Thanks very much. It's my pleasure to be moderating the first Fireside Chat I've done with the Neumora management team, and the company's president and CEO, Henry Gosebruch. Maybe you can give a brief kind of background overview of Neumora, your programs, the phase III depression studies, and then we can do Q&A. Great! Sound good? No, it's great, Paul. Thanks so much. Awesome. Thanks for having us. Look, we're only four years old, but the idea really, when we were founded in 2019 was, let's go after neuroscience at scale, right? Let's not sort of go one-off, try, you know, try one asset or two assets. Let's really build something that can fundamentally address these very, very big diseases, and when you look at us now, four years later, that's really the mission we're on, and that's what we've accomplished. So we have a really nice pipeline of seven, seven assets. The first two are in the clinic already. The third will just be about to be in the clinic, and we have four really nice preclinical assets. We have, you know, over $500 million in cash, right? We have a fantastic team. Lots to do, and so, you know, we're, we're excited about, a big year for us in 2024. You asked about the, navacaprant. So our lead asset is in, three phase III studies for MDD. The first one of those will, will read out in the second half of next year. Obviously, that's a big focus, but again, there's a lot more to the company than, than the MDD program. We're very excited about the MDD program. Obviously, it's a huge, huge need, still a very, underserved, market or poorly served market with, you know, many older line medicines that leave a lot on the table. So we're very excited about that, but again, it's a broad platform, and we're, we're looking to attack some, some really broad, markets. Great! Awesome. Well, yeah, let's talk about the core first, and then we can kinda go through and talk about the M4 and the other stuff you're working on. So maybe to start, do you guys wanna just give some background on the core mechanism? You know, there were earlier studies with the J&J compound, and like, how did we get here, and what makes this mechanism so compelling in your mind? Sure. Good to see you again, Paul. Yeah. I'll take the first question, Bill Aurora. So when we think about the core pathway and core antagonist, more specifically, there are multiple points of data that help to validate this target. The first of which is the NIMH-sponsored FAST-MAS study, in which kappa opioid receptor antagonism showed benefit in treating anhedonia in a transdiagnostic neuropsych population. So validating that this mechanism, in fact, underlies and treats the circuitry for anhedonia. Secondly, we've got data from the navacaprant program. Obviously, our program, which we can talk about in further detail, and J&J's demonstrated efficacy with aticaprant in their phase II program. So multiple lines of clinical evidence that support this being a novel treatment target, an area where there hasn't really been much innovation over the last 30 years as monotherapy is concerned. Paul, I would just add, I think, you know, the core class is very similar to what we're seeing happen with the M4s and schizophrenia. You know, both could be the first novel mechanisms approved for the respective disorders in decades, and both have, you know, multiple different pharmacologies that have shown that this truly benefits, you know, patient and, you know, serves an unmet need. And so we're really excited about the validation behind the class and, you know, as Henry highlighted, really focused on, you know, moving forward with our phase III program. Makes sense. You know, when you guys have met with investors, and then some of those investors have talked to me and tried to bounce kinda thoughts off, you know, the main question that really everyone has is, look, depression is hard. Sometimes good, clear-cut phase II data doesn't translate. How can we have confidence in Neumora's phase II data, given that the study on an ITT basis just showed trends? And so maybe just kinda walk through the history of that trial, the work you did to really try to elucidate a clear-cut signal there, and why you're confident in phase III translatability. Sure. We are approaching phase III in a way that really is well-informed by our phase II design. Phase II was initially kicked off by BlackThorn. Neumora made some adaptations to a study that they had kicked off, looking to model FAST-MAS, in which they enrolled mild populations for depression. Neumora stepped in, introduced a design change that allowed for moderate to severe MDD patients to be enrolled, consistent with the FDA guidance in 2018, consistent with what other sponsors have studied. And in that population, you saw really favorable results in the phase II study. That is, in fact, the population we are moving forward in phase III to study, and we are utilizing the MADRS in that particular program, a scale that we think is best suited to capture the clinical