Hey, thanks very much for joining, everybody. It's my pleasure to be moderating this panel with Kyle and Samir from Neurocrine. I think in this discussion we're going to try to hit a few Ingrezza questions first, a few CAH questions, and then in the spirit of this CNS-focused conference, dig a little bit deeper into the pipeline and the muscarinic program and the AMPA program. Maybe to start, Kyle, you guys have obviously talked a lot with investors about what's going on with Ingrezza, what's been changing with Ingrezza. I think given the surprise of the fourth quarter and the guide, I talked to a lot of investors who really don't even know how to sort of model this going forward. What would you sort of say to someone who says, you know what, we saw this steep drop-off in Q4, the guide is a big change. How can we be confident that you guys are forecasting this franchise correctly and that everything is still sort of, generally speaking, on track? I guess I'll start with, first of all, Paul, thanks for having us here. Samir Patel will be taking on all the muscarinic and BD questions. On the Ingrezza side of things, it's amazing to think here we are eight years into launch. We're talking about still a growing blockbuster, $2.5 billion in revenue is our guide for this year. That's 10% year-to-year growth at the midpoint. Still a lot of growth to be excited about there. I know that that comes on the heels of a very large growth year in 2024. In fact, that was the largest growth year that we've seen really since launch on a percentage basis. Appreciate the feedback, the questions that we've gotten externally. I guess I would just start by reiterating some of the things that we've been pointing to that we've seen over the course of 2024, in particular in the area of payer dynamics. Certainly been tightening up and making it more difficult, hurdles being put at patients, physicians wanting to get Ingrezza, what the net effect of delaying prescriptions ultimately getting filled here and paid for patients. What that meant for us coming from Q4 to Q1 is really a reduced new patient start momentum relative to prior years. That is not something that you like to have starting a new year. On top of that, for this year, when we think about Q1, it is always a reauthorization quarter, which is tough and challenging. At the tail end of this quarter, we also have one less ordering week. Those two pieces at the beginning of the quarter and how you end the quarter are really quite impactful for how we view the start of the year. We all know that this concept of the earlier you can get patients on Ingrezza, on a medicine like Ingrezza in terms of a specialty medicine in the year, there is a compounding effect that you see as each quarter goes by. When we think about guidance for the year, we certainly kept in mind and looked at the variables that we see presenting themself, coming into Q1 of this year, the low patient start momentum, the knowledge of the fact of one less ordering week. We do also have a 3%-4% gross-to-net change going from Q4 to Q1. These are all variables that played into our guidance. Ultimately what we see here, Paul, is Q1 is going to be more challenging than we've seen in years past. There'll be a recovery in Q2. With a lot of investments we've made over the past, you'd say, three to six months, we would see an acceleration of growth the second half of 2025. That's all these things played into that guide that we have, that $2.5 billion-$2.6 billion guide for the year. Thanks, Kyle. All makes sense. The only piece I'm still trying to wrap my head around here is you and I've talked to Matt about this too, have talked about reimbursement challenges, maybe a lower conversion rate between an NRX that's written and a patient actually going on therapy. I guess as we sit here today in March, how much of this is actually in your control and modifiable in this calendar year? Because in my simplistic understanding, I think, okay, access challenges, that means more contracting, giving back more on price. Usually that kind of resets and is done on an annual basis. As we think about the next nine and a half months, to what degree can you actually improve some of these underlying challenges? Yeah, no, that's a fair question. I guess one of the things that I'll start with is that what we're really talking about here, for the most part, that is, are getting new patients on Ingrezza. The patients that are already on Ingrezza and getting a repeat prescription throughout the course of the year, there's a stickiness to this medicine. It's easy to get those patients a refill of their prescription. The new patient starts, that's where they see the payer hurdles the most prevalent. There are things that we can do as an organization to help make that better. Certainly, we have an experienced field reimbursement team that's out there in the field. It's something that we continuously work on, scale, and educate to navigate quarters like Q1, but then throughout the year on an evolving payer landscape. I do believe the payer landscape evolution that we've seen in terms of tightening this whole process of getting a prescription in the hand of patients is the result of IRA uncertainty by the payers and plans that we're currently engaging with. Aside from that, working with the field and reimbursement team, it still goes back to making the disease aware in the minds of the physicians, the nurse practitioners, and putting the disease state front and center because ultimately these are the individuals that are going to be fighting for the Ingrezza script once it's written for the patient and helping those physicians understand the importance of treating the disease. Part and parcel to that will be just increased marketing messaging around the attributes of Ingrezza, of why they're aligned with meeting the unmet needs of patients with tardive dyskinesia. I think I'd start with, we're talking about new patient starts here, not patients already on medicine. There are things that we can and will continue to do in terms of improving, challenging the plans and