Good morning and good afternoon. My name is Todd Tushla. I'm the Vice President of Investor Relations at Neurocrine Biosciences, and on behalf of our entire company, welcome to our 2025 R&D Day. Whether you're here in person, on the webcast, or reading the transcript, we're grateful for your time. We will be making forward-looking statements today to refer you to our latest SEC disclosures. Our speakers for today from Neurocrine will be Kyle Gano, Chief Executive Officer; Sanjay Keswani, our Chief Medical Officer; and Jude Onyia, our Chief Scientific Officer. As far as tenure at Neurocrine, Sanjay joined us in June, Jude joined us in 2021, and Kyle joined us in 2001. Wow, that was a long time ago. We're also fortunate to have with us today Dr. John Krystal, a world-leading expert in the field of neurology and psychiatry and a professor at Yale University. Dr. Krystal, thank you for being here. Dr. Krystal will be joined on stage by Jaz Singh, our Vice President of Neuropsychiatry Development, for a KOL discussion. The agenda over the course of roughly three hours. I'll be turning things over shortly to Kyle, who will provide opening remarks. We'll then have Sanjay come up and provide an overview of our industry-leading neuropsychiatry portfolio. We'll then have Dr. Krystal and Jaz come up for a moderated KOL session. Following that session, we'll open it up to the audience for questions to Dr. Krystal. They're going to cover a lot of ground on Osavampator and Direclidine, so hopefully you find that engaging and ask some good questions for Dr. Krystal. We'll then take a quick five-minute break. After that five-minute intermission, we'll transition to Jude, who will come up and provide an update on Neurocrine's R&D transformation progress since he last spoke to the investment community two years ago. We'll then open it up for the second round of questions from the audience, and then Kyle will provide closing remarks. Now, for those of you who have made the trek to Southern California, and I know it wasn't easy, but for those who have made it, there's nothing quite like having tacos from world-famous Seaside Market for lunch. So we'll provide you lunch out in the quad outside. It's a beautiful day here in San Diego, and you'll have a chance to interact with Neurocrine leadership in a very informal, friendly setting. So with that, that's the agenda. It's time to turn it over to Kyle Gano, Chief Executive Officer at Neurocrine. Thanks, Todd, and good morning and welcome, everyone. Thanks for being here today. It's great to have you all here with us together on this occasion of Neurocrine's 2026 R&D Day. In case you're wondering, for those of you coming in from New York, I think it's supposed to be about 32 degrees-34 degrees. It's going to be 30 degrees warmer than that here, 35 degrees warmer than that today. So I hope you're able to get out and enjoy a little bit of the weather here in San Diego. If you came just in time or if you're here earlier this week, hopefully you got some time out and to enjoy what San Diego has to offer. So a couple of things. Welcome to our beautiful new campus here. I'm reminded of two things every day when I come into the office. I'm reminded of how far we've come over the years. The company was created back in the early 1990s, and some of the members of that team are in this room today, but we started in a garage about five miles down the road. So if you think about starting in a garage to coming to this campus, you really do get reminded of how far you've come. The other one is that many years ago, I was a chemist, and I come into this campus every day and I see our labs, and I think to myself, boy, I could have really been something if I would have had these labs when I was going through graduate school. But those are all things now that our employees get to enjoy here. And the other point that I'd bring up about this campus is that it represents this year the first time all the departments from research to development to commercialization are all under one roof. And I know I'm incredibly excited to have us all here. I think many of the employees feel the same way. As we move into 2026, that would be the first full year that we'll all be together. So going to meetings, walking across campus, these are all things that we used to have to drive to because many of our labs were not located in the same spot of our previous headquarters. So a very exciting time. We're hoping to share that with you today. We've got some tours planned, I think, this afternoon. So I would encourage you to take part in those and see what we have ongoing here at Neurocrine. A couple of pieces of just housekeeping for me. I do want to thank you for your time and interest in coming out all this way, especially this time of year, especially some of the difficulties in traveling. We know you have other things that you could be doing, and for Neurocrine, it really is an opportunity for us to share with you why we think we're moving into a new era here, so to that end, today is going to be all about really showing you the depth, the momentum, and the focus and future of our science and pipeline. I think given our success with Ingrezza and Crenessity, we're actually going to pause and also reinforce our ability to convert innovation, innovative science to life-changing medicines, and you're not going to hear a whole lot about Ingrezza and Crenessity today, and that's by design. It's all about research and development today. So beyond a few opening remarks about these and my introduction, you're not going to hear much from Sanjay or Jude. Again, that's deliberate. But as we think about the future, then it's going to be sharing with you today what's in store in terms of our innovation across research and development, our near to midterm value drivers, and then we'll give you a feel for where the R&D is pointed in terms of the future. Now, before I get to my opening remarks, I would like to pause a little bit. Todd mentioned who's going to be joining me today, colleagues-wise, to help me speak and share with you what's going on. He was very formal in his presentation of Dr. Sanjay Keswani and Dr. Jude Onyia. Our management team, we travel a lot together. In many ways, I spend more time with them than my family. So the reason why I'm saying this is that when I refer to them in my introduction and my closing, you're going to hear me say Sanjay and Jude. That's how I know them. So you may hear that as we go through the presentation. So I just want to give you that heads up that that's the familiar way that we refer to each other here at Neurocrine. It's part of our culture. But together, Sanjay, Jude, and our entire research team, really across our enterprise, the past couple of years in particular, we've transformed our research and development capabilities into a real competitive advantage, and it's with that view that me personally and others, we believe we're well on track of becoming that next great U.S. biopharmaceutical company. Like most R&D days, there are always themes, takeaways. I'd like to frame the discussion here for you as well. First, kind of going back to my opening remarks and theme, I believe Neurocrine is entering a new era. We're moving away from a single-product biotech company to a multi-product diversified biopharmaceutical company with scale. And by scale, I mean, here's our headquarters. You're seeing it today. We have 2,000 employees. We have capabilities across research, development, commercialization, and we have two commercial products. That's very rare in our space. We did all that here in San Diego, and it's rare for San Diego itself. If you think about Ingrezza and Crenessity, just a few more times you're going to hear this, both of these products provide revenue and revenue diversification growth for the near to midterm, long term, and really provide durable cash flows. Those two pieces give us a strong foundation from which to invest in R&D, and that's really why we're here today. Second, we're executing on an industry-leading neuropsychiatry portfolio. It's positioned to deliver multiple, best, and first-in-class medicines this decade. So before 2030, that's what we're looking at here. Programs like Osavampator for major depressive disorder, Direclidine, and schizophrenia are next-generation VMAT2 inhibitor programs. These all anchor a differentiated neuropsychiatry portfolio. I haven't even touched the muscarinics yet. Our scaled muscarinic franchise focuses on orthosteric agonists and antagonists. We're the only company that has these. So it does provide a competitive advantage as well versus other companies in this space. Third, we have an R&D engine that's fully transformed, fully operational, and in my view, it's over-delivering on innovative science today. In fact, you'll see through some of the work from Sanjay and Jude when they present it, we're delivering more high-quality programs faster and across more modalities than ever before. Now, I'm only going to have one more slide on the R&D engine because I don't want to steal Jude's thunder. I'm going to let him go through the updates that he has from the last time he presented on our R&D engine. But needless to say, I'm very excited about what's going on in the research side of the organization. Fourth, we're going to be leaning into our 30 years of experience and expertise in CRF biology. By CRF, I mean corticotropin releasing factor. It's the same underlying biology that is tied to Crenessity's success in CAH. We're going to lean into that, and we're going to have a two-pronged strategy moving forward. One is we're going to have NYX and follow-on medicines that will combine with Crenessity over time, employing and utilizing the CRF1 mechanism, antagonists in particular. And we're going to be expanding that portfolio into CRF2 agonists, in particular peptides. And this is going to take us into a range of metabolic disorders, including obesity. And our first program is going to be targeting weight loss with muscle preservation. You'll see some really interesting data on that today. So our lead program, NBIP-'2118, is going to be in the clinic the first half of next year. So if you put all these pieces together, I hope it paints a picture of a time of sustained catalysts between now and the end of this decade. Now, of course, we're going to have an early-stage pipeline that's always going to deliver phase I data. It's pretty rich today, and that's going to be important because that's going to define the mid-stage pipeline. But more importantly, in 2027, you're going to see all of our phase III trials start reading out Osavampator and MDD, Direclidine, and schizophrenia. You're going to hear here today that Direclidine has already started its bipolar mania phase II trial. That's going to read out in the same time frame. And we also just initiated a phase two trial in schizophrenia with our dual M1, M4 agonists that will read out in the same time frame as well. And then I just mentioned NBIP-'2118, which will deliver data in patients over that same time frame. So a lot going on over the next few years. It does require very exquisite execution, and that's something that we'll continue to do over time. So those were the key messages. I would like to take a moment and remind the audience, those listening in, that my history here at Neurocrine, you heard I've been here for about 25 years. In fact, some of you know I started here as a summer intern, which, funny joke there, is probably that our HR program really has a really good program for interns coming into Neurocrine if you're interested. But in terms of our history, as well as my own, it is founded in neurology, psychiatry, endocrinology, and immunology. In fact, I'd like to spend a few minutes telling you about that history because I think it's important here. It does take us back to the 1990s, early 1990s. I mentioned we started in a garage not on the road, but with foundational contributions across the four therapeutic areas and with help from our founders, Dr. Wylie Vale at the Salk Institute brought us into all that corticotropin-releasing factor biology. And that took us into a lot of areas that spanned neurology to immunology. And then the other half of our founding technology came out of Dr. Larry Steinman's lab at Stanford. He contributed what we called ultrapeptide ligands, and that took us into endocrinology and neurology via multiple sclerosis. So if you look across the field today, you'll see their science still influences a lot of companies in the work that they're pursuing. And if I think about Neurocrine, we've followed that science ourselves over the past 30 years, and we've followed the science that's come from that. And that's taken us to areas that's required patience, persistence, and original thinking to stay true to those therapeutic areas that we're investing in. So a couple of pieces that I'd mention about that time. Being a company that's been around for 30 years, you develop a culture. You develop a focus on how you tackle problems. And that's what this was able to allow us to do. The culture that came from these 30 years, three decades' worth of work, served as a basis to stay true to those areas that our teams can innovate at the highest level. It also gave us the insights of what it takes to win on complex biology. And what we did over this time frame, before you know it, you wake up and you find out that you have deep institutional knowledge that no other companies possess. So for us today, if you think about kind of the sequence of things, it's Ingrezza. It's neuropsychiatry, deep institutional knowledge there around that and movement disorders. It's VMAT2 biology, which is tied to Ingrezza. If we look at Crenessity, deep institutional knowledge in endocrinology and CRF biology, and an area that we don't often talk about, but is near and dear to my heart because it's where I learned about drug development, endocrinology again, but on the GnRH receptor that ultimately led to the approval of Orilissa, which AbbVie now commercializes, so a lot of institutional knowledge that we created over the years. What most companies do, what we do, is we follow the science that we learned from that, and we take that into new areas, so continuing on that theme, let's look at the snapshot of a presentation from Neurocrine in 2000. Now, the reason for showing you this snapshot is not to show you our rough PowerPoint skills from back then or to the poor choice of colors, which I did try my best to match it to Jude's suit. So see if you can compare those colors when we break this afternoon. But really, it's to show you a couple of things. One is you can see at this earliest stage of our pipeline programs across neurology, psychiatry, endocrinology, and immunology. Number two, you see programs of different modalities: small molecules, peptides, and biologics. The third thing requires you to pull out and focus on two programs here: type 1 diabetes and multiple sclerosis. If you go at a 10,000-foot level, a program in endocrinology and a program in neurology. Seemingly disparate therapeutic areas. These are programs that came from Dr. Steinman's lab at Stanford. But the one thing that requires for their success, conversion from a Th1 to a Th2 immune response. So two unrelated therapeutic areas requiring something to happen from an immune-based perspective to win. That view on science, following the science, is what drives our R&D engine today. Sometimes it takes you into other areas. You exploit, you win, you see how that applies to your institutional knowledge. So going beyond that, looking at our pipeline in 2005, a couple of things pop up here. An expanded endocrinology portfolio, moving a program in phase II for endometriosis. That program became Orilissa. You see a program in obesity. You see early investments in immunology, in this case, chemokines, an important class of immune-based targets in therapeutics back then and even today. And you also see the expansion of our CRF biology from CRF1 antagonist to CRF2 agonist. In this case, we're developing urocortin II, which is the endogenous ligand of the R2 receptor for acute decompensated heart failure. And of course, as I already mentioned, over the entire history of Neurocrine, we've been steady investors within CRF. We took six CRF1 antagonists to clinical development. One of them became Crenessity. I just mentioned the CRF2 investment as an agonist in heart failure. We also had an effort on binding protein, small molecule inhibitors of the binding protein of the CRF receptor. This developed our early institutional knowledge across neurology, psychiatry, endocrinology, and immunology with just one mechanism. The other thing that we've learned over the years that's applicable today when you hear from some of our R&D interests in the near term is the value of being in endocrinology. For the most part, you get biomarkers, you get objective endpoints and the ability to see activity early on in development with the molecules that you're developing and investing in. So compare and contrast that to our portfolio today, industry-rich, leading neuropsychiatry program, but you don't have all those same benefits. So diversification can also give you benefits on probabilities of technical success as well. So how do we bridge this past to our present and future? I guess a couple of things before I jump into that. For those of you that already know Neurocrine and our pipeline, that's probably most of you here because you have seen our pipeline. We have talked about it with you over time. There are many similarities in the pipeline today that I've shown you in years past, 2000, 2005. But there are a lot of things that are different about our company today than back then. First of all, some of the programs that we had in our pipeline became medicines. The valbenazine, our CRF1 