pharmacology benefits of a kappa opioid receptor antagonist, with it being heavily anchored to anhedonia symptoms, where we've shown efficacy. C onsistent with that, you know, we've moved to a 6-week duration of the study that allows us to capture the efficacy benefits in a timeframe that we think is appropriate. Yeah, yeah. Yeah. Just to, maybe just to add to Bill's comments again to phase II, the ITT population in the moderate to severe, ended up being 101 patients. So very robust, for the size so, again this was not sort of a small study. It was a pre-specified endpoint, so it's not like we kinda look back at things. S o that gives us a lot of confidence, plus the, as Bill talked about, the other validation for the class, and then the changes we made for phase III to even arguably have a more responsive scale, and certainly a better endpoint to measure things. Yeah, makes sense. Do you wanna talk about your guys' dose-ranging work? How you arrived at, I think it's 80 mgs, right? And why you think it's the right approach to just go with one dose versus a range in phase III. Yeah, Paul, we chose the 80mg dose based on receptor occupancy modeling, where 80mg has been shown to provide 90% receptor occupancy at kappa opioid receptors. That's really important when we think about this as a proxy for efficacy. And in that context, the 80mg dose studied in phase II showed a strong efficacy profile with a very good tolerability profile. So the rationale to go lower than 80 just wasn't there. We didn't see any adverse event at a rate of 5% or greater in the phase II, and so 80 mg was the dose that we took forward in the design as a part of our end of phase II meeting with the FDA in May. We gained concurrence for the program and are progressing with that single dose in phase III. Keep in mind, when we think about G protein-coupled receptors and aticaprant in J&J's program, they too used a single dose, 10mg Yeah. In phase II, t hat's the single dose that's being advanced in their phase III program. From a regulatory perspective, the idea of finding the minimally effective dose you don't think is important here? We believe we have found the minimally effective dose. When you think about the phase II data- Yeah. The efficacy and no AE above 5%, there's a risk for under-treating patients. Right. Quite frankly, we believe we've optimized benefit-risk with the dose we've selected. Yeah, makes sense. Paul, as we thought about it, potentially pushing dose higher, you know, in our phase I study, you know, we looked at multiple ascending doses up to 160, single ascending dose up to 240. If we had doubled the dose from 80mg- 160 milligrams, you only really move the receptor occupancy coverage from 90% to 95%. Based on the literature that's out there for G protein-coupled receptors and what you wanna target, there's not a lot of additional efficacy benefit that we could potentially confer for going higher. And so, you know, as Bill highlighted, you know, we've, you know, talked with the agency at the end of phase II meeting and, you know, gained alignment on the path forward. Makes sense. So do you guys wanna talk a little about safety tolerability? I mean, I think the tolerability data is one thing that's really stuck out with this class and historically has made, you know, drugs big in mood disorders, to kinda put it simply. But some of the things that when we kinda compare your compound to aticaprant that we wonder about are GI side effects, things like itch. And, you know, how bothersome are these issues, and how should we think about the differentiation between the compounds in which you are more or less likely to see in as more patients are treated? So you're absolutely right, Paul. Adverse events, tolerability matter in this population. We did not, in our phase II, see troublesome side effects like sexual dysfunction and weight gain that many of the currently approved products are, are treating. Our pharmacologic profile is such that we've got 300 times greater selectivity for kappa over mu. In contrast, J&J's aticaprant is about 30 times more selective, so we've avoided mu-mediated adverse events while still being able to push the dose to gain a 90% receptor occupancy. So what that means is we didn't see side effects like diarrhea that they saw reported at a higher prevalence in their phase II program. So in that context, less than 5% were all the AEs that were most commonly reported in our phase II. A tolerability profile that in a population in their 20s, 30s, 40s, with weight gain, sexual dysfunction not being reported, matters and could result in greater adherence to product, in addition to, of course, the interest in starting therapy to begin with. Is it safe to say pruritus might be an on-target risk in some patients, given the precedent for, I think, the opposite mechanism of action in treating them? The pharmacology for pruritus, as you're suggesting, is complex. Okay. So there's a kappa-mediated component, there's a mu, as well as other