Good afternoon, everyone. Welcome to our Fifth Annual INI Conference. My name is Yatin Suneja. It is my pleasure to host our next presenting company, Neumora. I think this is your first sell-side conference that you are attending as a public company, so it's a pleasure to have you guys here. From the company, we have Henry Gosebruch, who's the Chief Executive Officer. We also have Josh Pinto, who's the Chief Financial Officer. Fireside chat format, but I'm gonna hand it over to Henry to maybe make some comments. Tell us about Neumora, what's happening, what are the next, you know, few milestone, and then we go into the Q&A. Great. Well, first of all, Yatin, appreciate the invitation. It's great to be here. Thank you. Look, we're very excited about the broad platform we have. One of the reasons, frankly, I joined the company over the summer, and many of us joined, is that we have a very rich set of assets and therefore, catalysts coming up. So in total, we have seven assets we're progressing. The first two of those are already well in the clinic. Obviously, the lead one is in phase III. We initiated phase III in September. We have a third asset that's about to go into the clinic, and then we have four earlier programs. The first of those will also be in the clinic next year. So that sets us up for a very nice and rich calendar of catalysts. The first one of those will be the navacaprant, so that's our phase III program. We'll have top line phase III data in the second half of this upcoming year. We will also initiate a bipolar study in the first half of the year for navacaprant. Again, as I said, we'll have the mid-stage asset move into phase II, and we have our third asset that will start the clinical program next year. Those are really just the catalysts that we can control or we are controlling. On top of that, there's, I would say, some other catalysts from other programs that are relevant around us. So J&J is pursuing phase III in a very similar mechanism at about the same time. So that'll be some read-through to us. Cerevel has emraclidine on the M4 side. They will have POC data by the end of next year as well, and given that our program looks structurally quite similar, there'll be read-through from that as well. So it really sets up a very, very rich and attractive calendar of catalysts in 2024 and certainly 2025 as we, as we go further. Very good. So maybe let's focus on navacaprant first. Obviously, you have a very selective KOR antagonist going after MDD. Can you just talk about why there is excitement around this mechanism? Not just you, I think J&J is investing significantly in it. They have big phase three program always, almost at the same time as you are, at the same stage as you are. So just curious, like, how are you looking at the pathway and what is driving the excitement? I think most importantly, it's really just the clear clinical validation that this mechanism has shown. So first of all, the government ran a broad study called FAST-MAS- Mm-hmm. with the, the J&J program, aticaprant. Then J&J replicated that same, that same study, as they ran it, and then, you know, we think most importantly, of course, over the summer, we announced our phase II data, and these were, you know, very robust studies. So we had in the MDD moderate-to-severe population, we had, 100 patients ultimately in the final, efficacy analysis. So again, these were not, you know, small phase II signal-seeking studies. These were all three very robust, very broad, you know, very multi-center, clinical studies. So in addition to all the excellent, preclinical validation and sort of general, academic validation of the target, you now have three clinical studies that really, show what this mechanism can do, and therefore, it's no surprise to us that we'll see other players come into it. Now, to get the chemistry, as potent as we have it, will be a challenge. So I'm happy to talk about that some more, but some of the players around us, we don't see them having the same, selectivity and potency, that navacaprant has. Yeah. But it just shows you the excitement around the mechanism that you'll see, you know, you'll see others come in and try to replicate that. Got it. Yeah, yeah, Yatin, I would just add, you know, when we did our market research with physicians, this could be one of the first novel mechanisms approved in the MDD space in decades. So I think from a physician perspective, there's really a lot of excitement growing in terms of having a therapeutic that works in a differentiated fashion. I think it's viewed very similar to how the muscarinics are really revolutionizing the treatment of schizophrenia as the potential first novel mechanism approved in that space, you know, in decades. And so, you know, I think the cores are very much analogous to that in the depression population. I think coming out of the pandemic, you know, everyone, I think, is quite aware of just how prevalent, you know, major depressive