payers to make sure that we get the prescriptions in the hands of patients most efficiently. Then when it comes to the plans specifically, I think probably more so than others, and it's not just, and other times, and it's not just Neurocrine, I think we're all taking a very close look at how we want to perhaps change our relationships with plans here in the near to midterm because they are trying to figure out what their new strategy is going to be for their own business as they're having to deal with medicines that go through the Inflation Reduction Act and their IPAY moment. We want to be flexible. We don't want to necessarily take us down one particular path that locks us into something. We need to make sure that we're on top of what the plans are dealing with and making sure that we always have that North Star maximizing the access for patients both in the near term and long term here. Yeah, okay. I guess from a practical consequence, does this ultimately mean to give insurers more certainty in a world of uncertainty that you're going to have to contract more on price going forward? I will say that since the launch of both Ingrezza and Austedo, Teva has been pretty much on all the plans from day one, and we have not been, and we've been able to successfully navigate the exemptions process for new patients. I think as time goes on, we're going to have to see if that's the best relationship and mechanism that we see moving forward for patients getting Ingrezza. I do keep an eye on what this first round of 10 medicines are going to go through for the IRA this next year and what other brands in those same therapeutic categories feel or sense with the plans that they're currently negotiating or may negotiate moving forward. Fortunately, we're in the position where we can sit back and learn how these dynamics are playing out over the next couple of years and see what changes to our own business that we might make to ultimately maximize the value and strength of what we have within the organization, specifically with Ingrezza. Yeah, yep, okay. All right, great, Kyle. Let's cover CAH briefly before we talk about the pipeline. I guess open-ended question, how are the first three months tracking relative to what you expected? Far, things are going great, Paul. Appreciate the question on this. It's always exciting when you're launching a new medicine. It's basically a first-in-class, our first medicine ever approved for disease state. I know we talk a lot about crinecerfont being the first medicine approved for CAH in over 70 years, but most patients don't know any better during the course of their life with CAH. It is a very exciting time. You can feel the energy in the organization and certainly in the patient and physician community to have something that's been specifically discovered and developed for their needs is quite satisfying here. I'll tell you that the initial receptivity across the patients, the endocrinologists that we're calling on, and even payers has been quite high. We think that given the data set that we have and the clean and broad label that crinecerfont has all the hallmarks of being a potential blockbuster. Yeah. I mean, you guys have hammered people on the idea that this is going to be a gradual launch, slow, have to build it. Is it the classic Neurocrine playbook of sandbag the early days? I guess, look, I'm half joking, but why wouldn't this launch just as good, if not better than Skyclarys or Daybue, right? I mean, you've got a drug that has a pretty good efficacy profile. The safety is clean. It's an oral drug. These patients are already on medication. This is on newborn screening, right, which some of those other diseases aren't. It feels like there's a coalescence of factors here, coalescence, excuse me, that lend themselves to a great launch. What am I missing or not appreciating about the first three to six months? Everything you said there is not a bad place to be in. I will say that whenever you're changing a standard of care for disease states, you normally start from the perspective that that's going to take some time. We've certainly seen that with Ingrezza. I would say Ingrezza's uptake over time has been pretty steady relative to other disease states that we've seen. It's probably because one of the things that you touched on, most of the patients in tardive dyskinesia or in that disease state aren't diagnosed. That's different than in CAH. Still, when it comes to changing the standard of care, we do expect a certain level of education that's going to be required. We know that depending on the patient type, they are limited in the number of interactions that they have with physicians on an annual basis. That is one of the barriers that we see, that limitation between the patient and physician interaction, whether you're a child who is in the office more frequently, but still not a lot with their parent, or if you're an older male who may be in the office one time per year at most. Those are the things that we need to work through. I think part and parcel of that is that there's a general apathy amongst the community, that they feel that a lot of the symptoms, a lot of their disease state, that it just doesn't, it can't get any better. Isn't that more of an adult phenomenon than a pediatric phenomenon? I think that whether you're talking about different levels of motivated patients or physician, in this case, I'm thinking about physicians, a lot of them think that just like in TD, that their patients are being adequately cared for with their hydrocortisone treatment. You have to work through these different dynamics. I think that the message is that you have to worry about this education piece. There is no open label extension pool of patients that's going to immediately roll over and be an initial set of patients on crinecerfont. That's another one. The other one is that you'll have to work through the reimbursement process out of the gate as all the plans come up to speed on the medicine and how it's ultimately going to be approved for patients. All that's going to take some time, we