Brian Abrahams, Senior Biotech Analyst at RBC Capital Markets. Our next featured company is Neumora, featuring their CFO, Josh Pinto, and their CSO, Nick Brandon. Actually, Nick, thank you guys so much for being here. Great. Yeah, Brian, really appreciate being here. So maybe to kick things off, I know we're not too far away from the readout, first phase III readout from your pivotal study in major depressive disorder. So maybe you could talk a little bit about just how the phase III KOSTAL studies for navacaprant and MDD are going. How's the enrollment been? Are these studies on track? Any surprises or anything different based on your versus your expectations that you're seeing? Yeah, no, absolutely, Brian. I think the studies are going as planned, you know, as we put out last week. There are, you know, we expect data for KOSTAL-1 in the 4th quarter of this year. So, you know, the studies are ongoing. We're not going to provide enrollment updates or any of the other metrics, but the studies are, you know, from our perspective, going very well. Good. Great. So yeah, I think, you know, one of the questions we get a lot about just MDD studies in general is the risk of placebo effect. And I know you guys have implemented a lot of different design elements, and techniques across the KOSTAL studies to really minimize this and ensure replicability from phase II to phase III. Can you talk a little bit more about these and what specifically you guys have put into place and how that's been going in the kind of real-world implementation? Yeah, so I think, as we think about it, there are two elements. So there's the design, and then there's the execution. So from a design perspective, you know, we feel like we've implemented the, you know, the right metrics. So, you know, as everyone's well aware, you know, the biggest response in our phase II was in the moderate to severe population. That is the population we're studying in phase III. We've changed the primary endpoint from the HAM-D17 to the MADRS. We think the MADRS is more appropriate to capture the benefits of this pharmacology. And the primary endpoint is six weeks. And we think that that will mitigate some of the placebo response. In terms of the execution side of things, you know, there are a number of elements. First and foremost is selecting the right sites. Our phase II had about 40 sites. Our phase IIIs will have about 50 sites. So we were leveraging the best sites from the phase II into the phase III. We have central raters that are confirming the baseline MADRS scores to, you know, ensure that we have the right patient population. And, you know, there are a number of other metrics that we're, you know, implementing to ensure that, you know, the execution is on track. We're looking at blinded metrics and a number of other measures. So, you know, we feel like the changes from phase II to phase III really helped to mitigate the placebo response. Great. Good. Nothing's gone. Okay. That's good. We often get asked how your drug differs from J&J's KOR antagonist, aticaprant, which is also in phase III with data, presumably reading out by year end. Can you give us a sense of what you view as the key differences between the two drugs in terms of selectivity, kappa receptor occupancy for navacaprant versus aticaprant? And where do you see this providing the potentially the biggest advantages? And certainly, two drugs in the same class in MDD can coexist. But just curious if, you know, where you might see potential distinction or similarities. Yeah, go on. I'll take that one. I mean, with navacaprant, I go back to the original discovery of it, and that was work done at Scripps Research, and it was all around trying to get as selective a compound as possible. So really, selectivity for kappa over mu and other opioid receptors. So we're around, you know, in one particular assay, we're about 300-fold selective over mu compared to, you know, aticaprant and other molecules, which we believe are around 30. And I think it's that selectivity which really does drive our differentiation. And then I'll fast forward to the safety data we have so far, you know, with navacaprant. If you look at our phase II study, as we know, as we've released, it's, you know, exquisitely selective with very, very few issues. I think that's because of, you know, our ability to push up the dose to get to an occupancy of around 90% at steady state. We've shown that with a PET occupancy study. You know, we feel with the other KORs, you know, because of the reduced selectivity, they start bouncing into, in particular, mu antagonism, and that does start to drive some of the side effects. If you, you know, recently published a aticaprant study. You know, you do see, you know, some diarrhea, some pruritus, and. But the pruritus mechanism is, you know, TBD, you can clearly see they're starting to hit it compared to what we saw in phase II, where we really saw very, very, you know, no pruritus. Okay. That's really for us, one of the key. I wanted to drill down on that point a little bit more, I guess. Like, how much do we know about the toxicities associated with antagonizing other opioid receptors? And I guess, like, how much do we know that about antagonizing mu being linked to GI side effects and possibly pruritus versus just perhaps, you know, in differences in receptor occupancy or bioavailability or biodistribution as being responsible. I certainly think the GI effects are thought to be mediated. Yeah, on the pruritus, you know, you can go into the