't necessarily think that all of those patients were appropriate or had the right flavor of MDD for a clinical trial. The challenges with KOASTAL-1 really boiled down to not enrolling the right patients. To your point, we made a number of amendments in early 2025 to KOASTAL-2 and KOASTAL-3 to help fix that. One of the amendments and changes that we made was we partnered with Massachusetts General Hospital and their SAFER program, which is led by Maurizio Fava, to really help instill the medical monitoring over the study and make sure we're getting the right patients. We also completely rebuilt our clinical development team with a seasoned set of neuropsych drug developers that have brought a range of programs forward, whether Abilify, you know, Vraylar or Cobenfy. We've brought in the right team. Brian, what you're hearing from us is over the last 12 months-18 months with KOASTAL-2 and KOASTAL-3, we've had much stringent oversight of every patient that's come into the study, and that's what's giving us optimism as we look, you know, forward this quarter. In terms of what we're seeing that gave us confidence to take the studies up to the maximum number of patients we could enrolled is, first, we were achieving that two-thirds female population. As we denoted, we achieved about 2/3 female population in KOASTAL-2 and KOASTAL-3. As you recall from KOASTAL-1, the drug actually had an approximately three-point separation in the female population, so where it did work. We're happy that we normalized that. We also saw a significantly higher screen fail rate with our medical monitoring and the SAFER process. It's working It's working effectively. As we've looked at those measures, the blinded data that we're seeing, that's what gave us the confidence, Brian, to invest the additional dollars and maximize the number of patients in KOASTAL-2 and KOASTAL-3. Got it. Any sense of what the study's powering is now with some of those changes? How might you be presenting the top line data? Will you break down patients who were enrolled prior to the optimization, or will this be kind of the full population? How should we think about interpreting what we'll see? Yeah, the studies were originally powered to 90% to detect about a 3.2-point change on the MADRS. Some of the key variables that we haven't disclosed that go into that are obviously the standard deviation, as well as the dropout rate. What I can say, Brian, is that in terms of standard deviation and dropout rate, one is slightly higher than our assumption, whereas one is slightly lower than our assumption. Assuming we've been able to control placebo response in the study, we feel very good about the power that is in the study. In terms of the readout that's coming, what we're going to see is top-line data from the KOASTAL-2 study, top-line data from the KOASTAL-3 study, as well as a pooled analysis of patients that came in under the SAFER protocol and with the more stringent medical monitoring. We believe that releasing all of this at once will be able to give us the opportunity to declare what is our path forward with navacaprant and give investors confidence that the measures that we added to improve the medical monitoring have truly impacted the study result. Got it. What do you think you need to show from a clinical robustness and statistical standpoint to support approvability? Will you be discussing primarily the kind of the SAFER population pool, the pooled population with the FDA? If it was one trial hitting and one trial missing under kind of the guise of the new FDA guidelines or policy, is that, is that good enough if you hit on one study in the SAFER population? Yeah understand the different permutations here because I know, you know, depression studies can be tough. It's a big deal to show a real signal with a novel mechanism. It's a huge unmet need. What would be apart from obviously both studies hitting statistical significance on every population, like, what are the different possibilities here? Well, I think you hit one of the key points, Brian, which is first you have to look at it from the unmet need perspective within MDD. The current therapies that are available today have good efficacy. They don't treat all of the symptoms. Right. They do not treat anhedonia, which is one of the core symptoms, and the side effect baggage is quite substantial. That's really what navacaprant's looking to move forward, is bring a program forward that can show a benefit on depressive symptoms, anhedonia benefit, but with a clean safety profile as well. In terms of what we believe we'll need to file an NDA, our working assumption is hitting statistical significance on the MADRS in one of KOASTAL-2 and KOASTAL- 3, so having a hit on the primary endpoint, plus supportive data, which could be the post-pause pooled data have gone through SAFER. It could be the SHAPS and anhedonia data. It could be the broad tolerability profile, given how clean it's looked, on our prior studies. We think that there's a lot of permutations that could support moving forward to a pre-NDA meeting and having a discussion with the agency about a path forward with a single pivotal study being successful. Got it. Good. Just remind us of the timelines for the data. Presumably, it's. It is- coming tonight, or you guys wouldn't be here. I think, in terms of when it's coming, we've disclosed that it's coming in the second quarter. Obviously, we're here