think ultimately. That is where we get to that measured launch view. What I would say is that while it is going to be measured, I think once we get some momentum here, I think you will see an acceleration to peak market share or peak penetration of the market much more quickly than we have seen with Ingrezza that has been that more steady launch over time. Are you seeing so far greater receptivity in the pediatric population? I think we've seen great receptivity across the board. I think it's still early enough days to not be able to say we're seeing a trend in one particular area or another. I think there's been good overall excitement in the category working with the CARES Foundation, the advocacy group that's out there to make the medicine aware for those patients that are dialed in. What we're seeing is that exuberance being attached to that particular patient population. I'd love to be able to answer that question in, say, a year's time, and we could speak more confidently about who's using the medicine and what patient population, et cetera. Okay. All right, last question. Let's pretend it's December 15. What do you want to be sitting on with this drug to say, okay, this was a successful year? You're asking for some detailed information there. Yeah, I'm asking for a specific revenue number. Yeah, we will be giving enrollment numbers on a quarterly basis. We'll be giving you the net sales number. I think that we're comfortable with that for the next couple of quarters until we can see where the market's moving. At some point, we'll be able to give additional color on what we're seeing right now. Where we stand today, and we're barely three months in of a new launch, everything that we're seeing thus far is going very well. Okay, great. To everybody listening, you can all see I tried my absolute best. Awesome. We look forward to the next quarter. Samir, maybe I can hammer you on some pipeline questions because I'm super interested in the AMPA program, and muscarinics are always really fun to talk about. Maybe starting with the AMPA potentiator, I guess, why has Neurocrine been so secretive about the phase II data? What's the upside for you guys? I feel like you don't run the company for the investment community, but a phase II new mechanism in depression is tremendously exciting, right? We see companies with positive phase II data in depression trade at billions in market cap, and it doesn't feel like there's anything close to that in Neurocrine stock. What's been the thought process with the disclosure so far? Yep, maybe I'll chime in on this one. You know, if you think about the program and the collaboration that we had with Takeda when we announced the phase II results, we were in a profit share type of arrangement. All this, when we moved into the number of programs we had into phase II, we agreed we weren't going to spend on anything else until we saw the phase II results. When it came to our AMPA potentiator in phase II, we got the spectacular phase II results. The next piece was to preserve the intellectual property that came out of those study results. We didn't have all that plan worked out, who was doing what, what group was going to file the patents, who was going to pay for them, et cetera. It did take some time to get through that dynamic. It's a good problem to have, but when you're working in a collaboration, it's important that you work with your partner to get to a good outcome there. Other than that, which was the major driver here for not disclosing as much information at the time of the phase II results, was the appreciation that we were going through a very high level of exuberance attached to the muscarinics. We do believe that the bias, the expectation bias that we were seeing across the muscarinic programs was something that was real and that we had a significant concern about for our own program as we were still in phase II at the time. The idea here was that no one had the expectation that an AMPA/PAM would work in MDD. Most of the other programs had fallen by the wayside mainly for safety toxicology reasons. We wanted to, excuse me, preserve that expectation bias or lack thereof for subsequent studies. The last point to point out that was a factor in what we disclosed or what we did not was we appreciate there is a number of AMPA programs on the shelves of many pharmaceutical companies. Certainly, we are mindful of not wanting to educate others at this particular time about the pathway and how to take these molecules forward. All those factors played a role here. At the end of the day, we are planning to share this data. What we are looking at is an R&D day later this year. I think this would give us a good venue to share a lot more information that we have across the psychiatry portfolio overall. Stay tuned on that. That'd be something nice to have some people out to our headquarters in San Diego and go through the portfolio together. Okay, that sounds great. The only thing I'd add there is that earlier this year, we amended our collaboration with Takeda on the AMPA program. Now we own worldwide rights except for Japan. I think that does speak to our excitement around the compound. To Kyle's point, you know we do need to be concerned about the expectation bias here. There's been a raft, unfortunately, of recent late-stage failures within MDD in particular, also in schizophrenia. We'll be measured with the disclosure, but certainly we know that the street wants more, and you'll see that throughout the rest of this year. Yeah, okay, that makes sense. I guess, you know, without showing the efficacy curves, which is obviously not realistic on this Zoom, you know I think when I look at phase II data in psychiatry, there's a couple of variables that I feel like are flags on the replicability of a data set. One is how does placebo do, right? Did placebo grossly underperform in a way that kind of questions the integrity of the results? The second is dose response to some degree. Understanding that a lot of psych drugs don't have a linear dose response, you want to see a dose response that at