Good afternoon, everyone. Welcome to Guggenheim Emerging Outlook Biotech Summit 2026. It is my pleasure to welcome our next presenting company, Neumora Therapeutics. Myself, Yatin Suneja, I'm one of the biotech analysts here at the firm. I'm joined here, with my colleague Dalma Khayati. We will be moderating the discussion here from the company. We have a few executives here. We have, Josh Pinto, who's the President. We have Nick Brandon, Chief Scientific Officer. And then we also have Helen Rubinstein, who is the IR and on the corporate strategy side. Josh, I think you have a few slides that you wanna run through some new data that you announced, this morning. Why don't you do that, maybe take, you know, eight, 10 minutes, and then we'll go into the Q&A, and we'll start with the new stuff first then. Yeah, absolutely. Thanks, Yatin, for having us today. As you mentioned, before we dig into the fireside chat, you know, I'm pleased to present some additional data we have that we previously released this morning from our phase I-B signal-seeking study for NMRA-511 in Alzheimer's disease agitation. Just a quick note that I'll be making some forward-looking statements during today's presentation. Just as a reminder, last month we reported data from the phase I-B study of NMRA-511 showing a clinical signal effect that suggests 511 has a potential as a next-generation treatment for Alzheimer's disease agitation. The goal of the phase I-B study was to understand the effect size of NMRA-511 in AD agitation, which it achieved that goal. In the study, NMRA-511 demonstrated a compelling clinical effect relative to what we've seen out of other programs in AD agitation, such as REXULTI and AUVELITY, on the CMAI total score. These effect sizes were achieved with a favorable safety and tolerability profile, which we believe leaves room for us to test higher doses, which we're gonna plan to do in 2026. As we further analyze the data from the phase I-B study, we've continued to see highly consistent results on additional scales, including the CGI-S and the NPI, and I'm pleased to share that data with you guys today. Before I dig in, I'll quickly remind you that this was a two-part signal-seeking study that was not powered to detect statistical significance. Instead, we used the study to evaluate the effect size of NMRA-511 to inform additional development in the AD agitation population moving forward. We also prespecified an analysis of patients with elevated anxiety at baseline because anxiety is a highly relevant clinical symptom within AD agitation, and it ties with the mechanistic rationale of NMRA-511. Here we have the baseline demographics and characteristics for the study. On the left-hand side of the page, you see the total population, which is generally balanced, except for the RAID score, which favors placebo. If the baseline RAID scores were balanced, we think that could even drive a higher clinical treatment effect in the total population, and this will be an element we'll look to balance and stratify in future studies. On the right-hand side of the page, we have the baseline characteristics for the elevated anxiety population. I'd note the characteristics here are generally balanced. The CMAI score at baseline is consistent with that of the total population, so despite the fact that we're enriching and elevating anxiety, we're not changing the agitation profile across the disease. The baseline RAID score in this was balanced between placebo and active. I'll just note that in this study, we did not enrich for baseline NPI agitation and aggression score of four or greater, which we've seen other sponsors like REXULTI and AUVELITY do in their pivotal studies. In the prespecified analysis of patients with elevated anxiety at baseline, NMRA-511 demonstrated an unsurpassed effect size with a 20.1-point reduction on the CMAI total score at week eight, representing a Cohen's d effect size range of 0.51-0.64. The CMAI subscore for the elevated anxiety populations are on the right, and in particular, the CMAI aggression subfactor score had a very robust effect with a Cohen's d effect size of 0.82. Additionally, we know from other sponsors that the FDA has been particularly interested in the CMAI subscale data, and so we're pleased to share that we see similar findings with NMRA-511 to those shared by other sponsors. Turning to the new data that we're pleased to share today, this slide shows the CGI-S agitation score, which is a clinician-rated scale used to assess the severity of agitation. You can see on the slide that NMRA-511 drove a compelling reduction across time points in the prespecified elevated anxiety population, with a clinical effect size of 0.78 at week six and 0.38 at week eight, which all while continuing to accrue clinical benefit. These data are in line and consistent with the CMAI total score and CMAI subfactor scores data we showed last month and support the potential of NMRA-511 in terms of reducing agitation. Turning to NPI agitation aggression scale, this is a tool used to measure dementia-related behavioral symptoms and overall caregiver distress. As you can see, in the prespecified elevated