pathophysiology that's implicated. So itching can be a kappa on-target mediated effect. We did see it in phase I, in our single ascending dose and multiple ascending dose at very, very low rates. Okay. These were doses at 240mg and 160 mg, but we did not see it in phase II. Right Which really speaks to the fact that we think we've optimized the dose to optimize efficacy relative to some of the tolerability safety issues. I was just gonna add, I mean, this—you of course know this, but the J&J program is an adjunctive program, whereas we- Right M onotherapy, right? Yeah. So, they're gonna still have all the sort of traditional side effects that come with whatever therapy patients are on. Whereas for us, the premise really is to bring something forward with similar efficacy, but free of that, you know, historical SSRI type. Right. So you don't inherit that baggage. You don't inherit that baggage. Yeah. So we really hope to really change the treatment paradigm, where these patients can have a therapy, you know, well-tolerated, much longer period of time, hopefully, right? Mm-hmm. Where you don't have to churn patients the way you have to now in MDD, which has been, you know, a big issue in that class. Yeah. Yeah, Henry, do you wanna talk about your decision to go monotherapy versus combo? Like I, I can totally understand the upside to monotherapy. The caveat is when we had talked to physicians during our diligence, there was a lot of enthusiasm in saying: "Hey, maybe this class could supplant the atypical antipsychotics, and, you know, having data there would be nice." So how do you kinda think about the pros and cons of your approach? Yeah, and so I think, Paul, based on our market research, you know, what we've heard from physicians is that if you're able to show monotherapy efficacy, particularly with our safety profile, they'd be comfortable using it in the adjunctive setting. The converse isn't necessarily true, because if you work in the adjunctive setting, they're not sure if the product will have, you know, the efficacy profile to work, you know, work in a monotherapy setting. And so, as we're thinking about our approach, you know, we think that the monotherapy strategy provides us with the broadest commercial opportunity. As we look post the coastal studies, you know, we may consider things such as investigator-sponsored studies or even a company-sponsored study to really look at, you know, the adjunctive setting. I think one of the really nice benefits of navacaprant, as well as the rest of our pipeline, is we have very strong IPs. We have composition of matter out until the 2040s for navacaprant and the rest of our portfolio. And so we will have the opportunity, post the phase III studies, to really explore not only additional opportunities within MDD, but also, you know, a range of other indications that we think this pharmacology could be beneficial for as well. Yeah. Okay, that's great. Well, let's talk about that, right? 'Cause I, I think your—the concept of doing bipolar is super interesting. I think one of the tricky things, right? And we always, 'cause making a call on mechanism in psych is so hard, so we always like to look at precedent and okay, like, what's the translatability from this to this? And, and MDD, the history of kind of that de-risking BPD is a little bit mixed, and there's controversy around the SSRIs. So what got you excited about the core mechanism here and optimistic that the efficacy is gonna be able to be carried over? Sure. There are multiple points of triangulation for why we think this represents a really favorable opportunity. First off, when we think about bipolar depression, we know anhedonia is a highly prevalent and a relevant clinical symptom as a part of bipolar depression. There's an increasing body of evidence that's being published upon supporting such a concept. When we think about FAST-MAS and the data that I mentioned previously, in that FAST-MAS study, there was a benefit in treating anhedonia that was demonstrated. Our own phase II data show benefit in treating MDD as well as anhedonia symptoms. So when we think about the core symptomatology in BPD, certainly there's an opportunity to show that benefit translating into this population. The rating scale assessment is also the same that would be utilized in Bipolar Depression, as is in a monotherapy major depressive disorder study, with the MADRS being the case. S o we plan to proceed in the first part of next year in kicking off that study to be able to conduct that study. To Bill's point on the anhedonia symptom, you know, we know through our phase II data as well as the FAST-MAS study, this pharmacology improves, you know, the anhedonia symptoms. Five of the ten items underscoring the MADRS are known as the anhedonia factor and particularly measure that symptom, and so we'll be using that scale in our phase III coastal studies. That's also the registrational endpoint in bipolar depression as well, so that gives us confidence that, you