literature. There are some, you know, there's some very elegant papers now and reviews talking about the roles of mu or kappa. I really don't think it's clear for us. We feel it could be a combination of both. You know, we did see, you know, in our phase I studies, you know, a small incidence of pruritus at high doses in the SAD study. So clearly, you know, whether that's kappa or, you know, we're bringing in a little bit of mu off at much higher exposures is unclear. So it's still TBD, I think. Yeah. But I think at the end of the day, the pharmacology debate is all around selectivity. And we feel like we've got the most selective molecule. By far. Yeah. And I think there's really a 10-, you know, again, assay to assay, but in our hand, you know, 10- to 10-fold difference, so. Okay. In the phase II study, which had supported moving into phase III, you guys had seen the best effects in the moderate to severe population. Can you remind us why you think that was, and why these drugs don't work as well in the more mild population? Is it because just the moderate to severe patients tend to be more responsive to pharmacological intervention in general, or is it because there's maybe less dynamic range to show an effect in a milder population, or is it a combination or both or something else? Well, I think part of it, Brian, is it's clear with the FDA's 2018 guidance document on MDD clinical trials that they've even established that, you know, mild patients tend to have a higher placebo response. Yeah. They just want to get better. And so, as we look at it, you know, the moderate to severe population is the right population to look at in pivotal studies. It's consistent with what other sponsors have done. And so that is that's one of the key reasons that we're moving it forward. Okay. It's certainly the more traditional path. So it would make sense. Joshua, you alluded at the beginning to the use of MADRS as the endpoint versus HAM-D in phase II. Can you maybe elaborate a little bit more on just the decision to move to MADRS, how it might impact your ability to show a treatment effect, and maybe even an expanded treatment effect, and how it impacted your powering assumptions? Yeah, no, absolutely. So, you know, both the HAM-D17 and the MADRS are, you know, scales accepted by the FDA for registration on MDD studies. The HAM-D17 is, you know, a score that's based on somatic symptoms as well. Gotcha. Yep. Yeah, we're good. Gotcha. All right. Perfect. So HAM-D17 is a scale that, you know, has a number of symptomatic domains, including core depressive symptoms, as well as a number of somatic measures. We moved to the MADRS because we feel like capture is the pharmacology better. It consists of 10 items. Half of them are, you know, really based on the core depressive symptoms. The other half, based on anhedonia. And given what we showed on SHAPS, we feel that that is a much better scale for us. And if we had, you know, frankly, kicked off the phase II, that is a scale we probably would have used. So so we feel like, you know, the MADRS is a much better scale to capture the core pharmacology. We've seen with J&J's phase II data that they, you know, were able to represent a very, you know, very robust treatment effect in that scale. Good. You know, short of going through all the details on the statistical analysis plan, I am curious to know some of the strategies that are going to be used to analyze the data here, particularly accounting for discontinuations, the statistical methods that might be employed for imputation of loss of data for any dropouts, and maybe how that compares in phase III to what you've deployed in phase II. Yeah. So, I think, Brian, the key thing is phase II was run during the pandemic. So there was obviously a number of patients that were lost, you know, for discontinuation or lost due to follow-up. I think what we're seeing so far through phase III is, you know, we're quite pleased with what we're seeing on a discontinuation and/or rollover basis to the long-term extension study. In terms of the statistical analysis plan, we're not going to comment right now, because we, you know, we're still working on what is the final approach. But as you think about what the, you know, the psychiatry division of the FDA has accepted, they have accepted a wide range of, you know, MMRM, LOCF, and other measures, as we've thought about it. So as we lock the, you know, the database and think about the statistical analysis plan, we will, you know, come out with more detail. But we are. But you're happy with what you're seeing in terms of the dropout rate so far, it sounds like. Yes. Yeah. As most sponsors would say, you know, that we are very happy with what we're seeing today. Good. Can you talk about the disclosure plan for the phase III? What level of detail should we be looking for in the topline press release? Is this something that will be press released and, you know, also presented around a medical meeting? Or how should we look for the disclosure later this year? Yeah. So part of it is, you know, Brian, as an emerging growth biotech, we're obviously, you know, this is a material event. We will, you know, disclose it, you know, as we see fit. But, you know, I would expect that we will disclose, you know, key efficacy and/or safety data once we have it in hand internally. And, you know, we're actually quite excited to put that out later this year. Good. What do you think the FDA's bar will be for approval? How many studies do you think we'll need to hit? So if you think about