anxiety population, NMRA-511 drove compelling effect sizes of approximately 0.46 at week eight. This scale is particularly important when considering the treatment goal of delaying time to institutionalize care for patients. Additionally, it's encouraging to see that these data, with the CGI-S agitation and the NPI agitation and aggression score, which are so highly concordant with the findings we had shared previously. The consistency between these scales helps to give conviction in the strong clinical effect that we've observed in the phase I-B study and supports our plan for future development. As we noted last month, NMRA-511 has a favorable safety and tolerability profile and, as I mentioned, support testing a higher dose, which we are gonna do this year in a MAD extension before moving into pivotal studies in 2027. And so to, to summarize on this slide, we've compared the efficacy data across NMRA-511, REXULTI, and AUVELITY in AD agitation. And what we've clearly seen here is that NMRA-511 has shown an unsurpassed efficacy and safety profile, and we believe a drug with this profile would provide a compelling benefit-risk profile for patients and be highly differentiated versus the other Alzheimer's disease agitated treatment options. We have three next steps that we're gonna undertake with this program here at Neumora. First, we plan to initiate and complete a MAD extension cohort of NMRA-511 testing a higher dose in 2026. We plan to transition the current BID formulation into a QD extended-release formulation that will move into the pivotal studies. Ultimately, that'll add more IP runway, taking our composition of matter loss of exclusivity from estimated to be 2046 to our final loss of exclusivity be, sorry, 2042, to final loss of exclusivity being 2046. And then we plan to initiate a pivotal phase II/III program in 2027. And so with that, you know, Yatin, I'll conclude the presentation, and we can move on to the next slide. Yeah, let's keep this, yeah, let's keep this slide on. Thank you. Thank you for that. Very good and consistent data across all these endpoints. So the question is, obviously there is a difference that we are seeing in anxiety population versus the total population. Mechanistically, what is driving it, and is there what fraction of these patients have elevated anxiety, and is there a way to design a study for that patient population? Yeah, so maybe I'll hit on it at the second part first, and I'll turn over to Nick to walk through the mechanistic rationale. So we've been doing a lot of market research, and what we've really found out is that the anxiety and agitation seem to be part of an overlapping symptomatic domain and really based on progression. We see the anxiety presenting early on in the disease and then that manifesting into the aggression and agitation. In terms of the epidemiology, we know that about 60%-70% of patients with Alzheimer's disease have agitation. Some of the market research that we've done suggests that upwards of 60%-70% of patients with Alzheimer's disease also have anxiety, and we believe that there's pretty consistent overlap amongst those. And so, Yatin, as we ultimately think about the epidemiology, we think that the anxiety and the aggression are more of an intertwined symptom that just manifests in different behaviors as the disease progresses. And so we think ultimately it is still a very large proportion of the market, and we think that's gonna give us the opportunity to, think about ways to enrich, whether formally or in nuanced ways, in our pivotal studies to get the right patients. And we know that both REXULTI and AUVELITY use different elements and scales to enrich in their studies, so we think that there will ultimately be openness to it. But Nick, maybe you can talk about just why anxiety with this mechanism. Yeah, no, I'll just talk a little bit about the sort of fundamental rationale, really, and also around V1a and vasopressin and, and anxiety and agitation, but also clearly why we prespecified the higher anxiety population. If you look in the literature, there is an overwhelming body of data preclinically that vasopressin and V1a regulate stress and, and anxiety across classical models, and that's, you know and some of our own data supports that. And then you look in the clinical data, so there's data in healthy volunteers where the vasopressin system's been perturbed. Like, you can intranasally dose vasopressin. You see increases in behaviors linked to stress and anxiety, which you can reduce with a V1a antagonist. And then there's the, you know, there's data, in clinical conditions where clearly, again, a V1a antagonist impacts anxiety and, and also importantly, aggression. So it's clear why we had that subcut prespecified, but also the impact on aggression is really why we, you know, one of the main reasons why we went into agitation in Alzheimer's disease is because of the, you know, aggression being such a key part of that. Got it. So in terms of the immediate next step, it's the MAD cohort, right, that you want to complete. But based on your PK, are you leaving efficacy on the table? Are you if you go on higher doses, is