investments became Crenessity. Our investments in endometriosis became Orilissa. But there are other programs that we had to pause. We had to pause because at moments in time, we didn't have the right team, we didn't have the right capabilities, or we had to focus on medicines like Ingrezza or Crenessity or helping a partner get Orilissa over the finish line. But that's not the case today. Today, we have the team, we have the capabilities, and we have the financial profile of a company to follow that science that I mentioned before all the way through. And that's the difference about Neurocrine today versus Neurocrine in years past. Now, when we think about connecting our past, present, and future, there's two things that you should take away from the slide. What we're investing in today and the cadence of investments we're making over time and where that's taking us. It makes sense. Our first medicine approved, Ingrezza, in 2017 in neuropsychiatry. There was a lot of value that came out of that approval. Most of that value, in my opinion, is for patients in tardive dyskinesia, and in Huntington's disease, chorea. But the other value comes back to Neurocrine, allows us to reinvest in the company. Of course, with the team that we have, the capabilities that we had at the time, you're going to build out your neuropsychiatry portfolio. That's what we did. That brings in Osavampator, the muscarinics, Direclidine, our next generation VMAT2 inhibitors. The next product that we got over the finish line was Crenessity. Obviously, a lot of endocrinology experience there, a lot of experience in CRF. Where do we go next from an R&D perspective? We stay in endocrinology and we pursue adjacent therapies within CRF to expand our reach there. And then over time, we have a very strong financial profile as a company, as you know. That gives us the ability to steadily invest in R&D, both now and in the future and across all of our therapeutic areas. And not many companies can say that. And I've said we have certain competitive advantages in different areas. Our profile as a company, our size, is also a competitive advantage. And I believe it's only one that's going to compound with the continued expansion and evolution of our pipeline. So there you go. You get the connection of our past to our present and where we're going in terms of our future and in what order. So we talked about the commercial portfolio previously, kind of outlined at the top there. We've got Ingrezza, Crenessity, our medicines partnered with AbbVie, and then our clinical pipeline and how that's evolving. How do those two areas inform our R&D strategy? Well, it all starts by putting our purpose at the center of everything, which you can see here, to relieve suffering for people with great needs. Then as we think ahead, our company has come together over time and we've put together, defined our strategic R&D pillars. And they're actually on the slide here. They kind of go in the sequence as if I had just told you where our investments are going. Lead the VMAT2 category. What that means is leading into our institutional knowledge on VMAT2 biology, on neuropsychiatry, take those learnings and apply those to our next generation VMAT2 inhibitors. We've got two molecules in that space, and you'll hear about that from Sanjay. In terms of delivering on the promise of CRF, we know there are areas in this biology that we missed in years past. We had to pause because we didn't have the right team, the right capabilities. We had to focus on getting Crenessity over the finish line in CAH. We don't have those constraints today. So delivering on the promise of CRF means doing all we can for next generation molecules for CAH on R1 or CRF1, and then moving into adjacent areas, in particular, metabolic diseases and conditions with CRF2 agonists. So that's a two-pronged strategy there for our CRF R&D strategic pillar. And then lastly, we want to maximize and evolve the pipeline. So there's two sides of the coin here. First side, obviously, maximize everything that's in the pipeline today. And there's a lot. There's 12 programs. You're familiar with those. But we got to make sure we do right by those. Number two, the other side of the coin, we want to do the same, maximize and evolve the pipeline for the pipeline of the future. So that takes us into our therapeutic areas, our next generation molecules, et cetera. So that's the goal for that strategic pillar. But the thing I would say about that, and I'm sure you can agree with me, that innovation here at Neurocrine hasn't always been internal. It's been external as well, and we'll continue to lean into that. And by that, I mean business development has served us well over the years. In fact, I believe it's yet another one of those competitive advantages. There have been times in our history, in the early 1990s, going back to when the company was created, that we used business development to bootstrap the company up to the next stage of its evolution. And that was done with a deal with a larger pharmaceutical company, for example. We've also filled pipeline gaps in years past recently to build our pipeline. More recently, we've used business development to bring in new technology to act as an accelerant for our research interest. If you look across all those categories, here's a representation of recent partnerships that we struck up, mainly in new technologies to help accelerate our research interests. But obviously, we've identified those companies that we partner with to bring in tangible assets from the outside as well. Business development will continue to be an active role, play an active role here at the company moving forward. Now, I talked about our R&D engine previously as one of the key takeaways for you today, one being fully operational and delivering as promised. In fact, I said over-delivering. But a couple of things about this. When Jude came on board in 2021, we all sat down around a table. It was in our old campus, and we tried to think about ways we could really transform our R&D organization. It was working. It was being successful. It's hard not to say things were not in a great shape because we had multiple medicines that had gotten over the finish line, or we could see that view. But really wanted to really give it some more horsepower and transform it in a way that we could get more productivity over time, so there are two areas that we identified that we could do this. One is, historically, we've been a small molecule company, which has really served us well over our future, but you can see in our early days, we actually had expertise in other modalities, and I can tell you, when we had to pause those other modalities, we still worked on targets of interest, but in many cases, the small molecules and the targets that we're interested weren't compatible, and despite our best efforts, we couldn't get candidates that we could move forward into clinical development. We made a list of all those targets, and we made a list of that biology that was difficult, and we saved those for another day, another day where we had the right team, the right capabilities to attack that biology in the right way. We brought in that team. Some of them are here in the audience today. We brought in the right capabilities to expand into peptides and biologics. So that was point one. The other point was that we wanted to reconfigure our pipeline so it had the right mix, not weighted to one side or the other, but the right mix of non-validated to validated targets. And by validated, I mean genetically or clinically. When we put those together, almost immediately, we saw a multiplier effect on the probability of technical success, in particular of our earlier stage programs that were of interest at the time. And we saw those start propagating through earlier stages of research to later stages of preclinical and now moving into clinical development. And with that productivity, we drew a line in the sand. We saw where the company was headed, and that's shown on this slide here. Remember four, two, three. We're expecting at steady state, four new phase I starts, two new phase II starts, three programs in phase III. And we're saying here at least this, depending on the productivity that's coming out of our labs. So this puts us in a pretty rare air in terms of other companies of our size. And I'll tell you now, I'll kind of steal the thunder of both Sanjay and Jude, we hit this phase I through phase III metric for the first time this year after starting this in 2022. So very good productivity thus far. It's the first time we've been this productive ever in our history. And if we do this year after year, we have very high conviction that we'll be able to deliver one new medicine every two years. So that's the plan. This is a snapshot of the pipeline today. This is the one that you're familiar with. We're not at steady state yet, fueled by that R&D engine that I just presented, so this does represent the programs that we're advancing now. You can see that there are molecules that span small molecules themselves as well as other biologics. We believe this is an innovative pipeline that will deliver a lot of value creation just this decade alone, not to mention everything that's coming behind it, so that's the pipeline. I think that as we turn it over here, just a couple of parting thoughts. Today, you're going to hear a few themes. I mentioned them already. But you'll hear words like execution, why that's important, evolution, repeatable innovation. These are not words that are aspirational. These are things that we're seeing pop up in our pipeline today. We're seeing these being the source of the catalyst that we'll observe for the remainder of this decade, so before I hand it over to Sanjay, I would like to say thank you to our research and development teams and really everyone across our organization. It's their commitment to scientific rigor and delivering medicines for patients that is why we're here. Many of the leaders across our therapeutic areas are in this room, as I mentioned just a moment ago. Hopefully, you will get a chance to meet some of them today. They're great people. They have a lot of information about what we're working on here in science that we're trying to deliver. I would encourage that. I think with that, I'll turn it over to Sanjay. Great. Hello, everyone. Firstly, thank you, Kyle, for the introduction, and thank you to everyone who actually managed to get here. I know it was an arduous journey for many of you, particularly from the East Coast, because of inclement weather. Really appreciate your time today. So I joined Neurocrine about six months ago. So I'm kind of the newbie here, really excited to have joined the Neurocrine team. And hopefully, it'll become evident over the course of today or this morning about why I joined Neurocrine. It wasn't because of the fantastic weather here, but clearly, that was an important factor as well. In terms of my background, I'm a physician scientist and neurologist trained in Queen Square, London, as well as Johns Hopkins, Baltimore. I was on the academic faculty at Hopkins for a while, where I saw patients with a wide variety of neurological diseases, as well as ran an R01-funded immunology basic science lab as well. And then joined the industry about 20 years ago, initially big companies like BMS, Lilly, where I had the pleasure to encounter Jude, our Chief Scientific Officer, as well as Eiry Roberts, who I'm transitioning from. From there, I went to Roche, where I was Senior Vice President, head of R&D for a number of therapeutic areas. And then I joined Small Biotech. I've been doing that for the last few years. I think that's been really helpful in terms of having a relatively hands-on approach with this ever-prevalent mindset of time and cost efficiency. So hopefully, I can bring some of those skill sets to this company. So today, I'm going to be talking about our neuropsychiatry pipeline. Really excited by this. It's broad. And specifically, it's driven by validated biology. We'll be talking about validation a lot this morning because we believe that relates to high probability of success. Admittedly, the psychiatry therapeutic area has been associated with a low probability of success. We feel we can mitigate this risk by utilizing highly validated targets and mechanisms. We have three pillars here. The first one is glutamate modulation. The validating mechanism here is ketamine. The premise here is to have ketamine-like efficacy in patients with depression, but avoid the baggage of safety and tolerability issues, particularly the psychotomimetic ones, the memory issues, et cetera. We're very excited about what we've seen so far with Osavampator, which is an AMPA potentiator. Got some terrific phase II data, which I'll present. We feel it leverages ketamine's mechanism, but is a much more convenient oral option, which, touch wood, has a great safety and tolerability profile. NBI-'770 is another molecule in our 2B NAM, which we recently talked about, or at least presented in a press release. We did complete a small signal-seeking study. We got some signals of efficacy, and we're currently deciding about next steps going forward. With respect to the middle pillar, we have a whole slew of muscarinic agonists. The validating mechanism here is Cobenfy, or xanomeline, which has efficacy in the schizophrenia indication. We have Direclidine, which is a specific M4 orthosteric agonist. It's currently in phase III development in schizophrenia. As Kyle mentioned, we've just initiated a phase II study in bipolar mania. And we feel by targeting only M1 in the context of some of these other molecules, we have NBI-'570 and NBI-'569 M1, and avoiding M2, M3, and M5, we actually avoid a lot of the issues associated with GI intolerability. We actually have safety data for all of these molecules, and we haven't seen much in the way of GI issues, and I'll be talking a bit more about that. In terms of other indications, we're exploring with these follow-on molecules, so really, this is a psychosis platform. In addition to schizophrenia and bipolar mania, we're also very interested in Alzheimer's psychosis, a huge unmet need. Clearly, it's a difficult area in terms of trial execution, and we're learning from the field. Clearly, there are others in front of us who hopefully will inform the whole field in terms of how to do successful trials in Alzheimer's psychosis. I should mention that NBI-'570 has a potential of being a long-acting injectable, which may be very helpful in terms of improving compliance in patients with schizophrenia, where potentially an oral medication might be difficult on a long-term basis. And then on the right, we have our VMAT2 inhibition platform. This is validated by our own molecule, Ingrezza, which obviously has done really well. We think that it's a really good medicine for tardive dyskinesia and Huntington's chorea. We know from a receptor occupancy point of view that it has very high levels of VMAT2 receptor occupancy. And to be candid, we know a lot about this area in terms of drug development, specifically how to correlate serum exposures with receptor occupancy in the brain, because we've done that correlation multiple times with both preclinical species as well as humans and patients. There we have two molecules, NBI-'890 and NBI-'675. And excitedly, they have the potential also to be long-acting injectables. So again, we feel that we can continue to be very present in the tardive dyskinesia community for the long term. So I'm going to start with Osavampator. I'm sure you're familiar with this to some extent. It's a first-in-class AMPA, positive allosteric modulator, or otherwise referred to as potentiator. This slide really relates to the huge unmet need in depression. And again, I'm sure you're very familiar with it, but I make no apologies here in terms of emphasizing the mental health crisis that we are facing really globally. In the United States, one-third of the 16+ million people who have depression don't respond at all to available antidepressants. And if one thinks about individuals who have an inadequate response to antidepressants, this proportion rises to just over half of individuals. So this is a substantial number. And again, I don't need to remind this audience about the alarming suicide rate in our young people. I know there's a debate about the contribution of social media and the COVID pandemic. What is not debatable is how alarming and real these statistics are with respect to this tremendous unmet need. So clearly, a lot of unmet need or room to improve with respect to efficacy. In terms of safety and tolerability, there are side effects with many of the standard of care molecules, including weight gain, sexual dysfunction, and sleep disturbances. Lastly, cognitive impairment is increasingly recognized as a big problem in major depression. It's something we're specifically interested at Neurocrine. Indeed, we have some interesting phase II data with respect to Osavampator. This is with respect to improving verbal memory and processing speed. Again, this is something we'll look further in larger scale studies. This slide depicts the mechanism of ketamine. This is on the left of this slide. And where Osavampator acts in this cascade. Ketamine blocks NMDA receptor on inhibitory GABAergic interneurons. It inhibits the inhibitory neurons. Essentially, it releases the brakes on glutamate. Hence, with ketamine, you see a burst of synaptic glutamate release. That results in an increase in AMPA activity, AMPA being another glutamate receptor, with an increase in M2 signaling and release of an important neurotransmitter called brain-derived neurotrophic factor. That results in synaptogenesis or the formation of new connections between neurons. This is thought to be really important in depression