it, it's obviously two studies. You know, we're running three. Statistical significance will be the key bar. I don't think they're looking for an effect size. I think what they will be looking for is statistical significance and a clear demonstration that navacaprant, you know, is superior to placebo. Yeah. And then monotherapy setting. Yeah. Which, as we know, the monotherapy commercial setting is much larger than the adjunctive setting. Yeah. Can you maybe elaborate a little bit more on that in terms of, I guess, you know, how you see the competitive landscape evolving with, you know, you're looking at monotherapy. J&J's looking at adjunctive. How do you envision physician, assuming both are successful? How do you envision positioning where will how will physicians potentially choose amongst different agents? And how often are these used? Would you expect these to be used as monotherapy versus adjunctive? How specific do you think the labels will be? So I think one thing is clear. 75% of scripts are used in the monotherapy setting. So monotherapy is by far the largest commercial opportunity. I think J&J came out this week and said they plan to run monotherapy studies for aticaprant post-approval. So I think that once again validates the fact that monotherapy is the largest commercial setting. And so as we think about how this will be used, you know, we view it as novel mechanism. We haven't seen a novel mechanism in MDD in about 30 years. Very simple dosing paradigm, once daily. Efficacy across both depressed mood and anhedonia, which we haven't seen before with existing agents. And, you know, a safety intolerability profile that is fairly unprecedented. We didn't see any rates of AEs over 5% in our phase II, higher discontinuations on post. So it just with this patient population, the AE profile can really drive, you know, patients seeking treatment. After KOSTAL- 1 reads out the first of the studies. Might there be opportunities to make any adjustments to KOSTAL- 2 and 3 in terms of endpoints or size or anything else? And is that something you would consider or be willing to do based on the KOSTAL- 1 readout? Yeah. Yeah, there's absolutely potential. We, you know, we're not going to disclose the exact plans. But, you know, KOSTAL-1 will read out in the fourth quarter of this year, KOSTAL-2 and KOSTAL-3 in the, you know, first half of 2025. And so, you know, as most sponsors we do, if we do see something that would require adjustment, we, you know, we'll absolutely bake in flexibility to do that for KOSTAL-2 and KOSTAL-3. I think this week you guys announced that you're moving into. You announced a little bit more about the movement into bipolar depression. Can you elaborate a little bit more around that? Maybe just talk about the mechanistic rationale for studying a KOR antagonist in bipolar, and maybe just talk a bit about how you arrived on the trial design. Yeah, no, sure. I'll start on that. Yeah. No, so really excited to issue that press release this week. Yeah. So taking the navacaprant into a second indication. And I think our KOR rationale is really based on the impact of the navacaprant on depressed mood and anhedonia in our phase II-A, combined with what we've seen with aticaprant in the FAST-MAS study on SHAPS. And, you know, obviously, the aticaprant phase II data. And as we think about bipolar depression, depressed mood, and I think a greater appreciation of anhedonia in that disorder. So that's really the KOR. And there's some, you know, I think, in terms of the sort of underlying pathophysiology of anhedonia in bipolar depression, again, we really see KOR mechanism having that potential to hit that. Again, as we see what's saying, you know, our primary will be MADRS again. And as we know, that scale, as Joshua said, is sensitive to the core mechanism. So again, we feel really great about, you know, getting this study going. And Joshua, anything more on? No, I think I think Nick hit the key points. But part of it is, you know, we understand that within MDD, 70% of patients have pronounced anhedonia, which is clearly a symptom that navacaprant and the KOR antagonists move. Within bipolar depression, if you look at some of the literature from Roger McIntyre or other KOLs, that is just as pronounced. And MADRS is the FDA accepted endpoint for both of those. Half of the questions on the MADRS are based on anhedonia. And so we think that this pharmacology can move the symptomology in both of the disorders. Okay. Great. Maybe shifting gears to your M4 PAM program. I know you had a recent setback with the lead program. Can you talk a little bit more about, I guess, where you stand with regards to that drug, 266, where some of the backups are, and kind of the latest status? Yeah. So I think, Brian, you know, given that we're in ongoing discussions with the FDA on the path forward for 266, we can't say a lot more than what we put in the press release. But I think, you know, given the great work Nick and the team have done, we feel really good about where we are with the backup programs. And we'll be back out, you know, in front of the investment community with, you know, PathForward and/or, you know, where we are with the backup compounds quite soon. Okay. And can you maybe just talk, recognizing you sort of can't go into sort of the path forward for 266 while you're involved in regulatory discussions. But maybe, I guess, from an analysis standpoint, now that you've had a little bit more time to kind of sit with the preclinical data, can you give us any