there more room to improve? Just curious where you are on the target engagement at the current doses. Yeah, and so in terms of what we'd previously disclosed, with V1a, there is no ligand for to run formal PET receptor occupancy studies in humans, so all the receptor occupancy is based on modeled work. So what we did see in the MAD studies, we were still seeing a progression of PK as we dosed from 20 up to 40. You know, we did our modeling work did suggest that we would have 98%-ish receptor occupancy at those levels, but it is still just a model. We think if we can push the dose substantially higher, we should be able to accrue more of a PK benefit, which should translate into more central target engagement. We just don't know, you know, kind of quantitatively exactly how much. No, exactly. And we have the safety margins, to be able to do that, so. When is that data coming from MAD cohort? We have not started the MAD cohort yet. We plan to kick it off and complete it this year. Okay, and then you'll go to the FDA after the MAD is done to sort of figure out the pivotal plan, whether you wanna enrich it or just go into that? Correct, yeah, and then we'll look at which doses we'll move forward to propose to the agency for the pivotal. Got it. And if we just zoom out and look at the landscape for this particular mechanism, who else is there? Is it just your program, or are there other competitors? Yeah, yeah, so currently, there is an ongoing study by a company called Newleos. So they in-licensed a Roche asset, and they're looking at social anxiety, and then they issued a press release earlier this year that's the other recent activity we've seen is a company who've been in this field for a long time, Azevan. They're on clinicaltrials.gov. We noted just a couple of weeks ago they're gonna initiate a study in Huntington's, in Fragile X, enriching, though, for patients with more aggression. So quite an interesting link to the work we're doing here. Okay, final question. And as the safety looked pretty good. There was maybe just a little bit of a finding on hyponatremia. Any clinical significance of that as you go higher on the dose? Nothing that we've seen from a safety and tolerability perspective. Yatin, if we go back and look at it, as you can see, typically within CNS studies, you'd look at things like headache. We see five cases of headache on placebo, two on active, so there's nothing really we've seen. And frankly, the one SAE for hyponatremia that we did see, we believe there was a number of confounding factors. It was an elderly, female who had just taken study drug after being on drug for weeks with no challenges, cleaned the house with bleach, ultimately felt dizzy, taken to the hospital. There was some confounding urinary tract challenge that we know can cause confusion and dizziness. Ultimately it was noted as, you know, potentially related to studied drug, but we think there's a lot of confounding factors, and the hyponatremia is not necessarily something that is mechanistic or drug-related. All right, very good. Dalma, you wanted to address the NLRP3. Yeah, maybe moving to obesity program. Of course, a lot of interest from investors there. And just zooming out to the class, maybe Nick, can you elucidate what do we know about the involvement of an NLRP3 in obesity? And what's more important, the regulation, the peripheral regulation of inflammation, or the central hypothalamic regulation of appetite to induce weight loss? Yeah, sure. So maybe we can sort of fully get both of your questions there. You know, our position on this is that for NLRP3 inhibition to drive weight loss and again, a lot of that information is coming from the preclinical models right now. You need to have high levels of NLRP3 inhibition, we believe IC90 levels, over the course of 24 hours in the brain. And in particular, the emphasis has been on in the hypothalamus, which would, you know, we believe regulates the, you know, critical feeding circuitry, regulating food intake. So for us, we think about that central inhibition with the weight loss. But then there's obviously the peripheral components, so whether that's inhibition in the liver, in the vasculature elsewhere, which could be delivering some of the clinical data we're seeing today, particularly on some of the cardiovascular, you know, biomarkers such as hsCRP, also IL-6, and others. So we really see it as that peripheral component and then the CNS component where you do need those high IC90 levels. When you look at then the class of compounds, we truly feel that the peripheral effects most compounds we've seen today, you know, which Ventyx, BioAge, others are clearly having that peripheral effect. Whether they're able to drive those high IC90 levels, I think that's a TBD. That's why with our program, you know, NMRA-215, that was optimized around CNS penetration originally for neurodegenerative disorders, but we obviously made the reprioritization to obesity as the data started to emerge. And maybe following up on that point, as you were saying, we have seen, like, disappointing mixed data in the clinics with other sponsored compounds. So what really differentiates yours from theirs and gives you confidence that you can fill the translational gap? Yeah, yeah, now when you look at the basic properties of the compounds across that class, I think around potency, selectivity, they all look good and written quite similar. Where we see a clear differentiation is around measurements of brain penetration and also durable brain penetration. So there's, for example, a measure of the Kpuu, which measures, you know, free drug in brain compared to plasma. 