Revolutionized the way therapeutics for neuroscience, you know, are developed. And with that, you know, we're looking to bring a new wave of novel mechanisms forward for patients suffering from both neuropsychiatric disorders as well as neurodegenerative diseases. One of the fundamental theses behind the company was really to build it at scale. And so, you know, over the last number of years, you know, we've built the company at scale from a balance sheet, you know, and capital perspective, raising over $850 million. That's helped to attract a world-class team. And then we've built what we feel, you know, is an industry's leading neuroscience pipeline comprising seven programs in clinical and preclinical development. Our most advanced program, navacaprant, is a highly selective kappa opioid receptor antagonist. It's currently in phase 3 development for the monotherapy treatment of MDD. With that, we are running the Coastal program, which incorporates three replicate phase 3 studies: Coastal 1, 2, and 3. Coastal 1, we're expecting to read out top-line data around year-end 2024. And Coastal 2 and 3, we're expecting top-line data in the first half of 2025. Beyond MDD, we're also studying navacaprant in bipolar depression in a currently ongoing phase 2 clinical study, and we expect data from that trial in the second half of 2025. Our second most advanced clinical stage asset, NMRA-511, is a vasopressin V1A receptor antagonist that is currently in a phase 1b study for patients suffering from Alzheimer's disease agitation. And we expect top-line data from that in the second half of 2025 as well. And then our third most advanced program is our M4 franchise, you know, and we expect to have one of our follow-on compounds into the clinic in the first half of 2025. We're in a very strong financial position as we sit here today. We just updated our third quarter cash balance yesterday, which was about $342 million on the balance sheet. And that gives us cash runway into the middle of 2026. And so really entering a period, you know, with robust clinical catalysts, you know, coming over the next couple months throughout next year, you know, supported by a very strong balance sheet. And we think a world-class team. So appreciate the invite today, Yatin. Very good. Thank you for setting that stage. Maybe Nick, if you can comment on, or can you just put in perspective the preclinical and the clinical data that has been generated on kappa opioid receptor antagonists in MDD, and why is this target becoming so important now? Yeah, no, absolutely can do that. So this has really been a body of data which has grown over the last couple of decades, both on the preclinical side and I'd say in the last five, six years on the clinical side. So what you have on the preclinical side with kappa antagonists is activity in a range of models, which, you know, you can have your own opinion on animal models of psychiatric disease, but, you know, suggestive of activity in depression, but also anhedonia. And that data set's been growing. I always look more to the clinical data and the clinical pharmacology, particularly, you know, looking at the underlying rationale for this mechanism. So again, it's grown over the years as we've got more selective compounds, but you have data with opioid agonists through to now more selective kappa agonists. And in a healthy volunteer, they will drive what looks to be stress, anxiety, depression, dysphoria, or anhedonia. So you can start to think about a flip side. If you antagonize that receptor, could you ameliorate depression, anhedonia? That data has now built, and that's really come through by the development of selective kappa antagonists. We'll talk mainly about our own compound, navacaprant, but also it's important to mention the J&J compound, the aticaprant. So there's now really three clinical studies we should look at. So with aticaprant, initially in the study known as the FAST-MAS study, people may know this, it was sponsored by the NIMH. It was a transdiagnostic study to look at the ability of a kappa antagonist to treat anhedonia. So these were patients not only with depression, but also anxiety-related disorders. And that study clearly showed in a monotherapy setting a kappa antagonist and aticaprant can treat anhedonia. Then you follow up with our own data. So in our phase 2 study with navacaprant at an 80-mg dose, we clearly showed robust effects in the moderate to severe depressed population on measures of depression and anhedonia. That's been complemented by the Janssen phase 2A study where, again, differently, as many of you will know, they're in the adjunct setting, showed again effects on depression and on anhedonia. And, you know, we're probably getting to that sort of discussion. But you've had a build of preclinical and clinical data supporting, you know, not only the underlying rationale, but now clearly with, you know, two therapeutic compounds, which are clearly showing activity. Got it. So now you, based on all of this evidence, right, you're moving into, you moved into phase three. What are the differences and similarities to phase two, how you have optimized phase three for success? Yeah, absolutely. And so there's a couple elements both from a design as well as a study execution perspective that we've optimized from phase two going into phase three. From a design perspective, you know, we've continued to focus on the monotherapy population as we believe that's the largest commercial opportunity within MDD. But we focused within the monotherapy space only on moderate to severe patients, which is consistent with where we saw the largest effect