efficacy. This rewiring helps to break these continual endogenous negative feedback loop circuits that one sees in depressed patients. Now, there are issues with a burst of synaptic glutamate. Particularly, it might be associated with side effects such as psychotomimetic issues and memory deficits, which one sees after treatment with ketamine and esketamine. We're hoping to avoid that with Osavampator, which acts directly at AMPA receptors. So it does not increase synaptic glutamate. Indeed, it leverages endogenous physiological levels of glutamate at the AMPA receptors. It's a potentiator, not a true agonist. This is super important because, again, to be candid, we've been trying to have a molecule like this in industry. This is not just Neurocrine. I'm talking about industry in general for decades. And it's been really hard to have a molecule with low intrinsic agonistic activity but be a true potentiator. And I believe we actually have that molecule. So I'll show you the phase II data, which essentially validates to some extent the safety tolerability profile that we're seeing. Specifically, we're not seeing any evidence of psychotomimetic and memory deficits. So the phase II study is called the Savitri study. This evaluated the efficacy and safety of adjunctive Osavampator. That's our AMPA potentiator versus placebo in individuals who had an inadequate response to antidepressants. So that's important to note, this population. These weren't naive patients. These are patients who already had an inadequate response to up to five antidepressants. And this was a double-blind treatment trial, eight weeks in duration, placebo and two active arms of Osavampator, 1 mg and 3 mg. And we had some safety follow-up to that. And this slide shows the results. So on the left, we see the efficacy as judged by the MADRS scale. That's the vertical scale. The MADRS is an important endpoint, a regulatory endpoint for depression. So as you can see versus the orange line, which is placebo, with both our active arms, we're actually separating from placebo. And we're seeing the best separation with our 1 mg arm, which is the black line at the bottom. These effect sizes are actually quite striking. As you can see on the right, at one month, we see a decrease of 4.3 on the MADRS. And that increases to 7.5 at two months with a p-value of 0.0016. It's a highly statistically significant. And this effect size of 0.73, again, is striking in the depression field. We're typically used to effect sizes for efficacious agents in the depression field of somewhere ranging from 2.5- 4. So 7.5 is a big effect size. Now, what was just as important was how well tolerated this molecule is. And I'm sure Dr. John Krystal, who will be speaking later, will comment on the importance of safety and tolerability for prescribing psychiatrists with respect to keeping patients compliant in the long term with their medications. In fact, the adverse event profile for Osavampator at both doses was comparable to placebo. No evidence of glutamate toxicity with seizures specifically. I've mentioned the psychotomimetic and memory dissociative issues. No evidence of that. The discontinuation rate was similar to placebo. Really happy with this tolerability profile. Based on the phase II study, we've initiated phase III studies, specifically three phase III studies, which are eight weeks long, testing in a double-blind manner and a placebo-controlled manner, 1 mg of Osavampator. This is one-to-one randomization, which I think is very important in terms of minimizing patient expectation and minimizing a placebo response. This slide captures the entire phase III clinical program. At the top, you have the three phase III studies, which are all identical. Of note, there are only 200 per study. This is absolutely deliberate. What we're trying to do here is keep the phase III studies roughly similar to the phase II studies. And that minimizes site heterogeneity. We're expecting top-line data in the 2027 time frame. We're also doing a randomized withdrawal study, or otherwise known as a maintenance effect study here. Everyone is started on active treatment, 1 mg for about four months. And then stable responders are randomized to either continuing the drug or going on placebo. And lastly, we're getting some long-term safety data as well. So we would be able to file shortly after receipt of the phase III data. By that time, we'll also have some long-term safety. Randomized withdrawal study is not necessary for approval, but clearly, it would be potentially very important for payers and potentially prescribers down the road. Okay, so I'm going to move on to the second pillar, which is our muscarinic agonist portfolio. So I think the first thing here is that we have a whole spectrum of muscarinic agonists. Arguably, we have deep expertise in this area over a number of years. We've been able to dial in essentially what we wish with respect to how much M1 and M4 with some of these molecules. We're avoiding the other muscarinic receptors, specifically no M2, M3, and M5. Very unlike xanomeline, for example. That means that we essentially avoid GI tolerability issues. There's no concomitant need to administer a peripheral antagonist, which carries baggage in its own right. For example, trospium is a reason for the food effect with the Cobenfy formulation because its AUC is changed by food. On the left, we have Direclidine, which I'll be speaking about a bit more. That's our M4 orthosteric agonist, which is currently in phase III trials. I'll be showing you that phase III program as well as the phase II data. It's a once-daily drug. We're in schizophrenia right now. Also started a bipolar mania study. Again, we're very interested in creating a psychosis franchise with this portfolio. With NBI-'570, we have the potential for long-acting injectables. That just started a phase II study in schizophrenia, so that's moving quite quickly. That's a balanced M1 and M4 agonist. Moving along, we have NBI-'569, which is also a dual M1, M4 agonist, but with very interesting PK properties, so it has a half-life of up to 50 hours, has a delayed Tmax of six hours, and that confers a really nice, and again, this is with our data so far, so clearly, we'll be doing more safety testing over time, but so far, really good tolerability in the elderly population. And that's why we're interested in targeting that drug for Alzheimer's psychosis because we feel we'll have a good enough safety profile to actually prosecute that indication. So Alzheimer's psychosis, I'm sure many of you are familiar with it. Huge unmet need. Half of Alzheimer's patients eventually develop psychosis. And this can be really troubling for patients and their families. It's dominated by delusions. And often, these delusions are directed at their most close family members, like, "My husband is having an affair," or, "My children are stealing my money," etc. And there can be agitation and aggression associated with it. And particularly, the caregiver might be relatively infirm and frail. There are safety issues as well here. So it's a major cause for institutionalization or nursing home placement of Alzheimer's patients. So as I mentioned before, we'll be learning a lot about this area from others who are preceding us, but very keen to use this specific molecule in Alzheimer's psychosis. And on the right, we have an M1-preferring agonist, NBI-'567. M1 agonism is thought to confer cognitive properties, and Alzheimer's is a good indication for that, particularly in individuals where cholinesterase inhibitors may not be working well, and the reason they may not be working well is because one sees cholinergic denervation in many patients with Alzheimer's disease, so they lose the capacity to actually even make acetylcholine, so by having an M1 agonist, we essentially bypass the need for acetylcholine because we're working postsynaptically. Schizophrenia is an enormous agonist, a devastating disease. 3.5 million people in the U.S. suffer from schizophrenia. It's devastating because it affects patients early in their lives, often their teens and 20s. It's essentially a lifelong disease if you have it, and it impacts essentially your identity, human identity and functioning, and again, very sobering data on homelessness and incarceration, social isolation, etc. I think it's particularly tough for these patients because the drugs that we use to treat them have such significant safety issues. I think it would be difficult, frankly, for anyone in this room to have long-term compliance with these medications, just with even the best motivation and willpower. These side effects include weight gain, metabolic issues such as type 2 diabetes, extrapyramidal issues. That's becoming parkinsonian with a mask-like facies, a flat affect, and also potentially an irreversible disorder that obviously we're all very familiar with in this room, which is tardive dyskinesia. We can do a lot better for these patients with respect to safer medications, which ultimately will confer, hopefully, greater compliance. We can do better in terms of efficacy, particularly with respect to negative symptoms and cognitive impairment. I mentioned the prevalent social isolation that is consequent in these individuals, the inability to have functional employment for many. Negative symptoms and cognitive impairment are thought to be key drivers of that. The more we can do in that space, the better. This is our phase II data with Direclidine. I'm showing the 20 mg dose. Here we see an improvement in PANSS, which is the regulatory approval endpoint for schizophrenia. The effect size is pretty large, 0.61. Again, that ranks pretty highly with medications in this field at the top range. The absolute mean difference with respect to PANSS is 7.5. Here, the p-value at week six is 0.011. With respect to secondary endpoints, the reason I bring this up is when you have a phase two study, you're trying to figure out if you have a real signal or not. Is this a good enough efficacy profile for you to invest in phase III? And one of the things you look at is, well, what about the secondary endpoints? Do they match the primary endpoint? And with all the secondary endpoints, we just had compelling improvements, that 20 mg dose. And you can see these p-values. I mean, I like to see all these zeros after the decimal point. So these are highly statistically significant. And again, these are important approval endpoints as well, recognized by regulators: CGI severity and the MADRS factors, both positive and negative. Now, with respect to safety and tolerability, again, I keep going on about this, but it really is important, particularly in the psychiatry space. So here we have the different doses that were tested. 20 mg is the dose we're utilizing in our phase III studies. That's in the left column. On the right, you have placebo. The only thing that stands out from placebo is somnolence and dizziness, which are relatively mild in these individuals. Headache, for some reason, is enriched in placebo. From a GI perspective, again, as expected or by design, we didn't see any GI issues that were different from placebo. The rate of discontinuation was also similar. This is a summary of the phase II data on the left. We have the efficacy data. I've mentioned the effect size of 0.61, the impacts on both primary and key secondary endpoints. On the right, the safety and tolerability profile and highlighted the GI adverse events, but also other adverse events that are really important for patients with schizophrenia. Although admittedly a relatively short study, we didn't see any weight increase versus placebo or any of the extrapyramidal issues that one sees, particularly with antipsychotics. On the left of this slide, we have kind of intramuscarinic competition. Some of the key features, these are highlighted as specificity at muscarinic receptors. At the top, we have our drug, Direclidine, which has high selectivity only for M4, orthosteric agonist to M4. Because of that high selectivity, in contrast to the middle row, xanomeline, one doesn't need to add trospium or a peripheral muscarinic antagonist to treat all the side effects. You don't have, again, any GI issues. Now, in contrast to Emraclidine, which is the bottom row, which also is specific with respect to targeting M4, we're an orthosteric agonist. We activate these receptors regardless of the endogenous ligand. But Emraclidine needs acetylcholine to work. It's a potentiator. So we do feel we have an advantage there. But clearly, I think the proof of the pudding will be over time when those trials get up and running potentially. And that selectivity has advantages from a patient prescriber point of view. That's in the right box on this slide. So once daily, no titration can be taken with or without food. This no food effect by itself may sound trivial, but it's actually a massive issue for patients with schizophrenia. No significant GI issues. And I mentioned, in contrast to Emraclidine, we do not need the presence of acetylcholine. Okay, so our phase III studies are simple, short studies, five weeks in duration, double-blind one-to-one randomization versus placebo with measuring or testing the 20 mg dose. And this is a snapshot of our phase III clinical program. So we're doing two acute studies, not too big, again, deliberate, 280 patients each at relatively limited sites, about 20 sites each. Top-line data expected in the 2027, 2028 timeframe. Also doing a randomized withdrawal here. Everyone is on the 20 mg dose for 20 weeks. And then the stable responders are randomized to placebo, continuing the drug for a further six months. And the endpoint there is time to relapse, so an event-driven analysis. Again, not needed for approval, but may be very helpful data down the road in terms of prescribers and patients because it relates to more longer-term or chronic treatment. And then clearly, we're getting long-term safety data as well. The last pillar that I'd like to speak up for, I turn to Jude, is next-generation VMAT2 inhibitors. So we have a very successful Ingrezza franchise. We think that relates to its good safety and tolerability in the context of high levels of VMAT2 receptor occupancy. Here, with these two molecules, NBI-'890 and NBI-'675, which we already have clinical data, and indeed for NBI-'890, we'll be shortly starting a phase II study in tardive dyskinesia, we have the potential for a long-acting injectable administration. That's why we've designed these molecules specifically for these LAIs. And we think that will unlock new patient populations where oral therapies are challenging on a long-term basis. So in summation, my sense is that we are advancing an industry-leading neuropsychiatry portfolio. I do feel good that we are tackling really important diseases, important for society, important for patients, important for families. And if we can make a dent here in this neuropsychiatry space, I think the world will be a better place. This is one of the major reasons I actually joined Neurocrine. Now, I mentioned psychiatry space has been difficult with a relatively low probability of success for a number of reasons. I introduced our own portfolio with respect to how we've mitigated that risk by utilizing validated mechanisms and targets. What's really important as well with respect to success in psychiatry is knowing how to run successfully psychiatry studies. We believe we do have that expertise and knowledge, largely because we have a terrific team. I'll be introducing Jaz Singh soon. Jaz, who is our head of the psychiatry therapeutic area, was the lead developer of esketamine at J&J and also has done a whole bunch of other things in the psychiatry space, including haloperidol and risperidone. We're very fortunate that he's assembled really a great team over the years. So two main factors here. Firstly, optimizing trial design. So I mentioned keeping it simple. And there's actually good data showing that the more visits you have, the more frequent visits, the more intensive the monitoring is, the more procedures you have, the higher the placebo response. So there's some intentionality in terms of keeping the studies simple. Secondly, one-to-one randomization. The higher the patient expectation that they're going to receive an active treatment, again, the higher the placebo response. Great data. This is not theoretical. This is all fact-based. So we've kept our studies one-to-one randomization to minimize that expectation bias. Keeping the studies relatively small with a high degree of selectivity in terms of which sites and investigators to choose is also a really important factor. And we are also conducting iterative blinded data analysis to ensure that sites are enrolling the right patients. With that, I can see that we have Jaz and Dr. John Krystal waiting. I think I've already introduced Jaz. He is kind of a drug developer extraordinaire in the psychiatry space. I think he will introduce Dr. Krystal. I'll hand it over to you, Jaz. Thank you, Sanjay. I want to welcome Dr. Krystal, who's joining us today from Yale University. He is the chairman of psychiatry at Yale University with a number of distinguishing things in his career. I think one of the ones I really want to highlight because it was a huge part of the work I did. Dr. Krystal, you started work on ketamine back in the 1990s. Quite an interesting story there, which is well published, but that was really a huge part in the development of ketamine as an antidepressant, as well as fostering the development of esketamine or Spravato since then. Having seen the journey, I think we're really in a very fortunate time that the development of these new mechanisms really fostered a renaissance, if you will, for novel mechanisms sort of going past the 50 years of monoaminergic. Let's talk a little bit starting with depression, then we'll