know, we'll be able to see read-through from the, the MDD to the bipolar depression setting. Yeah, makes sense. How do you think about the risk of mania with this mechanism in BPD? It's an important question. So does one look at BP two, BP one? Is it monotherapy? Is it adjunctive? The team spent a considerable amount of time- Right T hinking through these issues and will be well poised to speak to the details as we move into, speaking more publicly about the design, the population. But certainly, there are aspects that we've contemplated pretty heavily in looking at, the mechanism for kappa opioid receptor antagonist in this space. Okay. Okay, great. You know, maybe the last question, right, is you guys decided to do three MDD studies. You know, what was the thought process there? Well, obviously, you only need two ultimately, right? To succeed, so from our perspective, again, we have the resources and the team to execute all three. Why not, you know, buy yourself that additional, call it insurance or higher probability? It's also financially, the investment going from two to three is not going from, you know, zero to one or one to two, right? So there's a lot of synergies and, frankly, just, you know, the feedback we're getting, the enthusiasm from KOLs and sites, et cetera, makes us feel really good about executing. Yeah All three. So, and that's really how we were, we're thinking about it, and it kinda goes back to the comments of just the scale of what we're building and the scale of what we have allows us to develop these programs in the way they should be developed and not have to sort of cut any corners or not, you know, sort of fully invest in these programs. Yeah, makes sense. Yeah, Henry, you know, you reminded me of one point, and it's such a salient point, given just, you know, trial delays in, in CNS and different areas. You know, with these three they're all pretty big studies, right? And I think your timelines, right, are late next year for data and then first half 2025. Like, how confident are you in this? I mean, we're quite confident. We kicked off KOASTAL-1 right around the roadshow, right? So we were able to tell investors during the roadshow that trial was initiated, right? So we're executing against that timeline. Again, it's going well. We're getting a lot of good take-up from sites and physicians. And so look, we built the team, and I feel really good about our ability to execute. Yeah. Okay. Paul, just to add to those points, you know, in terms of running three programs, you know, MDD, particularly coming out of the pandemic, I think we all understand, is a very large population health disorder. New treatments are needed. You know, we had the team and the capital to run three. So from an investment perspective, you know, gives the program the highest probability of success, but also from a patient and social need perspective, this will give us the opportunity to really get the product to market, you know, as quickly as we possibly can. So, you know, we felt that it was important for us to really, you know, make sure that we were focused on, you know, delivering this medicine to patients as soon as we could. You know, that was also part of the discussion in terms of why do three versus two. Yeah. The geographic footprint, Paul, for the studies and such, that gives us added confidence. So we're in the U.S., we're in Latin America, Europe, and being able to enroll and execute in the manner we've described. Yeah. Okay, that's great. Any questions on MDD, or we can keep going? Do you wanna talk about... Sorry. Do you wanna talk about your muscarinic program? Absolutely. Absolutely. Yeah, no, look, we're quite excited about our M4 program. So, we have made a lot of progress on that program. Again, it's right in line with what we said on the roadshow, so we'll initiate clinical studies very early in the year. It is an M4 PAM. And so just to step back, obviously, there's Karuna with the M1, M4. You all are probably following that very closely. But our view, and we're not the only ones, obviously, with that view, but our view is that the PAMs will ultimately be, you know, a superior option for patients, both in terms of dosing, so the once daily dosing versus, you know, suboptimal dosing. And secondly, the side effect profile that you do see with the M1. So, um- W e think the PAMs will be really well positioned to do that. Now, we're behind another PAM. I seem to be coming in and out, and if you can hear me okay. So we're behind another PAM and frankly, there are some advantages to that. I mean, we have a very clear pathway in front of us in terms of the FDA. They've They've seen those programs before and us following behind and knowing exactly how to execute. So we think to Josh's earlier point, this is gonna be a huge class. And the more broadly speaking, the muscarinic will really be the first new treatment in that class for quite a long time. So I think there's a lot of upside, a lot of enthusiasm, and the