today, so I think you can, you don't have to hold your breath for this evening, Brian. We did announce, at the end of March when we released our 10-K that we had completed enrollment by that point. As you guys know, it's a six-week study, and so, you know, you should expect to see the data at some point before the quarter's over. Maybe shifting gears to 511. You reported some intriguing data relatively recently. Can you talk to your confidence in the signals that you're observing, both in the total population and the high anxiety subgroup where you saw even more robust effects? Guess where are you now with regards to next steps, exploration of higher doses, this MAD extension study that you're prosecuting now? We're really excited about the data that we've seen out of NMRA-511 from the phase I-B study in patients with Alzheimer's disease agitation. From a top-line perspective, what we've shown is a product profile that has a very mild side effect profile, so definitely competes favorably against Rexulti or Auvelity within that arena. From an efficacy perspective, we've seen across a range of measures, not only the CMAI primary, but subfactors and secondary outcomes such as CGI-S and NPI, an efficacy profile in the broad population that is comparable to Rexulti, and that is within a population that is similar to what Rexulti and Auvelity both studied in their pivotal trials. We think as close as you can come on a head-to-head comparison, 511 looks like a much safer version of Rexulti's efficacy profile. We also wanted to look at how the drug performs in patients with elevated anxiety at baseline because the vasopressin 1a antagonist pathway is thought to be anxiolytic. This is one of the unique times, Brian, in neuropsychiatry where you can tie a broad clinical result actually to a mechanistic hypothesis. Yeah. As you know, that's very challenging. What we saw in patients with elevated anxiety is across each of the measures, an elevated clinical effect size. That gives us confidence that if we can focus on enrolling a population, that from an inclusion-exclusion criteria is close or similar to what Rexulti and Auvelity did, and through medical monitoring, ensuring we're getting and balancing appropriate levels of elevated anxiety, should allow us to really test this product in a patient population that it's well-suited for, while also preserving potential for a broad label. In terms of next steps, we'll be completing a MAD extension study this year. We'll read that out in the second half of the year. As we've mentioned in the release, the 20-mg BID dose was very safe and well-tolerated, so we want to look to push the dose higher to see if we can capture more efficacy, and so we'll look to do that. After that, we'll look to move into a phase II dose-ranging study. What are gonna be the key takeaways from the MAD extension? Will it be primarily on safety? Are there kind of biomarkers or anything? What I would say is, from a safety and tolerability perspective, that's obviously going to be the primary goal. We want to see what is the maximum tolerated dose. How far can we push 511 up? That'll be the primary goal. Yeah. On biomarkers, Brian, we did look at a range of things from the phase I-B. You might see some more data coming out from us as we move forward, and that could be, you know, things that we ultimately look at in the MAD extension and future studies as well. In terms of biomarkers, you know, we're still doing a bit of work. Okay what we might want to study in the MAD extension. I guess, how are you thinking about what indications might be best suited for the V1aR mechanism here? I guess, is there internal data from preclinical models or data from other compounds that can guide your development path? Yeah maybe you could also touch on some of the key differences? Sure NMRA-511's pharmacological profile relative to other V1a agents that could give it a, maybe a better likelihood of showing success across whatever indications. Yeah for sure. Yeah. Brian, I'll take that one. Yeah. I mean, we've obviously paid very close attention to the literature, both preclinical and clinical data, and obviously tracking, you know, other V1a antagonists which have been put into development. I think you go back to what's been published around the vasopressin V1a system, it's so closely associated with stress disorders and anxiety. Whether in rodent, non-human primate, through to human experimental systems, increased vasopressin, you drive anxiety, stress-like states. You dampen those with a V1a antagonist. We have our own data in the non-human primate model, a marmoset model, which, you know, really corroborates that. You know, what we've also seen in those studies is, and this is, I think, becoming a common theme, the impact on aggression. There's one clinical compound from Azevan, SRX246, which in the Huntington's disease study did show you know, an effect on aggression. We actually look at on non-human primate data. It also is very suggestive we could be impacting on aggression-like behaviors. Azevan has recently started a new study in Fragile X with enrichment for people, you know, patients with aggression. For me, as well as you've got this anxiety theme, you've also got the aggression, and that links back to agitation and Alzheimer's disease. Yeah. Yeah. Yeah. Yeah. where we had our biggest impact. That's where, you know, our first study. As we look forward with this, you