follow with other things. As a practicing researcher and clinician, what do you think are the current unmet needs primarily for depression? Sure. We have dozens of antidepressant medications. We have a number of approved antipsychotic strategies for augmenting the effectiveness of antidepressants. We have TMS. We have ECT. We have esketamine now. And yet depression remains a tremendous unmet need in our society where people are inadequately treated, commonly in clinical practice, where patients have low expectations about the possibility of getting better from available treatments. And so that depression remains one of the most substantial public health burdens in our society and around the world, with inadequately treated depression associated with about a 10-year reduction in life expectancy. If we were talking about cancer, everybody in the room would nod their heads. But it's a surprise for many people to think about depression as something that takes such a terrible toll. Yeah, 10 years of reduction is putting us back in the 1930s as overall life expectancy has increased. That's pretty shocking. Now, your lab has done a tremendous amount of work in characterizing the mechanism. In fact, Ron Duman, I think one of the earliest folks who really laid out the pathway that it wasn't just monoaminergic changes, but the downstream changes. Having done all that work on elucidating the mechanism of monoaminergics and then ketamine, I think that's going to pave the pathway for some of the work we're doing now with Osavampator and AMPA positive allosteric module. What do you think about this mechanism and how it differentiates from the effects that we see with ketamine? Sure. Well, Sanjay laid out the work that Husseini Manji first identified AMPA receptor as a key mediator of antidepressant effects of ketamine. Then Ron Duman worked out the circuitry of that. Sadly, Ron has since passed away. But our group has been studying, trying to translate these animal research findings into humans. And we've used a number of novel neuroimaging strategies to do that. And so we've been able to show, for example, that the magnitude of the increase in cortical glutamate produced by ketamine relates to the magnitude of the antidepressant benefits that it produces. And we've also been able to show that a single dose of ketamine can in depressed patients with synaptic deficits, as measured with SV2A PET, can increase synaptic density in those patients and that the magnitude of this restoration is related to the benefit of the antidepressant effects of ketamine as well. So the scenario that Sanjay laid out earlier related to antidepressant effects, which highlights a potential role for AMPA receptor stimulation in producing these beneficial antidepressant effects associated with ketamine, can be targeted potentially more directly with a drug that selectively activates or facilitates the function of AMPA glutamate receptors. What do you think would be the, I mean, ketamine, esketamine clearly are effective, but there are significant limitations in terms of adverse events which require monitoring of use, which limits its accessibility? Where do you think having sort of a mechanism like AMPA-PAM clinically would mean in terms of safety, monitoring, accessibility? Sure. You're absolutely right, which is that ketamine, esketamine are best administered within the clinic because it has to be administered at the dose range where it can produce dissociative symptoms, nausea and vomiting, and some other side effects. And so while the access to ketamine and esketamine is growing rapidly, esketamine's now in over 6,000 clinics and a market of, I don't know, almost $1.8 billion or something a year, that still constitutes only about 1.7% of the patients with treatment-resistant depression in the United States. And so treatments that are delivered in the clinic will probably not. There probably won't be sufficient access to address the major problem of inadequately treated depression. And a drug that is so well tolerated, like Osavampator, I've been practicing saying that drug name, Osavampator has the possibility of reaching a large number of patients that really can't come into the clinic or won't come into the clinic to get their treatments. And I think since you speak of this, we'd love to get your thoughts on what you saw from the study in terms of its efficacy as well as the safety data from the phase II study. Yeah, very impressive data. Almost over a seven-point drop relative to placebo at 56 days for the 1 mg dose is very impressive. Kind of interesting that at 26 days, both doses had a kind of similar degree of improvements, 28 days, excuse me. So I think that's pretty impressive, pretty impressive improvement, particularly since these are patients who have an inadequate response to treatment and probably would have a very poor response if they were treated with another standard antidepressant medication. What do you think about the safety features and especially in concern with the ketamine, esketamine, and the accessibility? Yeah, it's really striking that these drugs don't produce the kind of dissociative profile, the abuse liability associated with ketamine or esketamine. And while the abuse liability is managed in the clinic, there's very little misuse of these drugs prescribed in the clinic. Both the safety and tolerability profiles and the abuse liability are drawbacks of a drug like ketamine. And this drug doesn't seem to have any of those effects. No, thank you. I want to switch very quickly then to directly the muscarinics for this thing. So starting with a similar question, where do you think are the largest unmet needs for treatment of schizophrenia? Well, I think that there are a number of domains that are really critical in schizophrenia. One is around efficacy. Second is around safety and tolerability. And safety and tolerability are really important in relation to adherence to treatment, which is a major challenge for patients with schizophrenia. Around efficacy, as you were talking about our work with ketamine, we were convinced by about the mid-1990s that there were domains of schizophrenia psychosis that were not dependent on increased dopamine release. Some of this came from our work with ketamine, some from a study we did where we measured dopamine release and found that dopamine release following amphetamine administration is not found in about a third of patients with schizophrenia. So that we needed other mechanisms besides dopamine D2 receptor antagonism to reach the kinds of symptoms that many people with schizophrenia had. The second part of this is something that I think everybody in this room already knows, which is that one of the reasons that we all have been seeking drugs that treat schizophrenia using other mechanisms is to avoid the extrapyramidal symptoms, including tardive dyskinesia, but Parkinsonian symptoms that people have talked about, but the problems of things like bradykinesia and akinesia, which look a lot like the negative symptoms of schizophrenia and make people who have schizophrenia feel dulled and slowed down and not quite themselves. These side effects make many people reluctant to continue the medications once they start them, and medication discontinuation is a big problem in schizophrenia, so one of the things that's really nice is that the Direclidine is so well tolerated. We saw the side effect profile presented, and one of the things that these drugs that target these mechanisms have that distinguish themselves from D2 is people don't feel dulled. They don't feel drugged, and that's something that I think is very attractive to a lot of people, so now that we actually have a different mechanism, as in Cobenfy, approved on the market, how are clinicians actually picking between a D2 antagonist as opposed to a Cobenfy, well, for whatever reason, I think access to Cobenfy has been really relatively slow to roll out. I mean, we have it approved in our medical center, and we've treated a modest number of patients with it. Our P&T committee has mostly restricted us to using it for patients who have refractory extrapyramidal symptoms on traditional D2 antagonists. And so I think we're not yet realizing the most important benefit that these medications can have, which is to get people started on these medications early in their illness careers and get them to establish good medication adherence practices. And that will augment the pharmacologic impact of the benefits of these medications. So it's the P&T committee sort of really limiting access to a certain degree, right? Yeah, to some extent, yeah. I think as more data rolls out that shows the benefits around adherence early in the course of schizophrenia, that the prescribing practice will broaden. Cobenfy works primarily both on M1 and M4 for its efficacy in addition to the other muscarinic receptors. Now, you've seen that Direclidine works primarily as an M4 agonist. And then we have others in our portfolio that work on M1 and M4. In terms of efficacy for psychosis, what are your thoughts on M1 versus M4? And then downstream from that, potential role for some of the other mechanisms that we have on M1, M4. Sure. I think Cobenfy, for example, is a drug that its potencies for the M1 and M4 receptors are not that different. But in terms of its efficacy at those receptors, it's several-fold more potent or more effective in activating M4 receptors than it is activating M1. So it's hard to know exactly how relevant the M1 activity of Cobenfy is to its clinical profile. For psychosis. But even for cognition, given the Cobenfy, an overall analysis was not significant in their phase II published paper. It was only positive in a secondary analysis. The fact that there were hints of efficacy from Emraclidine in their phase I-B study that are echoed and amplified in the study that you all conducted, where you map out the nice dose-related effects of Direclidine, really, I think, argues that a lot of the antipsychotic efficacy that we've seen Cobenfy is probably related to M4 receptor activation. This issue of M1 and M4 is something that's going to need a lot more research to better understand because M1 receptor stimulation from the work of Amy Arnsten and Vijayr aghavan in non-human primates, it tends to have an inverted U dose response curve in terms of enhancing prefrontal cortical activity related to working memory. That suggests that in order to get pro-cognitive benefit from these drugs, you have to kind of get the ratio of M1 to M4 right at the dose that you're prescribing the drug, so I think this is a really interesting and potentially promising area, but the M4 story seems a little simpler at this point, a little clearer than the M1, M4. That certainly is. Before I get to the dose response for M4, I think that's very encouraging, at least the M4. You spoke about the different muscarinics and efficacy. I would love to get your thoughts also on the different muscarinic receptors and its relationship to safety. Sure. The challenge that Cobenfy has had is that its lack of selectivity for M1, M4 has contributed a lot to tolerability issues. And it was a brilliant thing to combine xanomeline with the trospium to block some of the peripheral side effects, the GI side effects, the nausea, vomiting, GI distress. Unfortunately, that depends on people actually taking the medication as prescribed, which is skipping breakfast to take the medication and waiting two hours after dinner to take the evening dose. And the problem is that many patients with schizophrenia have a hard enough time organizing themselves just to take the one pill a day at all, let alone timing it right for the GI interactions. And so what's happened for some people that have been prescribed Cobenfy is if they don't get it right and they take it on a full stomach, then that makes the tolerability a real problem. We've had in our center and other centers have had some patients discontinue due to GI side effects probably related to not taking it quite in the right way. Since you brought up the dose response, when you saw the data from the phase II study, what do you think of the dose response seen in terms of efficacy from the phase II study with Direclidine? I think it's really interesting. There are lots of reasons why you might have an inverted U dose response, why you might have a more robust signal at lower doses than higher doses. This is a common attribute in terms of cortical function for drugs that enhance cortical function by engaging inhibitory tuning. This is a drug, M4 receptors are on cholinergic terminals and glutamatergic terminals. It's enhancing the function of the brain by enhancing tuning, inhibitory tuning. But I think there's still a lot to learn about exactly why you have this apparent more robust signal from 20 mg relative to the other doses. One of the things, though, that was impressive to me and that gave me greater confidence about the 20 mg dose, the robustness of the signal there, was the fact that although it wasn't statistically significant, the magnitude of the clinical improvement in the 30 mg BID dose was practically the same as what you saw with your 20 mg dose. I think I'm confident about the robustness of that 20 mg signal. That's very helpful. What do you think, having worked on emraclidine as well, what do you think from an efficacy or safety perspective, sort of contrasting an orthosteric with an allosteric modulator for M4? Yeah, I think the allosteric modulators do depend on the availability of acetylcholine to stimulate the receptor. And they facilitate the activation produced by acetylcholine. We don't really know about in vivo acetylcholine release in schizophrenia. So it's hard to know whether these are really comparable approaches or not. An orthosteric agonist removes acetylcholine from the equation, as Sanjay highlighted, and so that you can directly stimulate the receptor regardless of background levels of acetylcholine stimulation. We don't really have strong evidence or really compelling evidence of acetylcholine release deficits in schizophrenia. But it is a little. Orthosteric certainly gives you a little more direct activation. Why don't we stop here and let the audience have some questions? Thank you. Thank you, Dr. Krystal. Thank you, Jaz. That was excellent. Let's open it up for questions. We have an awesome mic runner in Matt Abernethy. If it gets to you, go ahead, state your name, your firm, and fire away to Dr. Krystal. Thanks. Brian Abrahams, RBC Capital Markets. Thanks for the really helpful presentation. Two questions on Osavampator, one for Dr. Krystal and one for the company. I guess for Dr. Krystal, you kind of alluded to this. If you look at the MADRS curves in the study, there's a sharp decline through day 28, and then the higher dose levels out, whereas the 1 mg continues improving. So I'm curious if there's any mechanistic explanation for this, and is there any risk you might foresee of tachyphylaxis with your longer dosing or higher exposures? And then for the company, I'm curious if you give us some sense of how far along the phase III studies are at this point in terms of enrollment, just kind of broadly speaking, and the types of safety interim analyses that are built in. I guess I'm sort of wondering when in the course of the pivotal studies are you going to be comfortable that an epileptogenic signal is unlikely to ultimately crop up? Thanks. Sure. I'll start. And then, Jaz, maybe you can address the epilepsy issue. So first, usually don't expect as much tachyphylaxis from positive allosteric modulators as you sometimes do for orthosteric agonists. So I doubt that that's accounting for this. I would also say that we have to be really careful about overinterpreting one phase II study terms of day 26. They're looking identical, and they just have some divergence for the second part of that study. I'm not entirely confident that 3 mg is really less effective than 1 mg. If it is, there are reasons that you can get inverted U dose response curves. I mentioned a couple of them already. Maybe you recruit more inhibition at 3 mg or something. Hard to know. I wouldn't really want to mislead you. Sanjay, do you want to cover where we're at from an enrollment? Yeah, I can. Jaz, I'm sure you can jump in as well. The phase II programs are enrolling well. Indeed, we have to be careful about enrolling too quickly, to be completely candid, because it's all about quality, not so much speed. But we're certainly keeping to the timeline of top-level readouts in the 2027 time frame for all our Osavampator phase III studies. So that's great. With respect to safety, obviously, it's iterative in terms of blinded fashion throughout the entire study. Our expectation for a seizure is really low because of the mechanism that we described. But clearly, that's something that we'll be looking for throughout the extent of these studies. Yeah, I think just to add to it, so we have a committee that evaluates any events. And starting off, there's a more than 15-fold margin of safety from where you see with the dose we're testing with Osavampator and where you might see it. And so I don't really want to comment about safety from ongoing study. But you would see those events as you progress, even as the study is going along. So you don't have to wait for certain time periods before you get an interim analysis. You see that as the study is ongoing sort of continuously. Go ahead, Sean. Yeah, good morning. Thanks for taking my question. Sean Laaman from Morgan Stanley. I think I got it on the high level, just the M4 versus the M1, M4 debate. It appears that, if I got it right, that adding M1, it's not really clear if that adds any oomph on efficacy. But what it might do is just introduce the tolerability issues in the periphery, if I got that right. So why bother with M1? Yeah. I think the main