disorder is. Got it. Could you then now touch a little bit on the challenges that we have seen with the, you know, prior KOR inhibitors, and then you just were touching a little bit on the chemistry. Would love to understand how you reached the selectivity that you have designed. How is that differentiated relative to J&J's? Mm-hmm. Yeah, and so, you know, I think there's been a lot of interest academically in the kappa-opioid receptor as a target for major depressive- for major depression for a, you know, a long period of time now. I think a lot of the prior attempts were not really selective from a chemistry perspective. Mm-hmm. And so, you know, they didn't have the selectivity that we have or even that J&J has with their aticaprant program. Some of the prior, you know, efforts also had mu agonist properties, which we all know can be problematic, you know, just from an abuse liability and scheduling perspective. So I think what we're really seeing now is the first wave of highly selective kappa-opioid receptor antagonists that are really hitting that late-stage development and garnering the interest from physicians. As Henry highlighted, you know, we believe we have the best-in-class kappa-opioid receptor antagonist, with 300-fold selectivity for the kappa-opioid receptor over the mu-opioid receptor. And we think that that's really driving, you know, some of the key differentiation that we're seeing play out clinically, you know, in our molecule. And that's really the key point. I mean, we're really happy with the chemistry, but the point is it's now actually proven out clinically. So you look at the phase II study, we had really a very, very clean safety profile while we had very, very strong efficacy. And again, we think that's due to the profile we just talked about. But my point is, it's actually now really played out, and you can look at the safety profile in phase II to have a sense of that. You don't see the GI type of side effects that, you know, you might otherwise see if you're hitting the mu receptor to some degree. Mm-hmm. We didn't see that. We had, we had a really nice, nice profile. Got it. So not only you are selective, but I think your development strategy is also different from J&J. You guys are going after mono. They're going after adjunctive. Why? Well, we're going after mono because, A, we're able to. And I think from our perspective, you really would want to go after it if you had the chemistry that positions you to do that. And why would you do that? Well, because it's a much larger market. And think about the current choices for physicians and patients in MDD are really, you know, far from optimal. So, you're gonna be on, you know, an older line generic. You're gonna have maybe you get some efficacy, but you will certainly have a fair bit on the AE side. So whether it's tolerability, whether it's weight gain, whether it's sexual dysfunction. And so what does that mean? Well, you'll see a lot of, unfortunately, in this population, you see a lot of churning of medicines, right? You stay on some therapy for some period of time, then, you know, you have some problem. You go to the next one, you go to the next one. Well, when you come in with a medicine that, you know, we plan to launch, i.e., you know, good efficacy, but a very clean safety profile, we think that's a huge opportunity. Going the adjunctive route, again, you're gonna be stuck still with that safety package, right? And so we think going novel is a much, much bigger opportunity. And by the way, doctors will probably end up using it. I mean, we're obviously, we're gonna be careful, and we may do some additional work in the adjunctive setting, but once you're validated as a monotherapy, you'll probably get adjunctive use as well. Mm-hmm. The reverse isn't really, isn't really true. Got it. And then the key area where the safety... I mean, yes, your safety is just squeaky clean, very clean. And then the main thing that maybe the J&J molecule had is more on the pruritus side or anything else? Pruritus and some GI, if you look at it, a 10% diarrhea. Yeah, and those are on target, you know, mu agonist or antagonist associated side effects. So it's not surprising, you know, with the selectivity profile that we have, that we haven't necessarily seen, you know, a lot of those mu-associated elements. The other piece behind it is, you know, given our selectivity profile, we've been able to really, you know, optimize the dose. And so we're, you know, moving forward with an 80 mg dose. That 80 mg dose is able to achieve 90% receptor occupancy coverage over a 24-hour period. We have to remember that kappa opioid receptor, G protein-coupled receptors, and so really to confer efficacy, it's well known in the GPCR class that receptor occupancy is critical. And so, you know, we feel like we've optimized the dose that we're moving forward with clinically as well. Got it. So one of the things. So the question is regarding the