size in phase two and consistent with, you know, FDA guidance on, you know, populations and how to design MDD clinical trials. We've also focused on moving the primary endpoint from eight weeks to six weeks. We know that the longer you monitor patients and follow them, the higher potential is for placebo response. Within kind of that four to eight-week range, you know, is well established to be, you know, within the FDA guidance as acceptable for MDD. From an execution perspective, an area that we've been really focused on is ensuring we can help to mitigate placebo response. We know that that's one of the challenges that can come up in neuropsychiatric development. Really managing and mitigating placebo response is what can turn, you know, a study into, you know, a positive one. To do that, really the core element is to make sure that you are getting the right patients into the study. It first starts with selecting a very high-quality set of sites. And so we've been very diligent around site selection across Coastal-1, Coastal-2, and Coastal-3 to ensure that we're selecting the highest quality sites out there that have robust experience, you know, within MDD clinical trials. We've also employed central raters. This is to ensure, you know, that patients at baseline truly do have a moderate score greater than or equal to 25, which confirms a moderate to severe diagnosis. And then as the study is progressing, you know, we've added a couple measures. One is an app called AiCure, which helps to confirm patients are compliant to medication throughout the study, as well as, you know, a placebo control reminder script. And so before every efficacy assessment, the site and the patient is reminded that the patient has a 50/50 shot of being on placebo or active, which is well established to mitigate expectation bias. And so, Yatin, in total, we think that we've employed, you know, a number of measures, you know, that collectively represent, you know, the full suite of tools we could bring forth to really, you know, execute, you know, a high-quality set of phase three studies. Okay. Could you also talk about the power and the size of the study and how should we think about erosion of effect size from phase two to phase three, if any? Yeah, so you know, erosion of effect size moving from phase 2 to phase 3 is a phenomenon that has occurred before in neuropsychiatric studies. I would highlight here that in phase 2, you know, our study looked at the HAMD-17 as the primary endpoint. The HAMD-17 is one of the two registrational endpoints that's accepted by the agency for studying MDD clinical trials. However, we know that this scale is really, you know, embedded with, you know, focused on core depressive symptoms within MDD, but there's a range of somatic measures as well. So there's multiple questions on sleep, multiple questions, you know, on GI effects, you know, and those are symptoms and elements that we don't necessarily think that the kappa opioid receptor antagonist class is going to move substantially. As you think about the moderate scale, which is where we've moved to in phase 3, it's a 10-item scale. Five of the 10 items are really focused on capturing symptoms of anhedonia and are known as the MADRS anhedonia factor. To Nick's points earlier, we know through the FAST-MAS study as well as, you know, preclinical biology and our phase 2 study that this class truly does improve symptoms of anhedonia, and so that we think by moving from HAMD-17 to moderate, we've shifted to a scale that has the potential to capture the true effect size of kappa opioid receptor antagonists. What we ended up doing is we powered the studies to 90% to detect about a 3.2-point placebo-adjusted change on the moderate scale, which is, you know, a haircut to the effect size that we ultimately saw in the phase two study on the HAMD-17 scale. Got it. Very good. I think on the call there was a little bit of a mention about, you know, your potential ability to change the size of the study. How are you thinking about that? Yeah, so we built flexibility into each of the Coastal study protocols where we have the ability to increase the size of the studies by up to 25%, you know, and so that's something that we built in to give us flexibility across the Coastal study. Is that sort of something you are considering or the guidance that you just updated sort of take into account all of that? Yeah, so for Coastal One, the guidance that we just put out has taken into account, you know, all the factors within the study, and we're looking forward to releasing top-line data for that study around the end of 2024. For Coastal Two and Three, you know, we're looking forward to releasing top-line data for those studies in the first half of 2025. And, you know, we could potentially look to, you know, modify the sample size for Coastal Two and Three based on what we see from Coastal One. Coastal-1. Okay. So the J&J also has a program. To the best of your understanding, why do you think or what's your hypothesis that they are going after an adjunctive study versus a monotherapy study or a population? It's really hard for us to speculate on why other companies would be taking the approach that they're taking. So maybe I'll comment on why we as Neumora elected to, you know, focus on the monotherapy opportunity. First, we feel really good about the pharmacology behind navacaprant. It's 300-fold selective for kappa opioid receptors over mu opioid receptors, which enables us to dose at the 80-milligram level to achieve about 90% receptor occupancy coverage over a 24-hour period. And so we feel really good about the pharmacology