reason to bother with M1 is the possibility of engaging these pro-cognitive cortical mechanisms if you get the dose right. Pro-cognitive effects of M1 are well described in animals and could translate not only to reductions in cognitive impairments, but potentially also to improvements in negative symptoms. And so I think that there's a lot of interest in trying to optimize that combination. It's just that it's hard to know, given the clinical profile of Cobenfy, whether they've achieved that. And we'll see whether the Neurocrine drugs can achieve that synergy. Go ahead, Tazeen. OK. Good morning. Thanks for hosting this. One for the company and then maybe one for Dr. Krystal. So for the withdrawal study that you mentioned, can you just clarify you do need it or you don't need it for ultimate approval? And then for Dr. Krystal, what kind of clinical advantage would data from a withdrawal study give to you to be able to prescribe the medication? And then maybe one top-level question. I think Marty McHarry recently talked about the need for potentially just one study across, I guess, everything unless otherwise specified. You guys are well into enrolling multiple phase III studies. But how does that potentially, if at all, change your game plan for how to seek approval? Thanks. Do you want me to take it? Yeah, why don't you start, and then I'll? Yeah. I think Dr. Keswani already pointed out the maintenance effect study is not a requirement for approval. So do you want to comment on the potential benefits of it? Sure. I think the discontinuation studies give you a sense of the durability of clinical efficacy once the medication is stopped. It tends to give a robust signal. It was a very robust signal for esketamine, the discontinuation study. That was helpful for giving added confidence to clinicians that the clinical benefits are real. Yeah, I just wanted to also address a prior question just to make sure there was clarification about M1 and adverse events. So we're not expecting any GI tolerability issues at all with M1. Indeed, the GI intolerability that's been seen with other muscarinic agonists likely relates to the other muscarinic receptors, i.e., non-M1 and non-M4. Most likely M3, but frankly, we're not sure. But not M1 and M4. So I don't want to give the impression that because we're targeting M1, that causes an issue in terms of tolerability. Then just to the question about randomized withdrawal. So yeah, this is really a nice-to-have, not essential for approval, actually for both our phase III programs. But we think we'll provide meaningful, durable data because obviously, a question that future payers may ask is some of the long-term efficacy data. And this provides that. Comment on multiple phase 3s and what we need to file in terms of. Yeah. And again, Jaz, I'm sure, who's been in this field for a long time, can address that as well. But so we need two positive phase IIIs. It's not unusual in the depression field to actually run three. But we need two to get the drug approved. Yeah, I think just to add, I think you commented on a specific publication recently on 2024 approvals that were all based on a single drug approval. That hasn't quite happened in psychiatry. But certainly, once we get our study, we will certainly put our foot forward and have that discussion with the FDA. So last question for this session. It's been really engaging. We're going to have some more Q&A after June. So everybody will get a chance to ask some questions. But Evan, do you want to wrap this up? Thank you, Matt. Evan Seigerman from BMO Capital Markets. So Dr. Krystal, you had mentioned that Cobenfy use is limited in your practice. I'm wondering how much of this is driven by the lack of adjunctive data or an indication. And more broadly, how important is adjunctive data for the potential of Osavampator? Yeah, that's a great question. I think we were disappointed that the adjunctive data were not positive for Cobenfy. And developing adjunctive treatments is more challenging than monotherapies because the effect size is smaller, giving you a risk of more negative results or failed trials, if you will. And I think for me, it's still an open question about the value of adjunctive data of M1, M4, and lots of unanswered questions in this space. But there's no doubt that a robustly positive adjunctive study would have helped us to make an easier case within our institutions for implementing it adjunctively. And the main issue there is around how do you transition patients from one treatment to another. And the most common way that medications are implemented is adjunctively. And then if you see good efficacy, you taper out the primary drug. So I think that practice will still continue in that way. But we hope to see more encouraging data from other studies. Great. I think we're out of time here. Thank you very much, Dr. Krystal. Thank you. Thank you for coming. I think you're sticking around for tacos. So if the audience has some questions for Jaz or for Dr. Krystal, he'll be out in the courtyard enjoying some fine food later. OK, we're close on time, a little bit over. Let's take a five-minute break, very tight five minutes, and then we'll start it up here with Jude. You have five minutes. If we can start gathering and sitting down again, please, about two minutes before the next part of the agenda today with Jude. While Jude is making his way to the stage, many of you may know he's been in industry for over 25 years, including a very illustrious stint at Eli Lilly, where his last role there was Vice President of Biotechnology Development Research. And then we were able to get him to join Neurocrine. Always a good day when I get to hang out with Jude because I just get smarter standing next to him. So Jude, why don't you come on stage? Talk about the R&D transformation progress that we've had since two years ago. And then once you're done with your talk, we'll open it up for Q&A with Jude and Kyle. Is this the clicker? Yeah. All right, Todd, thank you for the kind introduction. Ladies and gentlemen, good morning. And thanks for joining us for today's exciting R&D day. It's a great pleasure and honor to represent the work of our entire R&D team in providing you a high level update on our R&D transformation. Three years ago, at our R&D day, we laid out what was a bold agenda, a vision, and a strategy that we had dubbed 20 in 5, a strategy that is aimed at transforming Neurocrine to a high-science, high-productivity R&D organization, but with emphasis on scale, sustainability, and competitiveness. In that conversation three years ago, we made a commitment, four key commitments, pretty high level. First is to deliver a credible growth strategy. The second is to build a team to deliver on the strategy. And the third is to build the platforms, the modalities for sustainable delivery. And the last, and perhaps most important, is really to deliver a vibrant early-phase portfolio that will give us the confidence that we can reliably and reproducibly drive molecules to the clinic, through the clinic, all the way to commercialization. I would say that the last three years has been one of the most productive, most exciting of my career. And if I had to summarize it, the high-level summary or headlines would be that we've made remarkable progress on most of the themes that we covered in our last R&D day. For one, our 20 in 5 strategy is alive and well. We have now built that engine, the engine referring to the people, the platforms, and the modalities. And that engine is beginning to deliver on the promise of the pipeline that is evident in well over 35 truly exciting programs in our early-phase portfolio. And these efforts span our current therapeutic areas to emerging therapeutic areas. While sticking to a mandate in psychiatry, in neurology, you would hear we're building emerging franchise in endocrinology, as well as immunology. Today, if you ask me, I would argue that we're now at the dawn of a new era in our transformation. The question isn't whether we can do this, for we know we can. It's now a question of sustainability, i.e., continuing to maintain the momentum of advancing high-quality, high-value molecules to the clinic, all the way to POC and beyond. So today, I will take you through how far we've come, but with particular emphasis on where we're going. First, allow me to introduce the team that is powering this transformation. At the core of our progress is the leadership team that you see on this slide. These are platform leaders, therapeutic area leaders, distinguished scholars, external innovation leader, as well as members of our scientific advisory board. Many of these individuals are here today. I don't have time to go person for person through the slide, but I'll drive home a couple of points. First is from day one, our goal was to build an elite R&D organization that person for person will stand tall against any company in our industry today, and we have now assembled that team, a diverse, strong, diverse leadership team with expertise from academia to small biotech, all the way to large pharma. Expertise across the therapeutic areas, expertise across the platforms that we will discuss. These are proven leaders, leaders, drug hunters, innovators with truly proven accomplishments. I now have had the opportunity to work with these men and women, and I can unequivocally tell you that Neurocrine R&D is indeed in great hands, and so with the team on board, we then scrutinized where we've been to better define and divine where we needed to go. To frame our transformation, this is an honest or candid summary of our R&D engine pre-2022. The decade pre-2022, candidly, was a decade of limited internal innovation. Our external innovation engine has always been strong, remains strong, and remains a core competitive advantage at Neurocrine. But given the realities of the priorities at the time for the company, we didn't invest sufficiently to modernize our internal R&D engine. And at the time, we were a single modality, small molecule company that focused predominantly on novel, risky, and validated targets, with an overweight on neuropsychiatry, with emerging opportunities in neurology, with quasi-therapeutic area structures, and with a focus on symptomatic care treatment. As we have heard from many of you in this room repeatedly, we needed to modernize our base to lower risk, higher value, higher probability areas as it relates to modalities, as it relates to also therapeutic space. To be the company that we envisioned with an eye on leadership in the CNS space, we knew ourselves that we needed to build a more capable, more scalable, a higher productivity R&D organization that can reliably fill the pipeline with high-quality, high-value assets from research all the way to the clinic, to POC, and beyond. This realization became the foundation of our transformation. In 2022, we rolled out a bold agenda, an agenda we described as 20 in 5, an agenda or strategy that is aimed at building breadth, depth, and with a focus on reinvigorating our internal engine productivity and to support our vision of global leadership in the CNS space. Specifically, we set out to build a robust R&D innovation engine that can reliably and reproducibly deliver 20 new development candidates over five years. This is just an average of four to six development candidates on the average a year through both internal and external innovation across a range of modalities across our therapeutic areas, that at steady state, we hope and will pay out one launch product every other year. We anchored this strategy to a couple of fundamental tenets that are summarized on the right. The first is diversifying our therapeutic areas. Second is multimodality. The third is focusing on proven biology. And the last and important is to amplify our journey through external innovation. All of this towards one specific goal of building and delivering a diversified and sustainable portfolio across our therapeutic areas. To give you an idea of what our innovation engine, R&D engine has evolved to, I'm going to double-click rather quickly at each of the tenets of a strategy that is summarized on the right, starting with the therapeutic areas. To compete, to lead in the neuroscience space, it was important to redefine, refine where we needed to play, how we needed to play the core competencies that are needed to participate, compete, and lead in any space of our choosing. First and foremost, we focused on rebalancing our efforts to areas of greater needs, areas of greater probability of success. Specifically, if you recall, pre-2022, a huge footprint in psychiatry, while we remain competitive and committed to psychiatry, we downsized our footprint, at least in the early phase, to 25% of the portfolio, upped our investment in neurology, endocrinology, and we built an emerging new franchise in immunology that is applicable to every one of the therapeutic areas. This mix balances our core strengths with new growth vectors, and with psychiatry and neurology as our legacy pillars, endocrinology and immunology as new growth innovative spaces. As you heard from Kyle echoing the point, these are endocrinology and immunology have proven biology, proven endpoints, good molecular markers in the clinic, good clinical endpoint with higher probability of success, areas we believe we can quickly really design competitive differentiated molecules and winner. One thing these therapeutic areas have in common is confidence, confidence in the scientific validation, confidence in the clinical opportunity and the commercial opportunity, a disciplined approach that is necessary to create a sustainable portfolio while balancing risk. So that's the therapeutic areas. Next is the modalities. So to deliver to the therapeutic area strategies and their priorities, we moved very quickly to modernize our capabilities. And today, multimodality has become a signature component of our new R&D engine. While maintaining a competitive position in small molecule therapeutics, today, our pipeline or our early-phase pipeline boasts about 60% from new modalities in peptides, antibodies, gene therapy, and conjugates. And to make this work, of course, we built, we bought, we borrowed, we partnered to get access to the capabilities. And by integrating internal molecule design and engineering with access to external innovation, allowed us to accelerate faster and accelerate smarter. When you look at this, this range of options, or this breadth of therapeutic options offer us a couple of things: flexibility, optionality to match multimodality with biology, and to focus on the best of the best opportunities and quickly build candidates and advise clinical candidates forward. With the therapeutic areas in place, the modalities in place, I think it's fair to ask the question, where are we pointing this engine and what is our innovation philosophy? A point I want to drive home is that our productivity begins with a disciplined approach to portfolio design, which is summarized in this slide. To get to the future that we seek and to do it rapidly, we took a very pragmatic approach, a pragmatic approach that focused on proven biology. These are high confidence, high opportunity, genetically and clinically validated targets that we believe that we can quickly compete and win in, so we skewed our portfolio 75% more to these high validated, high confidence, high validated targets. A key component of the strategy, of course, is molecule design differentiation through molecule design and engineering, and to make this work, we went out and hired some of the best molecule designers and engineers that we can hire, and today, I can only unequivocally tell you that our molecule design and engineering is not just a competitive advantage, but we can stand competitive against just about any company, particularly any company in our size, and the last pillar of the strategy is around external innovation, a reminder that external innovation has been a true accelerant, major accelerant to our productivity. Our external innovation group, formerly, as you know, led by Kyle, and now led by my buddy here, high horsepower, Samir. We have seamlessly integrated external innovation with internal innovation as a boundless force of ideas, platforms, sometimes molecules, as the case may be. And today, our pipeline, especially early-phase pipeline, has a contribution for external innovation for about 50% of the programs. And again, this is an intentional strategy, a model that allows us to punch above our weight. And as we go forward, let me point out the deals such as deals with companies like Biocytogen, NeoMab for antibody discovery, peptide programs with Sentia, gene therapy with Voyager, small molecule with TransThera, just to name a few, allowed us access to differentiated starting points with very low entry costs, but with strong strategic value. And as we go forward, this build, buy, borrow, partner approach will continue to allow us to expand our reach, crush timelines, as well as also deliver on really great return on investment. And so three years into it, it's also fair to ask the question, what has this transformation delivered? I'll quickly add that the strategy and investment is truly delivering on the promise of the pipeline, evident in the momentum we see with new development candidates and the rapid advance into the clinic that we've seen. Three years in a row, we have met and exceeded our planned deliverables. You remember the four to six candidates a year. And today, cumulatively, we have delivered about 24 new development candidates through both internal and external innovation. These candidates are driving the flow of molecules to the clinic, evident in the increasing number of FIHs. This is also occurring at an accelerated timeline, a measure of improving R&D efficiency. This is also associated