signal or the efficacy that you show in that moderate to severe, because I think that's the patient population you are studying in, in phase three, right? The KOASTAL program. Is there a biological reason that the drug which should behave better in moderate to severe, or it just in general, most of the drugs behave better in more severe patients? So, you know, Yatin, I think if you actually look at the data, you know, in the total population, including milder patients, we actually that we put out in the press release this summer, we actually did show a benefit, you know, in the total population. I think from a development strategy perspective, you know, the FDA's guided with their 2018 MDD guidance document, you know, to study moderate to severe patients. That's what a lot of other sponsors have done, and so that's what, you know, we're gonna do. That'll ultimately, you know, should enable, you know, the broad, broad label. You know, but we ultimately think that given the pharmacology, not only... The benefits, not only in treating depressive symptoms, but also anhedonia, coupled with the side effect profile, that, you know, this product will be viable for all patients, regardless of severity. From a clinical trial perspective, you know, we're focusing on the classically studied moderate to severe population. Got it. Josh, you just talked about anhedonia. I think that's one thing, it's a big issue for MDD patient population. Mm-hmm. So can you just talk about this mechanism in general as it relates to anhedonia? I think even in that phase two study that you ran, the SHAPS, you did show a nice separation. And how are you capturing it? What is the clinical significance and the commercial implications of it? Yeah, absolutely. And so, Yatin, to your point, you know, anhedonia is a big underlying core symptom of major depressive disorder. And so when patients with MDD present to physicians, not only do they have the core depressive symptoms, but upwards of 70% of patients also have pronounced anhedonia. It's not a symptom that any of the currently approved agents are known to treat, and so it's really a core unmet need within the MDD market as it sits there today. The reason that the kappa-opioid receptor antagonists, you know, are viewed as being a novel class, is it's the first agents that are designed to directly treat the anhedonia symptoms, and that's due to the tie you know the kappa dynorphin system being tied together. As you highlighted in our phase II, we showed a very robust signal in SHAPS. That's one of the, you know, well-validated classical measures of anhedonia, and we have the SHAPS as a key secondary endpoint in our phase III studies, that we ultimately think, you know, will, you know, allow us to, you know, really, you know, show that benefit as we move into the pivotal studies. Got it. With regard to the KOASTAL program—one study is up and running, right? What about the next two, the timeline, you said second half, what would you like to show in those—in at least the first readout? Yeah. So as you said, we are running three identically designed phase III studies. The first one initiated in September, the other two will initiate, you know, very soon. So all three will be, you know, fully up and running and enrolling by early next year. At the end of the day, we only need two of those to succeed. So you may ask why we're running three. Well, we're running three because, frankly, we have the backing and the resources to run three. There's some good operational synergy, and so from our point of view, it's just prudent to run three of them. We expect all three to be positive. And again, the first one of these, KOASTAL-1, will have a top line down in the second half of 2024, and you'll see the other two coming in thereafter. So by early 2025, we'll have all three of them readout. Got it. You know, these MDD studies are particularly notorious when it comes to placebo. Like, we have seen many studies not performing well. What are you doing to make sure that the placebo is kept in check in these studies? Yeah, I'll start off, and I'll have Josh add to mine as well. I mean, that's really been a core focus by us as a team to really study all the various execution tactics that will minimize placebo response. So first, it starts with the sites. So getting the highest quality sites on board, and again, here, it's very helpful that we had 40 sites in our phase II study, so it wasn't like two or three sites, it was 40 sites. So we have a pretty robust universe there that we can pick the best sites from. In addition to that, obviously, we looked at where other folks have run studies, what our CROs experience has been. So having the right sites is number one. Number two is, who are the right subjects to actually go into the studies, right? So a whole bunch of tactics on those. You know, one is central raters. So we've seen in some other studies that some sites perhaps might lean to inflate baseline