and our ability to engage the target centrally in humans at quite an effective dose level. We also know that the monotherapy opportunity is very large from a commercial perspective. Anywhere from 60%-85% of prescriptions based on published literature from commercial databases would suggest that, you know, the large proportion of prescriptions are written for the monotherapy setting. We also know too that, you know, getting approved in a monotherapy, you know, physicians sometimes will use those, you know, products off-label in the adjunctive setting, and so from a pharmacological perspective, we feel really good about navacaprant, you know, and the potential it has in the monotherapy setting, particularly following the great results we saw in phase two, and from a commercial opportunity, you know, we feel that the monotherapy setting, you know, is the much larger commercial opportunity. Got it. In terms of the baseline of the patient that you have enrolled in Coastal-1, are you able to comment on like how these patients are, what level of severity they are based on what your visibility is? And again, also talk about the level of anhedonia that these patients might have. Yeah, and so with the COASTAL programs, we've set the MADRS score of 25 or greater as the baseline cutoff. So that's going to naturally enrich for a moderate to severe MDD population. We looked at a number of longitudinal data sets out there to understand the correlation between baseline MADRS score and baseline SHAPS score, which is a measure of anhedonia. Through our analyses, you know, it was clear that patients that had moderate to severe MDD as measured by a MADRS of 25 or greater would also generally have, you know, moderate to severe anhedonia. And so there's almost a natural enrichment for anhedonia within that population. And so we feel quite good about the, you know, inclusion-exclusion criteria that we set to support, you know, randomizing and enrolling the patient population that we think, you know, is appropriate for the studies. Got it. Anything you're able to share on the dropout rate or the sort of discontinuation rate that you're seeing, at least on a blinded basis? So, you know, what we've said, you know, in phase two, the dropout rate was a bit higher than historical norms. And part of that was driven through the fact that the phase two study was run during the pandemic timeframe. And so you just lost a lot of patients to follow up. What we have commented on from the phase three studies that we are seeing, you know, a lower dropout rate, but we haven't commented on specifics. The phase three is powered based on a phase two discontinuation rate? The phase 3s are powered based on a discontinuation rate, you know, that comprises both the phase 2 study as well as historical averages. Okay. And then so the lower discontinuation sort of gives you even more power if that is happening. Yes, yes. You know, that's obviously how, you know, the discontinuation rate factors into a power calculation. Okay. Now, in terms of the actual data, what do you think is a good, what would you like to show? So on the moderate, really hitting statistical significance is our bar there. You know, if we hit statistical significance on two out of the three studies at least on the moderate at week six, that'll be the basis for filing an NDA. And so we really feel like stat sig on the moderate is critical. We also think another feature of the product that's going to be highly attractive to physicians and patients is the safety and tolerability profile. We saw in phase two, there were no AEs over a rate of 5%. There were higher discontinuations on placebo than active. Within this market, we know that 50% of patients diagnosed with MDD are not on active pharmacological therapy. And the biggest reason behind that is the AE profile of the existing agents, as well as the biggest reason for discontinuation of agents right now are AEs and tolerability profiles. So we feel like bringing a product forward with a moderate benefit and an attractive safety profile could be quite, you know, appealing to a range of physicians as well as patients. And then beyond that, you know, we've clearly seen with this mechanism and with our drug in our phase 2 study, you know, quite a robust benefit on the SHAPS scale, which is a measure of anhedonia. Anhedonia is one of the two symptoms that can form the basis for a diagnosis of MDD. The existing agents today don't really effectively treat anhedonia, and it's a symptom that's highly prevalent in upwards of 70% or more of patients with MDD. So that could provide, you know, really another basis. And so I think at the end of the day, you know, stat sig on the moderate plus an attractive safety profile provides, you know, a highly, highly attractive product profile. And then, you know, an anhedonia benefit beyond that just continues to expand, you know, the quality of the. Is SHAPS the secondary endpoint, a key second, one of the key secondary endpoints? SHAPS is the key secondary endpoint. What is a good result on SHAPS? Because I think we are more familiar with the MADRS, maybe help us understand what is good for SHAPS. Yeah. And so given that the existing agents that are available today haven't really shown an anhedonia benefit, there's not as much established literature in terms of what is the bar to overcome on SHAPS. And so with that, you know, we think that hitting statistical significance on the SHAPS will provide the first real phase three data set that shows a drug can benefit that symptom. And ultimately, that would be, you know, a highly attractive product feature for navacaprant. Got