with increased productivity of both our small molecule engine at a time our biologics innovation engine has fully come online with the rapid delivery of seven peptide, three gene therapy, five antibody new development candidates. But importantly, behind that 24 candidates is that we have a prioritized pre-development candidate portfolio, high-value pre-development candidate portfolio that is prioritized one through end that gives us confidence that we can do this year- over- year. I can see two years. I can see three years out. This is best highlighted by this slide. In a short period of time, we have transformed and strengthened our early-phase pipeline. And today, we have the deepest, the broadest, the strongest pipeline in our history, a pipeline that spans across our four therapeutic areas, as you can see in the columns, a pipeline that now reflects our multimodalities, every single of the modalities that I mentioned earlier. While the numbers are impressive, what I'm particularly proud of and what my team is most proud of is the quality inherent in these candidates. Going from right to left, nine assets in phase I today across the therapeutic areas, 15 programs. These are 15 additional development candidates that are going through IND enabling studies. Four or five of these have already completed IND enabling studies with a plan to deliver maybe four, maybe up to seven in the clinic next year. And to the left, behind that is a pre-development candidate portfolio that is prioritized, ready to reload the development candidate portfolio. What this gives us, ladies and gentlemen, is reliable and reproducible flow to the clinic year- over- year. If you ask me, this is a portfolio that is built for durability, a portfolio that is built for long-term value with the flexibility, with the optionality for the patients that are waiting, and this brings me to this very important slide that was framed earlier nicely by Kyle, the importance of this slide, because the intent and the goal of all of this is to get to this vision of one launch product every other year. While we can debate the exact number, the exact flow, 423, we can debate the exact flow, but one thing is clear today, and what I can only unequivocally tell you is that we've built the engine. It has the scale. It has the diversity. It has the disciplined prioritization, the positioning as well, a positioning as well towards this future goal of one product launch every other year. At a high level, I hope this gives you an idea of the progress we've made in the last three years. Again, our 25 innovation engine is live and well. We have built that engine, the talent, the people, the platforms, the modalities, and it's delivering on the promise of the pipeline across our therapeutic areas. While sticking to our mettle in psychiatry and neurology, we're building rapidly an emerging franchise in newer growth areas such as immunology and endocrinology. In the interest of time, but candidly, for confidentiality reasons, I can only double-click on one therapeutic area today, and that will be endocrinology. I promise in the coming year, at an appropriate time, when Darin signs off on my ability to do that, we will discuss immunology as well as some of the other platforms, and so, on endocrinology, to understand our endocrine strategy and our progress, it was nicely framed by Kyle, back to the future. We leaned in on our proud past to create what we believe will be a truly, truly exciting future. As Kyle summarized earlier, and as you saw in the hallway coming in, Neurocrine was founded on the science of CRF. One of our scientific founders, late Wylie Vale, helped clone CRF, the ligand, and purify CRF1 in the late '90s, and cloned the receptor CRF1 and CRF2, and later some of the other ligands such as the urocortins. And since then, we have invested in multiple cycles of scientific insight, clinical learning, and this includes, if you look to the bottom left, as you heard from Kyle, advancing several CRF1 antagonists to the clinic, starting in psychiatry and to the right at the bottom to congenital adrenal hyperplasia. And as Kyle also pointed out in the middle top, in 2012, despite a successful proof of concept with our first CRF2 agonist program, this is urocortin II, a native ligand to CRF2, despite a successful POC in acute heart failure, we made a strategic decision to pause that program. And that strategic decision was a decision to prioritize Ingrezza. And looking at it today, what a beautiful and nice decision that funded Ingrezza. Bottom line, a 30-year head start that has culminated with Crenessity as the first CRF1 antagonist for congenital adrenal hyperplasia. I would say, given our leadership in this space, we know what we missed. We think we know what the rest of the industry missed. And we believe that we know how to do better with this pathway. And with this, consistent with that, in 2022, during our strategic refresh, we made CRF the strategic pillar for our endocrine franchise. We really focused our efforts on high-value endocrine diseases that have CRF as underlying pathology. And since then, I would say that the momentum in our endocrine pipeline has truly been exceptional. Specifically, we are focusing on an integrated two-receptor strategy that is summarized on this slide. To the left is CRF1 on the hypothalamic pituitary adrenal dysfunction. And to the right is CRF2 in metabolic disease, specifically obesity with muscle preservation. So let's take it one at a time. To the left, on CRF1, given our success with Crenessity, we believe, we know that we have tremendous opportunities to, frankly, strengthen our leadership, extend our leadership by building a moat around CRF1, by making sure that we provide the patients, the congenital adrenal hyperplasia patients and adjacencies, all the tools they need to better manage their disease. And we will do this by hitting this pathway a little bit different, a little bit harder, a little bit better, with new small molecules, longer-acting peptides, antibodies, as well as bispecific molecules, up, down, and in the middle of the pathway. And consistent with this, early in the year, we advanced our full-on molecule Crenessity, NBIP-'1435. This is a Q-weekly, perhaps Q2-weekly, long-acting peptide that hits CRF1 a little bit harder with longer exposure that is currently in phase I. We are also poised to advance additional innovation, additional candidates as antibodies, as bispecifics along this pathway, combining multiple components of the pathway for both congenital adrenal hyperplasia as well as the adjacencies. Speaking about adjacencies, to the right is our focus with CRF2 in metabolic disease. For avoidance of doubt, Neurocrine has been here before with CRF2 agonists, as I pointed out, with urocortin II in acute heart failure. I also have been here before in a previous life. Consistent with this, we will be advancing a novel, potent Q-weekly CRF2 agonist into the clinic in the first half of next year. With CRF2, and I hope to show you data that this offers a differentiated approach with relevance to cardiorenal metabolic disease, but with a specific focus with obesity and muscle preservation. But with CRF2 as a strategic anchor and entry point into obesity, we didn't stop there. We built a broader, what we believe is a complementary portfolio around current validated mechanisms, I'll show you validated mechanisms, and additional mechanisms that we believe could be combinable with CRF2 and so on. This would include a Q-weekly GGG agonist, a Q-monthly GGG agonist. And I'll get to some of the data in a minute. So why CRF2? And why CRF2 in obesity? We can all agree today that obesity is a big deal. Obesity therapeutics are changing and reshaping the world. While remarkable progress has been made in second and third generation obesity programs or the likes of the Incretins, we can agree that tremendous opportunities, of course, remain to shape and reshape this emerging space. And to this, take a look at current market leaders. The current market leaders, as well as much of big pharma, are scrambling, scrambling to reposition and position in the next round of innovation in this space. And that underscores our interest, next round of innovation. And while GLP-1, the epicenter of obesity today, is highly competitive, we can also agree that there is tremendous opportunity for new mechanisms, new combinations, delivered a bit differently. And so to this, importantly, we believe that CRF2 offers an important and attractive and differentiated entry into the obesity space. And given our leadership in this space, we see this as a vantage point and an entry for us to get into the obesity, the adjacencies of obesity with muscle preservation. And so I'll tell you a little bit about CRF2. So to the cartoon on the left, this system, the CRF system, is a four-ligand two-receptor system. We previously talked about CRF1. Unlike CRF1, that regulates the hypothalamic stress response and hypothalamic pituitary adrenal axis, CRF2 regulates stress recovery and homeostasis. Loss of function of CRF2 results in increase in anxiety, altered metabolic homeostasis, including stress-induced hyperphagia. And to the right is the expression of CRF2. It's expressed in good levels in the brain, in the periphery, in the heart, skeletal muscle, kidney, adipose tissue, and somewhat in the gut. And when you agonize this system, at least in animal models, all the way to non-human primates, you see a robust reduction in food intake, a robust reduction in body weight. But in addition, you build muscle. You enhance cardiac function, and you improve renal function. This is particularly important, given that current therapies in the obesity space, the likes of the incretins, while they deliver really great weight loss, 20%-40% of it today seem to come from lean mass. Considering the importance of muscle in support, in mobility, and in metabolic health, muscle preservation in the context of weight loss represents a future state in obesity. Consistent with that, we moved very quickly to build a Q-weekly potent, novel, very well-behaved CRF2 agonist, which I will, for simplicity, call NBIP-'2118, with a goal for obesity with muscle preservation as monotherapy, but considerations as potential add-on, follow-on, combination therapy, maintenance therapy, as the case allows. I'll show you some of the data on NBIP-'2118 next. In our gold standard diet-induced obesity mouse model, as you can see, doses of NBIP-'2118 in the shades of blue color, as you can see, a dose-dependent decrease in food intake to the left, a dose-dependent decrease in body weight in the middle, and improvement in glucose tolerance to the right. What is perhaps most important is that this is competitive or more than competitive against an industry-leading dual GLP-GIP benchmark that is shown in the orange. Of course, while we're excited about this data, we're even more excited about the body composition data. And again, going from left to right, like the industry-leading dual GLP-GIP benchmark, NBIP-'2118 drives a dose-dependent decrease in fat mass. But unlike the industry-leading dual GLP-GIP benchmark that decreases lean mass robustly in the middle, NBIP-'2118 is either sparing or actually increases lean mass. This is best illustrated to the right in the qNMR data showing the contribution of fat in red and lean mass in blue to the overall body weight loss. The first bar there is the industry benchmark dual GLP-GIP. In our experiments, we see anywhere from 20%-30% weight loss driven from lean mass. By comparison, so in contrast, NBIP-'2118, as you can see, dose-dependently decreases weight, but driven mostly from fat, with little to no decrement in lean mass. In fact, as you can see at the lower doses, the first three bars, you can see an increase, actually an increase in lean mass. This is very exciting. Needless to say, we've completed IND-enabling studies with this program. And the program is on track to go into phase I in the first half of next year. Well, in case it's not obvious, we're super excited. We're super excited about the differentiated option that NBIP-'2118 or CRF agonism can offer, robust weight loss, but without sacrificing lean mass. And so to win on CRF2, we have taken a disciplined, a very disciplined approach, a disciplined approach that has allowed us to think about future combinations with currently validated mechanisms, and frankly, future mechanisms that I won't talk about today. A dual strategy, at least for the purposes of today's discussion, that focuses on the ability to combine our favorite CRF2 agonist with our own proprietary GGG Incretin, either as co-formulation or co-injection to the left, or building a univalent, all in one molecule that combines the pharmacology of CRF2 with that of the Incretins. This dual approach, of course, gives us the opportunity for multiple TPPs to meet. Again, when you look to the left, it's variable ratio. To the right, it's fixed ratio. This multiple TPPs allows you to meet the varied needs in the growing obesity market today. Of course, each of these approaches has its strengths and, of course, its challenges. It suffices to say we've done both, and I'll show you some of the data. We began, first and foremost, with building our own proprietary GGG Incretin, a GLP-GIP glucagon agonist, a Q-weekly molecule. And as you can see here, the combination of this triple agonist with the CRF2 NBIP-'2118, if you look at the pharmacology, pretty compelling data in terms of weight loss. In the red is NBIP-'2118, a dose of NBIP-'2118. In the yellow is a dose of our proprietary GGG. Combinations of these two are different ratios in the light blue, brown, and in green, different ratios. As you can see, you see a rapid, a deep, durable weight loss. And to the right, again, going back to the body composition data, again, much of the body composition, when compared to GGG, which is the first bar there, we're at 23%. We typically see 23%-25% or more coming from lean mass. As you can see, the combinations drive weight loss through fat with little to no effect on lean mass. So going back to the dual strategy, this is the combination or co-formulation approach. We have also built a univalent, all in one molecule that combines the pharmacology of CRF2 with a GLP and a GIP. So this triple agonist is what you're looking at. This triple agonist, as you can see, also drives a dose-related and dose-dependent decrease in body weight. And to the right is the exciting body composition data. As you can see, the last three bars there, when compared to GGG, where you see losses from lean mass, almost all of the weight loss is coming from fat. In fact, at the lower doses, as you can see, you see an increase in lean mass. Taken together with the combination studies that I've shown you, we believe that this is the kind of profile that is needed in the post-GLP world: profound weight loss without sacrificing lean mass. And again, we are moving as aggressively as we can to advance these molecules and combinations thereof to the clinic. But we're not done. We have also built what we believe could be a leading Q-monthly, maybe Q3-monthly, best GGG incretin with emphasis on superior weight loss and convenient delivery. But given the flat exposure profile of this molecule, we believe will also improve tolerability. This molecule, TGFc, combines, of course, the triple agonism from GLP-GIP glucagon to drive maximal efficacy, but with an intentional design that tones down the glucagon activity, that tones the Fc region for half-life extension. As you can see, pretty compelling biology to the left in the diet-induced obesity maps. A rapid, dose-dependent, durable weight loss. In fact, at the highest dose, which is by no means even a high dose, you are pushing the limits of what you can actually do in this diet-induced obesity. Animals are losing 50% of body weight in two weeks. As engineered, the PK profile of TGFc is indeed another differentiator. A single sub-Q injection of TGFc, as you can see, in non-human primates, you can see TGFc levels are high. They are stable and flat all the way. If you look at the table, we have a half-life in non-human primates of 21 days. This level of durability is very difficult to achieve using other current peptide platforms. For comparisons, we just included in the table two examples of molecules that are currently in the clinic that have Q-monthly potential. To summarize, I hope this gives you an idea of the progress we're making, at least in the obesity space. In a short period of time, we've built quite a portfolio, a portfolio that boasts multiple opportunities. Central to our strategy, of course, is this strategic entry through CRF2, a differentiated mechanism that focuses on better quality weight loss. But we didn't stop there. We've built a broader portfolio, a broader differentiated portfolio that we believe is complementary, combinable with current validated mechanisms, as well as future mechanisms to come. This gives us the opportunity to address different needs while minimizing the risk of relying on a single product or approach. We believe that this strategy and this portfolio, which I will argue is the tip of the iceberg, really, really positions us well to be competitive in the future obesity space. Speaking about the future obesity space, I want to end by impressing on you. We're not trying to beat the GLPs. We're designing and advancing the next generation after them. I think it's important that I emphasize that some of us actually contributed to the discovery and development of some of the much-celebrated Incretins today. I want to end with a high-level introduction of some of the members of our teams. Behind every member I introduce, remember, there is a layer of commensurate expertise and experience. I will start with Krister Bokvist. Krister is a senior director in