scores, right? They wanna. They're excited about the study, they want to get, you know, patients into the study. Well, we're independently assessing each subject coming into the study to make sure that they truly are a 25 moderate or greater. So we want the right, you know, severity to go into the study. We've invested in internal resources to do additional monitoring. Again, the sites are doing, obviously, their screens, initially, while we have a whole team that will look at that, and we'll just make sure that they truly have the kind of profile that we think is the most interesting, and the highest likelihood. And then I would say, on top of all of that, we've also, we've redesigned the phase III relative to the phase II, where we're looking at a six-week endpoint. And the FDA, to Josh's point earlier on, the guidance has very clearly said, "Look, you can do six weeks or eight weeks, in that range." We think six weeks is optimal. You know, the longer you have, you know, medical intervention, the more likelihood probably exists that there's some response, even if you're at placebo. So going with six weeks, we think, is another technique to make sure we optimize, we optimize that. But look, it's a huge topic of discussion and analysis, and I'm sure there's other things that I've just missed that Josh can cover. Yeah, no, Henry, I think you hit a lot of the key points that we're gonna do in phase III. I think the other thing to remind folks of is we ran a very robust phase II. We ran it at 40 sites in the U.S., we enrolled 204 patients. And so as you think about translating the effect size from a phase II to phase III, you know, we feel like operationally, the phase III's are very similar to the phase II's in terms of size and scope, and so, you know, we should be able to see, you know, a robust, you know, effect size in phase III's. We've also made, in addition to the things that Henry has highlighted on the placebo mitigation, a couple other key, you know, amendments to really look at maximizing the benefit of this drug. So we've changed from using the HAMD-17 as the primary endpoint in phase II, to using the MADRS as the primary endpoint in phase III. Both of those are the two, you know, registrational endpoints accepted by the FDA. J&J used the MADRS in their phase II study for aticaprant, which showed a robust effect. We feel like with this pharmacology, the MADRS is really set up to show maximum benefit. And so, you know, five of the 10 items on the MADRS scale are known as the anhedonia factor, and given our product is specifically designed to treat anhedonia, we think that, you know, changing from HAMD-17 to MADRS should be able to, you know, even potentially, you know, improve our effect size. And so, you know, just wanted to highlight that, you know, we've made key structural shifts, but the Phase II was a very robust Phase II study. And again, just to underscore, I mean, efficacy obviously is important, but this is not a game of chasing efficacy, right? The key with ours is we'll have very good efficacy. We're not worried about that, but it's coming with that very clean safety. That's the key difference, right? So, there just isn't any program that can have that same, that same profile of very good efficacy, a new mechanism, a novel mechanism that people are excited about, but then coming with this very clean safety that will just set us up commercially in an optimal manner. Just think about all this churning that happens now in this population, given safety, right? So when you come with a clean safety profile, we think in terms of compliance adherence, it's a whole different game, and really that's why, back to your earlier question, I think that's why there's so much excitement about the KOR mechanism as a new class. Got it. Maybe final question on the MDD side, how do you see the commercial positioning? I mean, obviously, a lot of stuff is generic, so I'm just curious, is it like frontline, or if you take a couple of generic and then you start on a new mechanism? How are you thinking? Yeah, and so, Yatin, on the back of the phase II data, we did, you know, robust market research, you know, with a third-party group, L.E.K. You know, I think, you know, in working with both physicians and payers, I think they really understood the differentiated features of navacaprant as a product. And so physicians are really excited by the fact that it could be the first novel mechanism approved in decades, as we highlighted earlier. It's a very simple once-daily oral dosing profile. In these large population health markets, where compliance has been challenging historically, that simple profile, you know, tested really well. Also, the safety profile, to Henry's point, is a key driver. As we know in the major depressive disorder market, the biggest driver of patients electing to not go on pharmacological therapy is the poor side effect profile of the existing agents. Most of these patients are early adults