least passes the smell test. What can you at least touch upon on these variables as it relates to the phase II data set and as it relates to your confidence that it's replicable in your phase III program? I would say the overall conduct of the phase II study was very high. We did not see anything unusual in terms of the placebo response here. We are right in the normal range. You saw the effect sizes there across both doses. I would say whether you are looking at the dose that did not underperform versus the other, in my mind, both doses were active here. That corresponds with a lot of the prior studies that we have done with this molecule. There were multiple doses that look good in various animal models of disease to the extent that you want to put any validity on that. I think the challenge here in a lot of psychiatric trials is a lot of us have not been used to seeing these types of phase II and phase II trials in depression relatively recently. You know, 20 years ago, there's a lot more companies in this space and producing. Kyle, we can still hear you. That was odd. In any case, I think that where I was trying to go with that is that there's a lot of trials that have been published in this space where there's a flat dose response. There's an inverted U, an irregular dose response. In our world, that's very familiar. We're not too worried about having one study dose outperform another if they're in particular talking about doses that are very similar. Ultimately, what we like, it was a high-quality performed study, a very well-controlled placebo effect, and we got a spectacular result. The question for us then is how do we manage a larger phase III trial and try to preserve all those elements that we saw in a smaller phase II trial? First and foremost, the phase II trial that we conducted was a pretty good size, 180 subjects, two doses of active versus placebo. It was across a number of clinical sites. We will be scaling the subject number up a bit, but not much. In phase III, you can see out there where our sample size is about 200. We will be simplifying the number of doses of active from two to one. It is a one-to-one active to placebo pivotal trial design in 200 subjects. We think that we will be able to control things like the variability in the outcomes at the clinical sites in much the same way that we did in this phase II because of the similarities in the scope and size of these studies. We are doing a phase III program that includes three phase III studies. They are all similarly designed. It is with the mindset that this is a risky area. We are trying to get at least two positive phase III trials that would be required for an NDA approval submission. That is kind of the mindset here on this. We are trying to preserve the simplicity that we saw from phase III by moving into our phase II, moving into phase III. You will see that across the board in the muscarinic programs as well, trying to preserve the simplicity element moving from an earlier stage trial to a later stage, perhaps larger trial. Just to underscore two points there real quickly, Paul, this absolutely was not a case where we had an abnormally low placebo effect in phase II. This was a placebo effect that's consistent with what you've seen with other phase II and phase III programs. We expect it to be right around that range in phase III as well. The results were not driven by a low placebo effect. Second, in terms of replicability, it's a fair point that you bring up. You look at our phase II results, seven and a half point placebo adjusted difference in one dose, three and a half point in another dose. I mean, you're talking about big numbers here. We think that we have an active drug. That's what's driving the confidence. You take a simple straight average, and maybe that's the most intellectually honest way to look at it. If we were to get something around that result in phase III, this is going to be a big winner commercially. Is this the kind of thing where you might take both doses forward, understanding that it's hard from a small study like this to really make conclusions dose to dose? Right now, we're just taking a dose that we think is efficacious, the same dose across all phase III studies. I will say that other than all the things that Samir just mentioned, just to pile on here, we think we're working in a validated pathway here. This is in the same pathway as ketamine. We work downstream at the AMPA receptor, which is what ketamine activates through the induction of glutamate. We think there are multiple reasons here to be excited about the approach here. What Takeda was able to fix was they developed a true AMPA/PAM, not an agonist. Mitigate the seizure risk? Is that? That's right. Mitigates the seizure risk on this. It gives you that light touch of activating the system. It doesn't necessarily work the same way as ketamine in terms of a fast onset of action, but it takes you to that large effect size that we saw in the phase II. Yeah, yeah, okay, great. phase III program starting, and we'll get data potentially later this year in an R&D event, or I guess more detailed phase II data. That's right. Awesome. Muscarinic, you know, same tune, right? I mean, I think there's been a lot. Like it's been a complicated eight to nine months for the M4 hypothesis, right? With your guys' data, which certainly looks promising, but the dose response is a little bit confusing. You have this whole emraclidine setback, which there's probably five variables that contributed to that. I guess going into phase III, you know, same deal, right? Like how much conviction can we have? You know, in a small study where you don't have a linear dose response, what does the debate look like inside Neurocrine when you guys are talking about, like, is this a real biological finding? Is it randomness? Should we take forward one dose? Should we take forward multiple doses? You know, where are you guys kind of leaning out on these things? Yeah, absolutely. Maybe I'll start, and then Kyle will look for you for additional detail here. We thought long and hard about this