commercial opportunity is quite substantial. Yeah. Yeah, and Paul, I think we've seen this play out in the schizophrenia and, you know, broader neuropsych market before. You don't necessarily have to be first to drive a large blockbuster product. We saw it play out with the atypical antipsychotics in the late 1990s, early 2000s. You know, product like Abilify, you know, launched multiple years after Zyprexa was able to achieve, you know, pretty significant commercial potential. In addition, you know, this is another program where we have very strong intellectual property, so our composition of matter patents extend into the 2040s for M4 PAM as well. So not only will we be able to fully explore the range of opportunities in schizophrenia, but, you know, other disorders as well. And so we think that sets us up really well to maximize the potential of, you know, the pharmacology that we have. Can I ask a biological question about the PAMs? There's this, there's this theoretical thing that some of the companies have brought up around PAMs when you go outside of Schizophrenia and Alzheimer's, and how Alzheimer's patients may have lower acetylcholine levels. You know, assuming that ADP is theoretically a great area for differentiation for the selective drugs that are better tolerated, how comfortable are you that the efficacy might hold up? So I think the jury's still out on how much of a role M1 will play, how much endogenous cholinergic activity is maintained, how much of the role of M4 is driving that effect versus M1. And so certainly, I think the jury's out on this. We haven't seen some of the benefit yet play out in the clinic. Yeah. Yeah, and I think, Paul, also from a biological perspective, you know, in older patients, and particularly those with Alzheimer's, there is a reduction in acetylcholine. It's not an absolute, you know, zero and so, you know, I think our view and based on the literature that we've seen, you know, there is enough, you know, acetylcholine activity, even in those populations, that a PAM, you know, should be able to confer quite significant, you know, activity as well. How are you guys? Do you wanna just talk about your program and kind of proving out proof of concept? Yeah, absolutely. And so, you know, as we stated in September when we went public, you know, we're looking to file the IND in the Q4 of this year. Henry highlighted, you know, quickly getting that into patients. You know, I think given that this is a class that the agency, as well as physicians, are comfortable with, you know, there's a clear roadmap in terms of, you know, being able to quickly move through our early healthy volunteer studies and then, you know, getting into a proof of concept in patients suffering from schizophrenia. And so, you know, as we get the IND filed and, you know, move forward, we'll start to provide more guidance. We think, you know, this is an area where, you know, having a precedent set for us will allow us to move efficiently through early stage studies and, you know, get to proof of concept, hopefully quite quickly. Are there other indications you guys think are interesting here besides schizophrenia and ADP, which is kinda widely been talked about? Sure. We have done a pretty comprehensive review of life cycle opportunities. Those are certainly amongst them, including the Alzheimer's psychosis or agitation. Bipolar mania certainly could be in that mix. We could be looking at adjunctive use to antipsychotics, and so we certainly have given it considerable consideration as it relates to company-sponsored work versus later down the road studies that we would conduct. Yeah, and, and again, just to go back to an earlier point, I mean, we have two mechanisms here that really have, a very, very long IP, and B, potential applicability across a broad range of indications. So we're thinking very hard about each individual in terms of, you know. Right W hat makes sense, but then we're also thinking together, right? Because we have that opportunity to sort of think about, is the core mechanism a little better here? Is the- Yeah M4 maybe better here. So, I mean, it gives us a lot of flexibility- Mm-hmm A gain, as we make progress in terms of designing additional indications, we'll obviously let the investment community know about that. Yeah. Okay, great. We have a few minutes left. I wanted to ask about V1aR and then ask just Henry a strategic question, but maybe just briefly on V1aR. You know, how did you arrive at agitation, and what's the development plan there? Yeah, so I think for the V1a program, you know, we've got a very, you know, potent, highly selective V1a receptor antagonist, and so we've looked at a range of different indications. We know the vasopressin system plays a role in regulating stress, as well as anxiety and, you know, agitation and aggression, and so as we looked at the range of indications, we've seen that there's other sponsors looking at indications such as autism, you know, bipolar or, sorry, PTSD- PTSD. You