in their twenties, thirties, and forties. Things such as weight gain, sexual dysfunction, nausea, dizziness that, you know, are associated with the existing agents are just really not palatable. So in addition to those, also the broad efficacy that we show. We talked about it earlier in terms of, you know, benefiting anhedonia. As you look at the three core symptoms that patients with major depressive disorder present with, it's core depressive symptoms, it's anhedonia and anxiety. We showed a benefit in all three symptoms in our phase two study, and we'll be looking to that in phase three. I think from a payer perspective as well, they appreciate the fact that this is a differentiated product in terms of novel mechanism of action, having a differentiated safety as well as efficacy profile. So commercially, you know, I think our view is that, you know, this should get a lot of significant uptake. You know, and it won't, you know, there will be some first-line use, and then, you know, it'll really be used second line, second line and beyond. Got it. it. Got it. Yeah. And keep in mind, we have, you know, exquisite intellectual property on that asset because, again, it was a novel program, and so we'll have into the early forties in terms of commercial runway, and again, that is very, very differentiated and will help us really on the commercial side to build, you know, a very, very large opportunity and to roll these other indications, of which bipolar will be the first one, but there'll be others coming after, and we'll have plenty of time to fully- Got it. fully pursue all that. Got it. Maybe quickly on bipolar, how strong is the rationale in bipolar? So there's a very strong rationale in bipolar. It's very similar to MDD, and so as you think about the patients within bipolar that have bipolar depression, you know, there's a growing body of literature that highlights anhedonia is just as prevalent a symptom in bipolar depression as it is in major depressive disorder. And so given that this pharmacology is known to specifically treat depressive symptoms as well as anhedonia, and it's been proven out by our phase II data, by J&J's phase II aticaprant, as well as the NIMH-sponsored FAST-MAS study, you know, we think there's very strong rationale. So I highlighted earlier as well, the phase III registrational endpoint in MDD is the MADRS scale. Five of the 10 items on the MADRS scale are really used to assess anhedonia. MADRS is also the registrational endpoint in bipolar depression, and so we think there's going to be significant read-through as you look at the MDD opportunity and the bipolar depression opportunity. Got it. Very good. Then moving to the other programs, right? The M4 program that you have. I mean, it's a crowded space, right? You have three companies that are farther along. Even Neurocrine has, like, couple of the programs. So how are you going to differentiate, and what is your view on that market, as it evolve? Well, first of all, it's a very, very large market, and in terms of where we sit in that market, I mean, yes, Karuna is there first with their M1, M4. So very different, you know, very different proposition. Our belief is that the PAMs really will dominate this market going forward, and there's really just the two in town, so it's emraclidine, and then it's ours. So we're, you know, we're right on the heels of emraclidine, and at the end of the day, look, this could be a $20-$25 billion market. And so do I think we'll have some differentiation that will emerge in the clinical program? We might, but the market is so large that we'll have a big opportunity, even if we're not as differentiated from emraclidine as I expect. But back to the main point, we think the PAMs will really take over this class. Why do I think that? Well, again, it's a combination of safety and, frankly, convenience. So we'll have daily dosing, once-a-day dosing, right? And schizophrenia, even more so than the MDD population, adherence and compliance are very big issues in this market. So with, you know, a once daily, I think there's a big opportunity to take that market. And so honestly, we don't worry that much about the other M1 and M4 programs. In fact, some of them, this team has seen our, you know, our folks at our prior companies and in some cases have dismissed because we thought the PAMs are really what will take over this market. Yatin, just to add to that, you know, we've seen it play out with the atypical antipsychotics. You know, these are population health disorder markets. You don't have to be first to win commercially. You know, if you look at, for example, Abilify, with a... which a couple of our team members were involved with back at Bristol, you know, it launched seven years after Zyprexa ultimately achieved, you know, very significant peak commercial sales. We've even seen, you know, the recent launch of, you know, products that have pharmacology similar to atypicals, whether Vraylar