more color on this rabbit tox, I guess, whether selection of the species may have augmented any toxicity, given that you didn't see anything in the phase I? And I guess, was this, I guess, anything more you can say about some of the studies? Is this something that was replicated in other species? Or, you know, might this be isolated to rabbits? Yeah, sure, Brian. I mean, as Josh said, we can't say too much at the moment just because of where we are. We'll keep our dialogue with the agency. But just to say, you know, we filed our IND, and we're allowed in. And, you know, we're able to go into our phase I study based on a, you know, a very sort of classic tox safety package in two species. So I think that, you know, the rabbit study was not part of that. So that, you know, is distinct. But I know, as Josh said as well, we're hopefully coming back to talk to everyone really soon with progress on 266. But also, you know, we've always said this. This wasn't just around one compound. We're a franchise. We've worked very closely with our partners at Vanderbilt to identify, characterize, bring forward a number of structurally distinct, potent, very selective M4 PAMs to give us some real optionality. So that's always part of our strategy, as is with all of our key programs. Can you talk more about, I guess, where the backup, the next generation programs are status-wise and how different or similar they are? Yeah. We're not giving specific guidance right now in terms of where the backups are. But I think, Brian, as we've talked to you and, you know, a number of investors and publicly about the backup strategy and follow-on strategy was always something we're very, very focused on. And so we will come, you know, with an update quite soon. Yeah. And I know you guys have always talked about a suite of assets through the Vanderbilt collaboration. So good. We're looking forward to that. Maybe just lastly, I know there's so much else to cover in the pipeline. But just in the last few minutes, can you give us your thoughts on, I guess, the NLRP3 drug that you have in development for Parkinson's? I guess what you're, how you're thinking about that mechanism. And then, I guess, any thoughts on potentially exploring that in other indications like weight loss? Sure. Yeah. No, again, really excited about NLRP3, one of the key assets in our preclinical portfolio, homegrown program, which we started when we, you know, in the early days of the early days of the company. Again, we really do think NLRP3 is this sort of key regulator of the innate immune system, has a role in Parkinson's, but potentially other neurodegenerative disorders. Looking at the area right now, it's exploding, particularly the number of other sponsors moving forward in Parkinson's disease. So yeah, that's where we've focused and really built our rationale. Again, a lot, you know, the field has seen a recent publication of work from another sponsor in, you know, looking at obesity. So again, as always, you know, being diligent as we are, we considered that. You know, as we go forward, we'll, you know, certainly consider other options. But you may have also seen, you know, we went into a sort of funding arrangement with Parkinson's UK, Parkinson's Virtual Biotech, which they announced recently. So we're very much focused on Parkinson's disease and really trying to have impact in that disease area. Yeah. And I think one of the other things, too, is, you know, we feel like we have best-in-class pharmacology, and we're just going to keep progressing that. No, no, exactly. Again, we, you know, when we started that program, we knew the limitations of the molecules at the time. And we've just very much focused on delivering highly centrally penetrant, selective NLRP3 inhibitors. And it's always, you know, the field is exploding. So there's a lot a lot of learning is happening right now. So we're, you know, excited to be in amongst it. Yeah. Good. Maybe just in the last minute or two, there's obviously a lot else in the pipeline that you guys don't talk about as much or maybe don't get asked about as much. What would you highlight as being sort of the next thing that you guys are most excited about that we should be paying attention to? Yeah. So obviously, you know, it's very, you know, clear that we're running, you know, the phase III studies for navacaprant and MDD, the KOSTAL program. We just initiated the bipolar depression study for that. I think there's a range of other indications we could go with navacaprant. You know, I think one of the underappreciated assets is 511, the V1a receptor antagonist. You know, we communicated a couple of weeks ago when we put out our first quarter earnings announcement that we will be initiating a study in Alzheimer's disease agitation with that program this quarter. And so, you know, I think we remain quite excited. That is a population that needs new novel medicines. If you look at what is approved today, that, you know, those are not purpose fit for the elderly, you know, agitated population. We think this pharmacology could really work there. So, Brian, as you're thinking about what is, you know, something we don't talk about or underappreciate, I really think it is 511. And it is, you know, close to going into, you know, a proof of concept signal-seeking study. Good. Well, we'll certainly keep an eye on that. Very much looking forward to the near-term data readout by the end of this year for navacaprant. So, Josh, Nick, thank you guys so much. Really appreciate the update. Thanks, Brian.