as we go into phase III. This isn't an insignificant bet for the company. These inpatient studies are timely, expensive to run, and resource-intensive. When we looked at our data, we do have confidence in our 20 milligram dose. That's the dose that lined up from preclinical models all the way through phase I with the mismatch negativity in ASSR data that looked good there into phase II. The inverted U dose response, as Kyle said, doesn't scare us. You've seen this before with antipsychotics. You look at Caplyta as an example. The 42 milligram dose outperformed the 84 milligram in the phase II. They took the 42 into phase III. That obviously hit. That's been a nice drug for them. Even within the muscarinic class, if you look at the integrated summary comments by the FDA for the Cobenfy approval, I mean, these are small ends that we're talking about. In that situation, their low dose actually numerically outperformed their high dose. The FDA themselves concluded that there was no dose response there seen between their pooled phase II and phase III data. For us, as we think about it, the phase III program, as Kyle's mentioned, similar to osavampator, is going to be very simple. One dose, 20 milligram versus placebo, one-to-one randomization, a tight number of sites, around 20 sites per study. We're going to have very high oversight and high engagement. You referenced one of our competitors that had a setback, obviously, in their phase II-B program. Some of this comes down to execution. Some of this comes down to trial design and patient selection. Ultimately, those are three things that we're going to look to optimize in our phase III results here. Kyle, anything you want to add? No, I think you captured everything there, Samir. It's a very similar story to osavampator. I think we're going to have very good oversight. We're going to have very simple studies. What we're asking in terms of scale going from phase II to phase III is very small incremental changes. We're not talking about an emraclidine phase I-B to phase III trial difference of, you know, multiple, five times the number of sites, five times the number of subjects, US and Europe. Those are not things that we are dealing with moving from our phase II to phase III trial. Obviously, science happens. The best of science can still lead to setbacks, but we're really happy with the profile that we have at the 20 milligram dose and believe that the data that we've seen comes with a large magnitude of effect. It's really up to us to do our best to manage the phase III. Okay, makes sense. Where are things with the M1, M4? Do you feel like you can develop an M1, M4 without a peripheral antagonist to cancel out the side effects? Yes. There will be no peripheral antagonist with this program. The M1, M4 phase I data are expected to read out by middle of the year. We'll be moving that program forward into a phase II study in schizophrenia by the end of the year. Right now, that compound's looking good. In vitro, it's very strongly potent on both M1 and M4. We'll see how that translates to in the clinic. The hope here is that this could be a more potent and, you know, slightly different pharmacology version of 568. It would be a nice sister compound to follow up with as a lifecycle management opportunity for the class. You'll get more detail in phase two study design as we, excuse me, as we move into the clinical study beginning at the end of the year. Kyle has referenced this R&D day, and perhaps that could be a good forum for us to share more detail there on the phase one data and how the phase two study design is looking. Okay, okay. All right, we got two minutes, and I'm going to try to squeeze in two more questions. Kyle, you have a BD background. Samir, you are now in Kyle's prior seat. Could we see Neurocrine do a meaningful BD transaction in the next year, or is your plate full? Samir, you're sure they had a BD. Absolutely. From my perspective right now, we have to put our heads down and focus on our phase three trials. You know, we're launching, obviously, with osavampator and 568. That's a lot of bandwidth internally. We've got the crinecerfont launch ongoing as well. Never say never, it would have to be the right opportunity. You know, certainly right now, our focus is on our ongoing clinical programs and the commercial launch for crinecerfont. Yeah, okay. One last pipeline question. I feel like you guys go out of your way to say to people, "Hey, don't forget about our NR2B NAM." What is the quick pitch there, and when are we going to get proof of concept data? This works a little bit downstream of ketamine at the NR2B subunit of the NMDA receptor. The hypothesis here, again, validated target, validated pathway, is that you can induce a hyperglutaminergic state, but not to the same extent as ketamine. Hopefully, you get that fast onset of action, but minus the dissociative effects of ketamine. That is the goal. That is why people have been attracted to this target. That is what we are looking at testing in this phase two trial that is ongoing now, three doses of active versus placebo. We will have data later this year on that. That will help us set the direction of where we go in terms of dose, dosing regimen for pivotal trials, learning a lot about this particular target right now and having a really nice molecule to actually look at a number of different parameters of using this approach in this biological pathway. I'm quite excited about this to see where this lands. As you know from Neurocrine, when we're working in difficult areas like depression, we like to pick a biological pathway that has some level of validation. We like to play along multiple parts of that pathway and see what ultimately will lead to the best outcome there for patients. We've got one upstream with 770, and we've got one downstream with osavampator. Awesome. Great. I think we're up against time. Anything else either you guys would like to add before we finish? Nope. Appreciate your support, Paul. Always happy to catch up with you. All right. Thank you, guys. Good conversation. Thank you.