the metabolic disease space, 25 years' experience in the industry, ex-Sanofi, ex-Lilly. Krister is one of four inventors of Mounjaro and Zepbound. Next is Adam Mezo. Adam is a VP of research in peptides and bioconjugates, again, 25 years of experience in biotech and large pharma, ex-Biogen Idec, ex-Lilly, ex-Ferring, while at Lilly, Adam led the peptide team that discovered Mounjaro, Zepbound, Retatrutide, and Mazdutide. Adam is the chemist and the inventor of Mazdutide, which is approved in China for obesity and diabetes and is currently undergoing clinical development in the US. Fiona Scott. Fiona is our VP for a neuroendocrine therapeutic area on the research side. Again, 18 years of experience in biotech and pharma, ex-Receptos, ex-Celgene, remarkable background in metabolic disease and immunology. Then Gene Chen. Gene is our VP on the therapeutic area on the clinical side, endocrine therapeutic area on the clinical side, an endocrinologist with 25 years of clinical research experience, including time at Amylin. Gene, in case you're wondering, Gene led with the clinical lead for a chronicity program, leading it all the way to approval. Next is Chad Paavola. Chad is Executive Director. Chad leads our biologics lead optimization team. Again, 24 years of experience in biotech, ex-NASA scientist, ex-Lilly scientist, inventor of Lyumjev. Lyumjev is ultra-rapid insulin. Next is Andrew Ratz. Andy is a Senior Vice President of CMC, Delivery and Devices at Neurocrine, 29 years' experience in CMC, delivery and drug combination. His last role prior to leaving Lilly was Senior Vice President of Delivery and Device. Andy led the team that delivered on the delivery and device of many of the biologics, including the most celebrated incretins. And last but not the least is Tom Bumol. Tom is a member of our scientific advisory board. Tom is also a former Senior Vice President of Research at Lilly. Tom, if you ask me, is the architect of modern-day biologics and modern-day immunology at Lilly. I reported to Tom for 12 years as the Vice President of Biologics Research, my last 12 years at Lilly. And together, we led a biologics research organization that delivered well over 65 clinical candidates, 10 of which are approved drugs today and counting. I share all of this for one reason and one reason only, and that is to say we know what we are up against. Thank you for listening. Thank you, Jude. That was awesome as always. Let's go into questions for about the next 20 minutes or so, and then Kyle will provide some closing remarks to keep us on time, so where is my mic runner? Oh, there you are. Here. Jude, thanks for everything. Thanks for that suit, well, it matched the slides and a lot of substrate that we now have in the company, so appreciate that. First question comes from Jay. Thanks, Matt. Hey, guys, thanks for hosting us here today and providing this impressive update, and congrats on nominating NBIP-'2118 as your lead candidate for the treatment of obesity. It's a really nice surprise, and of course, it raises a lot of exciting questions, so I'll try to limit myself to a few, but with regards to target validation, is there any human genetic data that may support the role of CRF2 as a target for obesity? And also, if you could please comment on the need for brain penetration versus peripheral activity for your CRF2 agonist. And then also, just curious if you plan to develop NBIP-'2118 in combinations that may potentially allow a lower dose of GLP-1, or do you plan to develop NBIP-'2118 more as a standalone program for induction or maintenance of weight loss? Thank you. Really quickly, we'll answer the first question. How about that? So we can get around this like an earnings call, Jay. Second one too? Okay, first and second. All right. So what is the first one again? Anyway, I get it. There is limited genetic evidence on CRF2. But what we do know is if you look in the literature, some of us have worked in the space for a long time. If you look in the literature, the preponderance of evidence in pre-clinical models all the way to non-human primates gives you confidence because you see reproducible pharmacology in, frankly, just about every pre-clinical species all the way to monkeys, and so the ultimate test, of course, like most novel target, really comes from the clinic, seeing what happens in the clinic, but if you look at the data in non-human primates, I'm betting on this one. The second question is the brain component, so how does CRF2 work? If I went through very quickly in terms of the receptor expression, the receptor is expressed in the brain. We see effects in the brain. We have done c-Fos positivity mapping regions of the brain where you light up with c-Fos. We see overlapping regions with GLP-1, but we also see distinct regions. We think that the weight loss effect, at least the food effect, comes from hitting brain centers for hunger, feeding, and satiety. We also see, we've also studied beyond the brain. We've also looked at activity in the periphery. In the periphery, you see effects in muscle. If you look at skeletal muscle, you see not just lean mass. You see actual increase in muscle mass. We see increase in muscle fiber. We see increase in muscle function. We've tested even effects on muscle force contraction. You see an effect in muscle force contraction. And when we look at the profiling in the muscle, what we do see is anabolic mechanisms, increases anabolic opportunities. If you look at the genes and proteins that play a role in building muscle, they go up. Genes that are catabolic to muscle go down. This is the opposite of what we see with the incretins, stark opposite of what we see in incretins. We see also increases in protein synthesis and so forth, so all suggesting anabolic effects in skeletal muscle. When you also look in the heart, you see increases in cardiac output. And the increases in cardiac output is pretty evident. Without increasing, having negative effects, you don't have cardiac hypertrophy. You don't see hypertrophy, but you see increase in function, increase in output, as well as a decrease in peripheral resistance. The one thing that I would add to this, obviously, it's an area of biology that we know quite a bit about. I introduced Dr. Wylie Vale as someone that was quite significant in our history here at Neurocrine in terms of setting up the company. We have someone almost an equal, say almost, because he didn't actually bring it directly to us, but he spent his entire career working in CRF. That's Dimitri Grigoriadis. He is here in the audience today, so if you ever want to pick his brain about CRF, he's here. But at the heart of the matter, CRF is central to the fight-or-flight response. So if you look up anything on CRF, you'll see how that plays a role. So when you think about that, it's increased alertness, it's weight loss, it's increased performance, and that's why CRF is such an attractive target for us, either on the side of CRF1 or CRF2. There's a lot of research that's been done over the years, a lot of it pioneered by Neurocrine, but it's an area that it's an incredibly important biological target within a variety of diseases. And that's why I say and introduce CRF2 as something that is going to have a broad applicability across a range of metabolic disorders. We've seen it. We've worked on those models here over time. Go ahead, Kyle. Kyle, I will add, while I was at Lilly, my first knowledge of Neurocrine was actually around CRFs, including CRF2. And to the question about clinical validation, to Kyle's point, our heart failure data reproduced the cardiac effects that you see in pre-clinical models. You see an increase in output, cardiac output with decrease in peripheral resistance and pulmonary artery pressure. So that part is validated. But that was an acute study. Thanks. Myles Minter from William Blair. Thanks for having us all here today. Appreciate it. My question's on NBI-'569, and I think the comment that it was well tolerated in the elderly population in the phase I there. Are we going to see that data? And if we're not, would you be comfortable in saying that it looks like the profile of Direclidine that you saw in the adults from a safety perspective? And then secondly, just the 35-5 0-hour half-life there, how does that impact titration in an elderly or an Alzheimer's disease population? Thanks. Yeah, really good question. So NBI-'569, just for everyone's context, is a relatively balanced M1 and M4 agonist. So I'd mentioned that with respect to its PK profile, we see a delayed Tmax of about six hours with a pretty long half-life, about 50 hours. So in our studies that we've completed with respect to an SAD and MAD study, largely in healthy volunteers and elderly individuals, we've actually seen good tolerability. What we're specifically looking for, obviously, are things like GI issues. We haven't seen much of that, and we're not expecting that because it's not hitting the non-M1 and M4 receptors. We're also looking at cardiovascular issues, the propensity for postural hypotension, and falls in an elderly population, which would be issues that might be problematic, particularly in an AD psychosis population, which is clearly where we're looking forward. I'm not going to quantify the data at this stage. I think that'd be stealing the thunder. I'm not sure about actual presentations. Maybe I'll turn to you, Kyle, in terms of that data next year, but we'll certainly have the ability, or we'll certainly have the data present next year if that's what you want to do. Yeah, I think we'll have the opportunity to look at a number of programs that could present phase I data. I mean, personally, I don't know how you all feel, but phase I data is in healthy volunteers. It's not in the patient population typically. So I think you can get some directional information, but the more attractive thing for me is if you see what you need to move the program into phase II. That being said, across the muscarinics, across some of our other neurology programs, across our VMAT2 inhibitors, there is going to be an opportunity for us to share phase I data. So I think it's a function of us getting together as a team and see what would be most impactful, hearing your thoughts on what would be the most interesting, and we'll see what we can get out for next year. So it is something that we'll look at. You will see phase I data next year. I think it's a function of what data it is that's going to be the most impactful for you all. Yep. Thanks, Corinne Johnson from Goldman Sachs. Maybe a bit of a strategic question, which is, what was your philosophy as you thought about leaping into the obesity market as to where this is going with respect to patient stratification across modalities, magnitude of weight loss, the muscle sparing benefit? And how do you think about where these programs could fit relative to a relatively intense competitive landscape? And then a related question on strategy is just how do you think about your capabilities to pursue late-stage development and commercialization in this market? Those are a lot of great questions. I think first and foremost, we believe with CRF and CRF2 specifically, that you've heard me say it a couple of times up here today, that's a real competitive advantage for us. We know the space very well. We know where the biologists can take us very quickly. And speed is going to be a very big part of what we look at here in terms of these programs across obesity and other diseases where these might be pointed towards. We do have a clinical team that has experience in endocrinology, along with Gene, and what she's done with Crenessity. That team continues to scale to help us bring those programs forward that are entering the clinical development space now, whether it's NBIP-'1435 or the programs that we mentioned here today. So those will grow with the teams as we need them to do so as they move from phase I and phase II. But we feel that we're well situated as a company to move those forward aggressively. And given the scale of the company that we have today and our financial profile, we think that we've got a good opportunity here to offer something differentiated for patients. And then when it comes to commercialization, let's get some data first in the patient population, see what that profile looks like, and then let's have that conversation. It's a fair question. Great. Thank you. Yigal Nochomovitz from Citigroup. Two questions. On the CRF2 mechanism of action, I was wondering if you've seen any evidence of brown fat preservation in addition to the lean muscle mass preservation, given the positive attributes of maintaining brown fat could have on metabolic health. With regard to going back to neuropsychiatry, for NBI-'569 or NBI-'567, did you consider potentially, or would you consider Parkinson's disease psychosis as an expanded indication? Thank you. I can comment on the brown fat component. We have not looked at brown fat, but overall, when we look at fat loss, as you could see, you see a significant loss in fat. Others have. As you know, the brown fat data in rodents have seldom translated to man. The extent of that data and the emphasis on brown fat in rodents isn't really a space that we have spent much time on. With respect to the second question, so actually we're very interested in Lewy body dementia, which has parkinsonian features as its core symptomatology. And so we may have an advantage with treating both psychotic symptoms, but also the cognitive impairment that one sees in these patients with dementia. I think in Parkinson's disease psychosis, the other complicating factor you have here with the muscarinics is that still the net effect here is locally to the target itself. You deplete or decrease dopamine, and that can complicate the treatment of Parkinson's. So certainly something on a radar, but not as straightforward or I think as validated as Sanjay suggested moving into Lewy body dementia. Thank you. Mohit Bansal from Wells Fargo. First of all, thank you very much for inviting us here. We cannot complain about the weather coming from New York. So two questions, if I may. One for Sanjay, one for Jude. So Sanjay, thank you very much for all the help about the simplicity of these trials because they are important. There are other elements as well in neuropsych trials, which are centralized review, making sure there's less variability among centers and everything. Can you talk a little bit about what you are doing more in detail to make sure you ensure success here? That's number one. And our CRF2, so CRF2 as a target is expressed in CNS. So given the history with CB2 target, I mean, the anxiety and/or depression, all those issues there, how are you ensuring that the weight loss doesn't come with the cost of some kind of CNS issues? And what should be the safety issues or tolerability issues we should be keeping an eye on, given that it's a different mechanism versus incretins? Thank you. Yeah, I can take the CRF question and the CNS. When you look at the expression of the receptors in the brain regions and what we have mapped, you see effects mostly on centers that drive feeding, motivation for feeding, as well as energy expenditure. Unlike what you see with the cannabinoids, which you referenced to, this mechanism actually is an anxiolytic. Its agonism is the opposite. It's an anxiolytic versus the CRF1 pathway, which actually drives anxiety and so forth. But it's an excellent question. For a new mechanism going into the clinic, you have to carefully, we don't think this is part of the mechanism, but in the clinic, you have to monitor carefully many of the safety considerations. The only thing I'd add to that, and there's a bit of humor in this when I mention this, but at least when it comes to CRF1, we've studied that mechanism in a variety of diseases, and we haven't seen anything in terms of psychiatry. So does that paint the whole view and picture? Maybe not. But it does lean you into thinking about this mechanism, whether it's R1 an antagonist or R2 being an agonist, of having more applicability when you're working in systems that have dysregulation of some sort, whether it's hyperactive or hypoactive. That seems to be the better place where we've seen efficacy. And I lean into Crenessity there as an R1 antagonist and CAH being a disease of HPA axis dysregulation. Maybe I'll just quickly address the first question in terms of how we mitigate the placebo response and essentially execute our psychiatry studies. Yeah, so to your point, careful site selection is important. We have some experience with that from our prior phase II studies. And essentially, really what we want is the best patients being recruited. There's unfortunately a phenomenon of so-called professional patients who go from one trial to another, who essentially inflate baseline scores just to get into studies. And then as they enroll in the study, there is a sudden big drop, which has nothing to do with the active treatment, essentially. So minimizing that is important. We do look at all the rater recordings as raters discuss with their patients or enrolling patients, and that's reviewed centrally to ensure that there is quality in terms of enrolling the right patients. Also, we have a blinded analytical process as well, where we look at patient data in a blinded fashion from sites, again, ensuring that they're enrolling the high-quality patients. Great. Thanks for taking our questions, Ash Verma from UBS. So how are you thinking about the psychedelic or non-hallucinogenic space as a focus of your pipeline? You have 770, but just in terms of extending your leadership as a CNS company, why not get more aggressive in this space, either internally or externally? I mean, I've seen a lot of good data, FDA, HHS support, and big pharma M&A validation as well. So just curious, what's your take on