know, we've seen some data on irritability in Huntington's. We really felt like, given the unmet need in Alzheimer's, particularly with the agitation and the symptomatic side, that this would be a great indication for us to go forward with first. We feel like this pharmacology is purpose-built to really target some of those symptoms, you know, and we're excited about moving the program forward there. We'll be initiating that, you know, that proof of concept study in the first half of next year. It's a population that has shown to be pretty sensitive to just drug side effects in general. You know, what work have you done there to be comfortable on the therapeutic index? Sure. Well, we're in the process of completing our multiple ascending dose studies, where we've been able to push the dose. And the tolerability profile thus far looks quite favorable, and so devoid of sedation, which can be particularly problematic in this population with what we've studied thus far. So more to come. Still early days, but we're really optimistic about what the profile pharmacologically, including the AE profile, could be. Yep. Okay, great. Maybe a few questions for Henry. So, you know, you joined the company formally, right? Over the summer. You know, you have this big pipeline. You obviously have a lot of capital, but you come from a background, right, of doing deals. How do you think about balancing, expanding the pipeline, you know, versus focusing on all the different things you have to execute on right now? Yeah. No, thanks for the question. So look, we're fully focused on execution. I mean, between the three phase III studies, again, the mid-stage programs we talked about, V1a, getting M4 in the clinic. We didn't even talk about our preclinical pipeline. So CK1δ, which is our fourth asset, will be in the clinic next year as well. So very, very heavy execution year. So, yes, I noticed that there was an article about me making some comments about BD last week or 10 days ago. And yes, I have a background in BD. This company has been incredibly successful in terms of business development. That being said, the hurdle for us to bring something else in is very high. We're fully focused on execution. Again, we have the team, we have the capital, we have the ability to raise more capital if we needed to. We could do BD, but the hurdle is very high and near term- Yeah. We're fully focused on execution. Do you envision you more as a company that is independently developing all of these assets? Or might you kind of say, "Hey, look, we've got this..." Just an example, right? Like, we've been really successful in psych, and this is our area of expertise, and neurodegeneration, it's really capital intensive to get any sort of proof of concept, so maybe we want to partner. Yeah. I mean, look, we have some strategic flexibility, but, again, at this point, we're funded to do all of it. A gain, when you look at the team we have, some of our R&D leaders have experience both in psych and Neuro D. So again, our plan is to take it on board as far as we can. Yes, there's always gonna be a strategic flexibility, but there's really no plans at this point to do anything else other than executing the whole pipeline. Okay. And then, I mean, the last question is really, so we all, like, hope kappa works and all the data is super promising. If the phase IIIs didn't work there, how well funded are you and positioned are you to kind of continue to take these other assets forward to real, you know, validating readouts, right? That could be catalyst for investing further and getting more capital. Yeah. I mean, Josh will speak to the exact funding in a minute. But look, this is going back to my earlier comments. This is exactly what we talked about is it's not just all about navacaprant. Of course, we're incredibly excited about navacaprant, but this company will have the ability, without any additional financing, to achieve a lot of important catalysts that we just talked about, right? So specifically, the bipolar signal study, we'll have the V1a in phase II. We'll have M4. We'll have our own phase data, but then again, we'll have potentially the additional validation from others in that class. And so we're funded to do all of that, right? So it's not just all about just a phase three, but Josh, go, go in a little bit more detail. Yeah. So Paul, on the back of the IPO in September, you know, we ended the Q3 with approximately $520 million, you know, on the balance sheet. And so we put out public guidance that, you know, that gives us runway into 2026. T o Henry's point, you know, we have the ability to read out beyond just the MDD studies in a multiple value creating milestones with the current balance sheet that we have. So we've got a, you know, a lot that we're really excited about in terms of, you know, executing on over the next, you know, 12 and then 24 months. Yeah. Okay, great. Any last questions? All right. Good stuff, guys. Cool. Thank you very much. Appreciate it.