215 does, from our perspective and data we've seen from other sponsors, seem to stand out. Also things like permeability. And also, one example, you know, there is a risk of drugs being effluxed from the brain. PGP is the classic mechanism for that. We clearly have no risk there. We don't have data on all of the other compounds. We know, though, for 215, highly permeable, low risk of PGP efflux. You know, other measures, you know, we've done a lot of work preclinically really trying to firm up our, CNS penetration data so I feel very confident about, you know, our statements there. Yeah, and then Dalma, just on your second question on what gives us confidence that it'll translate in the clinic, as we know, the DIO model is probably one of the most translatable preclinical models into clinical effects. We've seen Nature publications that have correlated, you know, it being as high as 0.9. We've seen the Incretins translate, Amylins, older classes, you know, serotonergic mechanisms, Lacasterin. We've seen novel things such as WAVE's mechanism translate. So we've seen the predominance of mechanisms translate. I think what we're just waiting for in the NLRP3 inhibitor is a highly CNS-penetrant one to come forward and test the hypothesis in the clinic. Got it. And maybe when we think to your next readout in the third quarter, so you will show some biomarker data, what shall we expect there, and will we get more conviction about the translatability for weight loss? Yeah, I think in terms of biomarkers, what we're gonna look to initially show is gonna be, one, that we can target IC90 coverage in the brain. And I think that's gonna be important 'cause that's really the underlying thesis behind how do you drive weight loss with an NLRP3 inhibitor. So I think that'll be critical 'cause without that link, it's hard to see a path towards weight loss based on the preclinical evidence. We'll also look at some of the cardioprotective biomarkers such as CRP and some others. And so when we bring 215 into the clinic, which, you know, our last guidance was first half of this year, we'll provide more details on this study and exactly what to expect throughout, you know, the rest of the year. Got it. And can we expect an update on newly possible indications since you will show also cardiovascular biomarkers? Yeah, I think as we bring the program into the clinic, we'll probably highlight some of the range of indications we could bring it into. We obviously aren't gonna be able to tackle everything with the first in-human study, but as we've seen, sponsors have taken these compounds into a range of indications, you know, even, you know, things beyond kind of classic cardiovascular obesity that we've seen recently. Yeah. The cardiovascular part has attracted, of course, a lot of interest from pharma. What are your thoughts about the recent acquisition of Ventyx by Lilly and how that affects, you know, the perceived value of your compound? Yeah, so I think what's becoming apparent to us is that the cardioprotective benefits are really, as Nick highlighted, being driven through peripheral engagement and inhibition of NLRP3. And we think that that signals it's clearly a class effect. Ventyx was the first company to really highlight this data. We've seen BioAge and others come through. And so we think what the acquisition does is it's clearly put the marker out there for what a cardioprotective NLRP3 inhibitor with initial clinical data could generate. But if you're able to push this beyond and drive weight loss, you could get, you know, much more robust effects. We've all seen kind of where companies are trading that have generated initial oral weight loss data. And so I think you can think about kind of the spectrum in terms of, you know, where, you know, 215 could take us. That makes a lot of sense. Thinking about commercial positioning there versus, you know, the GLP-1s and competitive landscape. Yep, absolutely. And so I think our data that we've put out thus far highlights really a broad set of opportunities for this product to be used commercially. I think by the time we get to the market, which is likely gonna be in the early 2030s, the GLP-1s will be fairly well-established as the backbone therapy. And so I think where we can have an immediate impact is gonna be in the combination setting. And we highlighted at our R&D Day in October, we can clearly have an additive benefit on top of a GLP-1 and drive more weight loss, or we can work in an incretin-sparing paradigm where you can dial back the dose of an incretin to remove some of the GIAEs and still accrue a compelling weight loss benefit. Then I think we have highlighted we're gonna come