know, really centering around anxiety and stress, you know, we are thinking about things like general anxiety, social anxiety, PTSD, and these are things we've really thought through very diligently over the last few years, and we're in the mix as we decide where to place 511. You know, when we think about our compound and how it differentiates, there's probably four compounds that you'd think about. Roche had balovaptan, which they took into autism, which, you know, was unfortunately unsuccessful. We actually look at a compound, similar pharmacology, but we're able to model projected receptor occupancy. There's no PET ligand, we can't actually do the empirical experiment. When we project the occupancies, 511 is really superior. Where with our 20 mg BID dose, we're somewhere between 93% and 97% over 24 hours. You know, we think balovaptan, which was they could only go up to 10, they were somewhere between 70% and 90%. Again, it's only modeled, but I think. Yeah What we have, the properties of five-eleven, you know, really give it better CNS properties compared to balovaptan. SRX246, which has been used in a number of studies, and particularly some really important clinical ones, very old compound. You know, we believe their, you know, their patent life may have, you know, passed. You look at the structure of that molecule, very, very different. Doesn't look particularly CNS friendly. Structurally, basic properties very different from five-eleven. Overall, we see five-eleven having the sort of best in class properties from a profile perspective, basic pharmacology, CNS penetration. Okay. Good. Maybe moving on to 215. There've been a lot of developments in obesity and the metabolic space. A number of companies here today and who'll be here tomorrow play in that space. There's certainly arguments for continued unmet needs. I guess I'm curious, what do you think's most distinct about the NLRP3 mechanism, and where a drug like 215 could fit in in this broader landscape? Yeah. For NLRP3, this is really the thesis we've worked through and still, you know, still are following, is clearly a role in the brain for NLRP3 inhibition. What's the story which has emerged in the last 18 months is that inhibiting NLRP3 at high levels, all the work is focused on the hypothalamus, which is, you know, probably the center of regulating key feeding circuitry. If you inhibit it there in preclinical models, you see significant weight loss. The key feature here is you need to see very high levels of central inhibition. You know, there's been some very nice publications, which is again, you know, we've confirmed with our own data, you need to be at, like, an IC90 level of inhibition over 24 hours. There's this piece which we think is critical for the weight loss, and we know it's by decreasing food intake. You also have the peripheral impact of NLRP3 inhibition, which we're seeing almost to be a class effect across, you know, other sponsors' impact on critical cardiometabolic biomarkers like hs-CRP, and even, you know, IL-6. There's two pieces to this. If you then have a compound which has good peripheral exposure, you're gonna see those peripheral effects. If you also have a really high CNS penetrant compound, we believe you have a chance of seeing, you know, changes to eating behavior and weight loss. Then that's certainly backed up by at least our preclinical data to date. Yeah. Let's talk about that, those data a little bit more. recently had 12-week data from a DIO. Yeah model where 215 maintained semaglutide-like weight loss when switched from a combo to a monotherapy. You've shown some other data showing monotherapy weight loss. Yeah. I guess, what are the key takeaways from these studies that you've run so far? Yeah preclinical models? I guess, what should be a realistic expectation for human weight loss efficacy in phase I, just based on the translatability of this model and for this class in particular? Yeah. Maybe just a reminder, on our original disclosures last year, you know, we showed both monotherapy and combination weight loss with semaglutide, which looked to be class leading in these preclinical models. When you look at both overall weight loss over 28 days or induction of weight loss, it looked incretin-like, which looked to distinguish 215. You know, more recently, we've put out these longer 12-week studies where we've tested a number of paradigms, Brian, like you mentioned. Yeah. We've done the maintenance, so where we've had animals on semaglutide and 215, and then we've just put them onto 215 alone. What we see is maintenance and maintenance of weight loss similar to what you would have with sema alone. We've just done, you know, a very, you know, one day to another, a quick switch from sema to 215, again, maintaining that weight loss. You know, our view, I'll let Josh weigh in as well, you know, it just seems this, whether it's monotherapy or particularly in combination, very tunable and, you know, very complementary mechanisms in terms of what could happen. Yeah, I would say this is a model I think it's one of the most highly translatable models that we have from the preclinical to the clinical setting. We've seen a number of publications that have been out there, you know, that have highlighted the correlation has been as high as 0.9, and we've seen this not only with GLP-1s, amylins, and older classes. This isn't necessarily just a GLP-1- Yeah mechanistic