it. Now, when you look at these baseline characteristics of patients, and if you, so there is HAMD, which is, you know, above 25, are you also able to get SHAPS patients that are on the moderate side of their anhedonia? Yeah. I mean, Josh mentioned it earlier, but from all the studies we know, we've analyzed, so we ingested a number of historical data sets where they had measures of depression and anhedonia at that level, so greater than 25 on the MADRS, you're going to enrich, almost naturally enrich for sort of. But their level of MADRS would be similar to the level of depression. That's what I'm just trying to understand that if you are above 25 on MADRS, what level of anhedonia do you have? Is it moderate, mild, or severe? You tend to have moderate to severe. Yeah. So it's sort of one to one. Yeah. Now, moving on. One more question. So you need two studies to file out of the three successful. How quickly you might be able to file once all the three studies are successful? In terms of the studies, as we mentioned before, we're going to read out Coastal-1 top-line data around the end of 2024, and then we're guiding towards Coastal-2 and Coastal-3 top-line data in the first half of 2025. You know, we feel like if we are able to hit those timelines that we should be able to potentially file an NDA for navacaprant by the end of 2025. By 2025. Moving on to the muscarinic program, I think there was some setback on the muscarinic program. Can you maybe help us understand what are the features for this second-generation molecule or the follow-on that is different? And also the, what should we think or how should we think about the AbbVie and emraclidine news? Sure. Yeah. No, so maybe just a reminder for everyone around our M4PAM program. So it was back in April, we were put on full clinical hold with NMRA-266. This was our first molecule at that stage. We were in the SAD/MAD phase and had dosed around 30 patients. The reason we were put on hold was some unexpected findings in a non-clinical rabbit study. But it's important to note that in those 30 healthy volunteers, we'd seen no, you know, the molecule was moving very nicely through. We'd seen no convulsion seizures. So with that compound, we are still, you know, in interaction with the FDA to see if there is a path forward for it in parallel. And I think you've heard us speak before, this was always, always a franchise. We're always bringing forward follow-on molecules which are structurally distinct, had their own, you know, baseline pharmacological properties, which we wanted potent, selective for M4, but also some other sort of defining characteristics. Our guidance, which we're still on track for, is to, you know, for a second IND to be filed in the first half of next year. We still remain very confident in the M4 approach from a mechanistic point of view. We clearly, as you all did, saw the AbbVie data readout on Monday. You know, we don't really comment on, you know, other sponsors' data, but there's clearly a lot for the field to learn from, and often I find, you know, when you are, you know, like us, we're following, there's a lot of learnings we can take. So, you know, we'll integrate and, you know, modify our approaches as we get back into the clinic. Perfect. I mean, in your view, are there functional and biological differences in terms of how a PAM behaves versus a pure agonist? I mean, going back originally to why people, when after PAMs with selectivity and, you know, what you see when you have a full agonist, you generally bring, you know, non-selectivity against other muscarinic isoforms. And that's, you know, for me, that's still the case. Clearly, we're all very excited by Cobenfy's approval, but still, you know, tolerability is still an issue when you're a full agonist and have, you know, it's very hard to get truly selective agonists. And I've worked 20 years on this, so I understand it. I still think there are lots of pros for the more selective profile. The other piece, you know, often the question we get is what happens potentially in the aged population where acetylcholine levels could be diminished. My response is always, to see the full activity of a PAM, you don't need too much acetylcholine. And even in an aged, say, Alzheimer's patient, it's not as if there's zero acetylcholine there. So I still feel that even in those situations, a PAM has the ability to have, you know, a strong effect. Okay. Very helpful. Moving on to 511, like what are some of the updates we should expect there? Yeah. So in terms of NMRA-511, that's our vasopressin V1A receptor antagonist. It's in the phase 1b study currently for patients with agitation associated with Alzheimer's disease. The next update there will be top-line data for the program, and we're guiding towards the second half of 2025 for that data. 25. Maybe one question on Coastal One. Have you communicated that the enrollment has been completed or you just said that the data are going to come around year-end? We haven't commented on enrollment completion. What we have said is that we expect to have top-line data around year-end 2024. Okay. Maybe then just final question is on the financials. How is the financial health right now? So we're in a very strong financial position. As I mentioned at the outset, you know, we're about to enter a period with very, you know, with a robust set of clinical catalysts coming forth. We have five major readouts between now and the end of 2025. And we ended the third quarter with $342 million on the balance sheet, which provides us cash runway into mid-2026. Got it. I think that's all I had for you, Josh and Nick. Thank you.