out with 12-week DIO data, likely in the first quarter here. What we're gonna be looking for in that paradigm is ultimately a maintenance setting. Can you switch from being on a stable, maintained weight loss on a GLP-1 over to an NLRP3, effectively switching out the GIAEs while maintaining the weight loss? We think that could be a very powerful paradigm as you think about commercial applications. Ultimately, I think once physicians get comfortable with the mechanism, we could start to see some monotherapy uptake. These maintenance and combo paradigms will be very important initially. We've already been able to demonstrate some very compelling combination data in the DIO study. Well, I have one question here. So obviously, on the cardiometabolic side, clearly a class effect on obesity still needs to be proven. What about the neuro side, right? Would you pursue the neuro indication with the same 215 molecule, or will it be a separate molecule? Because the pricing consideration will be different there as well. Yeah, so I'll let Nick maybe highlight some of just the scientific components. But Yatin, I think you hit it from a pricing perspective. And that's one of the reasons that we have invested in follow-on compounds. And so Nick, maybe you wanna highlight what we're looking to do there. Yes, so we have work ongoing to bring forward the next, CNS-penetrant NLRP3 compound and also peripherally restricted. So we're making good progress there as well to give us, again, a full range of options. Got it, very good. Then, moving on to, I mean, you have definitely a lot more programs. So, I wanna touch on the M4 PAM. Where are we with the two assets that you have? Give us an update there. Yeah, so we have two compounds currently in phase 1 studies, NMRA-861 and NMRA-898. So, currently, yeah, in a SAD/MAD study. And, you know, we've said that we'll give an update middle of the year on those two compounds with a view that, you know, minimally we will be talking about taking one of those forward. But yeah. But how would you decide? Like, how what will you—I understand from our communication you'll tell us, "Hey, look, we're moving forward." But what are the things that you're looking at for you to make a decision? Yeah, yeah, I mean, so we're obviously comparing two compounds but also thinking about other compounds of this class such as emraclidine and the properties we'd want to really have to move forward. So both of our compounds we've shown this, you know, previously, both very potent, selective M4 PAMs. We've again optimized for CNS penetration. And we do think, you know, they have advantages over other compounds such as emraclidine on that property. Other pieces which will come from the human phase I data is things like PK variability, you know, getting CSF measures of drug there as well just to make sure all of our preclinical work maps out. And obviously, we've got in the background long-term Tox studies ongoing. So all of that's gonna come together for us to make good decisions, you know, middle of the year. The data we've released today, though, you've seen it before, Yatin, you know, they're both really two quite good compounds in terms of basic pharmacology and properties for development. The hope is to advance it to a phase II program relatively this year? Yeah, so we don't necessarily know if it'll be a phase I-B or phase II, but we will be advancing it next to a proof of concept study. And I think as we're thinking about it, we're probably thinking more similar to what Karuna did in terms of size relative to a skinnier, smaller one like emraclidine did. But we'll come out with more details around that after we have the mid-year update. Got it. And then maybe in the last minute or so, a couple minutes on navacaprant, what's happening with the KOASTAL program? When are we gonna get the data? What modification you have done? Like, why have you increased the size? Yep, so the data is coming for both KOASTAL 2 and 3 in the second quarter of this year. We announced at the beginning of 2026 that they're coming in a combined joint. Yeah. Readout, the reason for that is we have decided to maximize the number of patients in. So we're gonna look to get as close to the 25% over-enrollment as the protocol enables for both of the studies. This is really driven by what we've seen coming out of the implementation of SAFER and VCT at this time last year. Screen fail rates are higher. Our team as well as, you know, our partners at Mass General are feeling like we're getting a higher quality of patient into the study, which Yatin has given us kind of the confidence in maximizing the potential and, you know, patients in the study and putting both studies to readout together in the second quarter. Got it, very good. And then just finally on the cash position, the burn rate, how is that? Yeah, so we expect our current cash position to support operations into the third quarter of 2027. And that includes funding for all of the catalysts we've discussed today, so the KOASTAL 2 and 3 readouts, the M4 update mid-year 2026, the 215 program, and 511. Well, very good. Thank you so much. Great. Thank you. Thank you. Thank you.