from AbbVie, that's, you know, guiding towards $6 billion in peak sales.... you know, or Caplyta from Intra-Cellular. You know, these markets are just so large, and there's so much cycling, to the points Henry raised earlier, that you don't necessarily have to be first to ultimately, you know, drive, you know, very large, you know... Yes - commercial uptake. Could your development strategy be different for M4? Rather than going into schizophrenia, you probably go in psychosis, Alzheimer's first, because they are... You know, everybody's just running the study now, a little bit less- Well, we think schizophrenia is first, just again, given that it's a huge class, and again, we think we're actually really well-positioned competitively. So as we look at it, we're really number two in that market. So will there be other indications? Absolutely. I mean, much like navacaprant, this is sort of a pipeline in a molecule. Again, much like navacaprant, we have intellectual property protection, and by the way, this is composition of matter. This is not method of use- Yeah. Out to the early 2040s. So we'll have plenty of time to think through other indications. And just like with navacaprant, you'll see us as we move forward into 2024 and 2025; you'll see us do other indications in parallel with schizophrenia. And again, to have both of these under one roof and not to mention the five others that I'm sure we don't have enough time to talk about is just a great, great place to be. Got it. So IND, sort of in the next few months or so, right? The clearance for that. Yeah, Q4 of this year, and then we'll be in the clinic early in 2024. 2024. Okay. Anything on 511 you want to mention? Also a very interesting asset, going after agitation. Yeah. It's a big, big area. Yeah, absolutely. And so we think that Our program, NMRA-511, you know, is really purpose-built to, you know, treat not only agitation and aggression, but anxiety. We all know the vasopressin system is critical in regulating stress response, anxiety, as well as agitation. We have a very potent and selective V1a receptor antagonist. And so as you look at the Alzheimer's market, you know, there's been a lot of advancements in terms of disease modification, but the underlying symptoms of the disease are still very prevalent. Upwards of 70% of patients have agitation and aggression, and we feel like this pharmacology is purpose-built to go after that. And so we will be kicking off a proof of concept study in the first half of next year with our 511 program in patients with Alzheimer's agitation. Yeah, and much like with our others, again, given how interesting this mechanism is, we're not, you know, we're not the only ones on this particular one. Yeah. Roche is also in Phase II studies, and again, we think we have a better chemistry, a better asset. But again, these are somewhat validated by the fact that others have noticed those same potential for this class. And similar to our other programs, Yatin, we have composition of Matter IP into the 2040s for 511 as well. That's a common theme across our entire portfolio. As this was constructed over the last four years, we were very diligent in terms of not only understanding the scientific and clinical rationale behind each of the programs, but making sure that we had, you know, a very strong IP position, so that we could really look to maximize these brands as they, you know, transition from clinical development into commercial products. Okay, maybe final question: How are the financials? Obviously, it's a lot going on from a spend perspective, with how well positioned you are. Seven assets you have, do you room to bring in more or just focus on these? Yeah, so in terms of the financial position, after completing the IPO in September, we're in a great position. We ended the third quarter with approximately $520 million in cash and, you know, cash equivalents on the balance sheet. That gives us runway into 2026. You know, as we've built the company, we've really focused on targeting our investments, and so we've been very strategic in terms of how we've built the underlying headcount of the company and are really focused on deploying the cash towards, you know, clinical studies as well as some of the research capabilities. So we feel like, Yatin, we're in a very strong cash position, not only to deliver phase III data and ultimately file the NDA for navacaprant in MDD, but also deliver proof of concept for navacaprant in bipolar depression, deliver proof of concept for 511 in Alzheimer's agitation, and ultimately to deliver, you know, proof of concept for our M4 PAM program, as well as then get some of our earlier stage programs into the clinic. So you know, really solid cash position and, you know, that enables us to have, you know, a very compelling, you know, 12-24 months ahead. Very, very busy 12-24 months indeed. Thank you so much. Great. That's all I have. Yeah. Thanks again. Thank you. Very good. Thank you.