this? Thanks. Well, I think we're thinking about it, right? Yeah, so we're watching the space very carefully. I mean, from a clinical trial point of view, I know there are concerns about can you really blind these patients because their experience is just so vibrant and clearly could be really hard to reproduce in a placebo arm. Looking very carefully at the companies currently right now, which are seeking approval. So I'd say we are interested in this space. We don't have any active efforts right now, though. He's looking at me. I think he's right. We're looking in the space. I think the key component is finding good tractable target handles that can allow you to separate the pharmacology, the good and the bad, and we have some target ideas, so I would say stay tuned. Yeah, I would say that first and foremost, do I think that there's value for patients here in psychedelics? Absolutely. I think that's something that has been reinforced over the past several years. Am I convinced that the molecules that are out there today, in particular those that are more or less natural products, give you the opportunity for strong intellectual property and commercial return? I'm not there yet. It's a very crowded field, and how you can convert the good data into a commercial opportunity that gives the company, not just us, but those in that space, the shareholders that return, that's what's still unclear to me. I think that's why we haven't seen a lot of compani dive into that with both feet in. Anupam Rama, JP Morgan. Excuse me. Any chance you might pre-announce? No, I'm just kidding. Just a broader strategic question for me. On the slides, it said 15% of your resources or kind of pipeline are coming from endocrinology, but we focus so much today on CRF. As we look five years, any chance that that 15% grows more given the history of the company and your background? You know, if I go back a couple of years, even before Jude joined in 2021, our program was heavily weighted towards more of a pure-play neurology. And it was done so for some of the reasons that I articulated here. In some of the therapeutic areas, you have, I'd say it's not 100%, but biomarkers, more objective endpoints, the ability to see probability of success or activity before a phase III trial. Neurology offers that more so than psychiatry. Interestingly enough, as time has gone by, our neurology assets didn't move forward. We didn't get the data. We didn't hit the profile that we're looking for, but our psychiatry assets won. So I think number one is you do your best to target an ideal profile, but you go where the science takes you, and you maximize that when you've got it. And that's where we are with psychiatry. When it comes to the other areas, I mentioned in my introduction this concept of bridging the past, present, and future. And it really is kind of a three-pronged strategy. It goes with building out neuropsychiatry first. That's what Ingrezza gave us the ability to do. And then with Crenessity, and given our recent investments in endocrinology, it makes sense to have invested in endocrinology as our second kind of next tier of programs coming into the clinic. And then our profile of the company allows us to invest in those other areas that we have strengths in. And we need to fill in the back part of the pipeline there in neurology and immunology. And kind of stole my thunder here, but in 2026, we'll look to get some time together to review the emerging pipeline in those therapeutic areas as well to see what's emerging there because they're trailing a little bit of what we're doing in endocrinology, but they'll catch up as well as things move into the clinic. But that is an ideal profile where you're looking after neurology, endocrinology, immunology comprise the larger composition of your portfolio because of improvements in access to biomarkers, objective endpoints, and seeing data sooner rather than later. And then the psychiatry portfolio, we would expect to have the right mix over time, which is maybe in the 25%-30%. But again, we're going to follow the science here in the pipeline. Well, tell us what that composition should look like. Hey, team. We're going to have our last question before we jump into Sumant's last question. I did have somebody in the audience ask when will they learn more about the gene therapy programs. So comment on that, and then Sumant will wrap it up. So on the gene therapy side of the equations, we have a number of programs that are still being executed and developed in the preclinical setting. One of the things that we've done in the gene therapy space, and it's probably not surprising to you all given some of the challenges here, is we've set a very, very high bar for safety, and we've overlaid that with putting the programs that will offer clearly transformational therapy in the disease states that we're working in. So we know that if we add this gene, we know that with certainty, we're going to be able to help that patient. So those programs are coming along. We'll have an update on those, I think, at the turn of the year on where we're moving those programs moving forward. But when you have a portfolio like we have now, we do have the luxury of having to choose among a number of different programs. And we do use prioritization as something that's a key part of our day-to-day kind of oversight and management of the portfolio. And that's a luxury that we do have and lean on. So we can set that high bar for gene therapy. You can be assured that as one moves into the clinic, all those elements I just mentioned would have been achieved with that program. Was there another question there? Sumant Kulkarni from Canaccord Genuity. Thanks for hosting us. When you eventually get to later stage trials in obesity, what specific endpoints do you expect to use to best tease out the quality of weight loss versus simply quantity? And on the muscarinic agonists, you mentioned a couple of times that you expect to learn more from others' experiences with those programs. So what specifically do you expect to learn from Bristol's Cobenfy experience on the ADP side when it comes to muscarinic agonist safety in older patients? I'm not going to comment on the clinical execution for obesity. I'll let Sanjay comment, except to make the point that one of the beauties of the obesity space is successful prosecution of many molecules. And second, the next molecules, muscle play, the combinations, the likes of bimagrumab, myostatin, and things like that will offer us great handles that we can follow. I suspect, once we get into phase I, we will be in a place to really begin to outline what it is we're going to do or not do. But I'm not. Sanjay can better comment on the clinical. No, I think he did a great job. That's brilliant. I mean, that's a nice thing. We have a template to follow. Clearly, it's not just about weight loss for us. It's about what kind of weight loss. But we have the ability to quantify, as others have done, in terms of what weight loss is being constituted, whether it be fat or muscle, et cetera. With respect to what we'd learned from Cobenfy, I think there's lots, actually, in terms of how to design appropriately an efficacy trial in AD psychosis with the appropriate endpoints, which ideally would change over time, offering a therapeutic window between placebo and active, understanding the appropriate patients as well, and also actually how to execute this study with respect to site selection. So there's a lot there. We're pretty bullish in terms of our safety and tolerability. So we're confident we're going to differentiate. But I think the learnings will be about how to successfully execute an AD psychosis study. All right. Very good. Thank you both for helping us out with some questions here. We'll have another opportunity after closing remarks, but I'll spend the last 10 minutes here giving you my final thoughts. All right. So I'm going to hold this slide here for a moment. I guess I'll start by saying it's extremely difficult, as you can probably tell, following these two gentlemen and their presentations. I've got Sanjay here with the accent and his medical background, and then Jude being the drug developer and engineer that he is. And he looks a lot better in a suit than I do. But I'm going to do my best here. A couple of things I'd point out just at the outset here. We talked a bit about in my introduction, and you heard bits and pieces either directly or indirectly in the presentations from Sanjay and Jude, things like execution, evolution, repeatable innovation. On execution, it means a couple of things to me. It means the organization is doing everything it can to meet the timelines that we're giving you. So I think that's point number one. Number two, it also means improving our probabilities of success. You heard through Sanjay and his presentation what we're doing to make sure that we execute very clean, very high-quality neuropsychiatry trials. That's very, very important for us. We do believe that is also a competitive advantage here at Neurocrine because we have the team that manages these studies with a white glove type of service, either alone directly with the sites or selectively in certain regions with the CRO. I think that makes us quite unique in this area. Number two, on the evolution side of things, there's some similar overlap here in terms of what we're able to get by evolving the pipeline. By evolving, I mean diversifying. So today, we're heavily in psychiatry. I love the area, obviously, been committed to my entire career here at the company. I also know that it can be risky despite all of our execution. And one way we can do that is by moving into areas that balance in the absence of those biomarkers, harder endpoints, and earlier signs on activity. So our way of evolving is leaning on to the endocrinology expertise that we've gained over the years and more recently solidified with getting Crenessity over the finish line, but building on that by moving into endocrinology with our background on CRF. So that's the link there through execution and evolution. You put these together, and that's where you get your repeatable innovation. And that's what we're here and hope that you leave with today. So thanks for spending the time here this morning. I do want to go back to the key takeaways that I presented in the opening session just to see how we did and see if you're coming away with the same kind of notes for today. Number one, I think we started with reviewing all the great progress our team has made across R&D. I think what you saw there was not just a set of programs, but an emerging durable, innovative R&D engine that's going to deliver one new medicine every two years. You also got some insights on where the R&D engine is going to be pointed for the future. Jude did a really good job of sharing with you his view that this engine is performing at max performance right now, maybe even faster than I thought, actually, Jude. But it is doing quite well for us and giving us a lot of differentiated molecules by which we can move into clinical development. Overall, this view kind of reinforces that execution, evolution, repeatable innovation. It puts Neurocrine in a strong position of sustained growth and having multiple value creation events for the remainder of this decade and beyond. The other things that I touched on is I revisited the strength of our foundation. In my view, if I tell the Neurocrine story to someone else, what makes us special? We're one of the very few companies our size that's discovered and developed multiple first-in-class medicines. We've also launched and developed a blockbuster in Ingrezza. And we also stand on the threshold of a new era with Crenessity, which I think is going to be poised to be our next blockbuster in congenital adrenal hyperplasia. So if you combine all these elements with the scientific rigor that you heard here, the execution, our commercial capabilities, it does allow us to pursue programs with conviction and deliver them to patients. And that's what we're here and all about. On the neuropsychiatry side of the portfolio, I think what you heard from Sanjay is that there's great and actually, Dr. Krystal, we presented this idea of an era coming about in this space of major innovation. And we're part of that with our first-in-class AMPA PAM with Osavampator. And I'll say about Osavampator, it's kind of the elephant in the room here. It sounds like a dinosaur. Maybe that's how you can remember it better. But Osavampator is a first-in-class medicine for major depressive disorder. It's one of the most exciting mechanisms that I'm aware of out there today in major depressive disorder. We've got a really special molecule here. We showed you phase two data that was robust, meaningful, statistically significant over placebo, and if you look at that safety and tolerability profile, it really paints the picture of a best-in-class medicine for major depressive disorder. You also heard all the phase IIIs are up and running data in 2027-2027 for Osavampator. The same can be said for Direclidine in schizophrenia, so Direclidine is our muscarinic M4 agonist. We showed you great phase II data as well. All the phase IIIs are up and running data here in 2027-2028, and then when it comes to the muscarinic portfolio, we showed you advancements here on Direclidine. We've already initiated a phase II trial in bipolar mania, and we just recently launched the phase II trial with our dual M1, M4 agonist in schizophrenia. Both of these phase II trials will read out the same time frame as our phase IIIs. And then we have the second generation VMAT2 inhibitors. We're moving them into tardive dyskinesia next year in a phase II trial, all of them offering very differentiated portfolio. In terms of endocrinology, we leaned on our 30 years of pioneering work on CRF to show you that we're evolving and expanding our footprint on this mechanism. Crenessity with CRF1 is the anchor, of course. It gives us the ability to move into HPA axis, dysregulated diseases like CAH. But you can see behind Crenessity, there's a whole number of other next-generation molecules and programs led by NBIP-'1435. On the other side of the coin, we opened a new door with CRF2 agonists and peptides in metabolic disorders. And we're leading with NBIP-'2118 and NBIP-'2118 in weight loss while preserving muscle mass. This is an increasingly area of high unmet need. And obviously, it's a very attractive field right now externally. But make no mistake, on CRF2, we do believe this is going to be a whole new mechanism within metabolic diseases. And we're hoping to be there at its infancy and leaning on all of our history to make sure we continue to be a leader in this space. So I showed you the pipeline early on in the introductory section. This is the same view. Trust me, it's the same 12 programs. But if we build out our phase two portfolio by progressing Direclidine into a phase two study in bipolar mania, if we progress our dual M1, M4 agonist in NBI-'570 schizophrenia, you see that phase II or mid-stage pipeline grow. We've also added in here our three endocrinology programs that Jude reviewed here as well. This represents the clinical program that we plan on having by the end of next year. Now, there are some programs that are absent here, and that goes back to my earlier remarks in our Q&A here on the immunology neurology side of things. We'll look to give you an update on that sometime in 2026 and what we're working on there. But a couple of other things, why this pipeline is here. Just a quick reminder, we have our R&D metrics that 423. We hit that this year. Four new phase I starts, two new phase II starts, and we had three programs in phase III. That's the first year since we put this in place that we've achieved these metrics. We need to be able to do this over and over again. That's the goal: execution, evolution, innovation to deliver on value creating events over and over time. As we look forward then into 2026, to get to that data readouts that I just mentioned, we know what's in store for us. It's going to be a year of execution across those phase IIs and phase IIIs. We would like to deliver phase I data. We had a couple of questions, Miles. I think you were asking about phase I data. We do look at sharing that with you next year. We've got a number of different programs that could be. So we're looking at that now when they'll be available and what's the most interesting. So stay tuned on that. And I mentioned that we'll give you the updates on our neurology and immunology interest. Just a couple of closing remarks, then, before I break here for lunch. If you look at everything that we presented today, there was a lot there. There's a lot of new information. You're going to need to take some time to digest it, have more discussions with us. But if I think about 2026, it really boils down to two key things: building strong momentum for the future and having smart strategic diversification occur across the portfolio. Now, I know I'm the last one before all of us here for lunch. So just some quick thank yous to everyone in the audience and everyone listening online. Our shareholders, clinicians, analysts, employees really appreciate you being here and providing continued support. I hope you heard from Sanjay and Jude and I the enthusiasm for everything that's going on here. It really does paint the picture of a very bright future. But ultimately, for me, as I stand here, I'm excited because I think it paints a picture for Neurocrine as being one that's enduring, where we can not only discover and develop medicines. We've shown you we can do that, but it's to reliably bring everything that's in the pipeline to patients. And that's why we're here. So I think with that, I'll close. And I'll thank everyone once again and maybe have some more discussion for lunch.