hypothesis. I don't necessarily want to state numerically where we think we would ultimately want to go in the clinic because that's challenging to do. What I would highlight is this is the only NLRP3 inhibitor that has shown semaglutide-like weight loss as well as induction. We feel like it's delivered, Nick, the best-in-class preclinical profile, and that's why we're excited, Brian, to test it in the clinic. Okay once we get through the repeat three-month rat tox that we're currently working on. Okay. Can you maybe give us an update there on the status of this repeat dose, repeat tox study in rats with the new CRO? Any color as you've kind of digested and analyzed the data on what may have happened with that initial study? Have regulators weighed in at all about the potential acceptability of the second tox study to de-risk the program to move into the clinic? Yes. Maybe I'll start with the original study. Can't really say too much more than what we've disclosed before. Yeah. You know, as a reminder, we did see a small number of animals in this three-month study, certain events which were correlated with procedural errors, at the same time. This did lead us to start a for-cause audit, which is still ongoing. We've got to remember, these were not dose dependent, no link to mechanism or the molecule, and the molecule behaved. Our data in 28-day rat, dog, and three-month dog studies, we know were really good and supportive of moving forward. Our belief that 215 clearly led us to re-initiate a repeat study, which we announced back in March. Yeah Which is, which is ongoing. Before, you know, we haven't been to the regulators yet because we obviously want to see the result of the three months, plus complete the audit, and which will put us in a good position with the FDA to get our first IND. Okay approved here. Good. Just maybe in the last couple of minutes, you have another program, the M4 PAM program. Yep. You know, two different molecules you're potentially looking at here. How do 861 and 898 differentiate both from one another? Yeah the predecessor drugs, just in terms of things like potency, brain penetration, selectivity? What would constitute a go, no-go decision point for further investment in the franchise? Yeah. Yeah. Maybe just as, you know, one of our more recent updates was that we have prioritized NMRA-898 over NMRA-861. Yeah. That's right. Yeah. Just to stay, both molecules are really good. 861, we have paused it, we could easily bring it back into development. The reason we selected 898 were just a number of attributes which also are key differentiators from other compounds like emraclidine. 898, very potent across basic pharmacology assays, which we don't see with all other compounds. The most selective M4 PAM we have seen, and certainly of all of our compounds. Importantly, both 861 and 898 were optimized around CNS penetration, and we believe other sponsors may struggle with CNS penetration, perhaps even with CNS efflux challenges, which we don't have with either of those compounds. As we went into phase I development, 898, the properties we've seen so far just made it stand out, so has a long half-life, around 80 hours-100 hours in the data we've disclosed today. As we think about schizophrenia, you know, where compliance could be an issue. Yeah. Yeah. You can clearly think this could be very helpful if individuals miss a day or two of dosing. It's also the variability in the human PK is so low. I personally haven't worked with a compound like this, where not only the variability, but when we model out the data pre getting any real data, it looks like textbook data. As we've thought about other compounds, and as we go into clinical proof of concepts, we're sort of de-risking a number of other features which other compounds may have faced. For us, it's all around, you know, obviously, we need to pick the right dose, which we're trying to do with our MAD study, just executing flawlessly, we think it'll give that, you know, 898 really, a real good chance of showing efficacy. Yeah. In terms of next steps, Brian- Yeah We'll come out with the MAD data in the second half of this year. This will include the multiple ascending dose data from healthy volunteers as well as patients w ith stable schizophrenia, and then we'll look to very quickly move it into a proof of concept study thereafter. Yeah. We're really, really excited about 898. Yeah It's been delivering thus far. Anything we can read through from the stable schizophrenia patients, just given they're stable. I don't know if there's anything necessarily on the stable schizophrenia point from an efficacy perspective. I would say from a pharmacodynamic perspective, we've already delivered some very interesting data. As you think about the increase in beats per minute from a heart rate perspective. Yeah, yeah. It's hypothesized quite strongly that that is driven through M4 central target engagement. Right. With our 15-mg dose, which we're continuing to move higher on, we've already seen heart rate level elevations comparable to what Cobenfy's seen at their highest doses. Yeah. We feel like we're engaging the M4 target. I think the really interesting data we're going to get out of the MAD cohorts will be some of the CSF work. Yeah as well as continuing to see how safety progresses in the two different- Yeah populations. We're out of time. Thank you guys so much. Great to catch up. Thank you, Brian.