Good day, everyone, and welcome to today's Neurocrine Biosciences Conference Call. At this time, all participants are in a listen-only mode. Later, you will have the opportunity to ask questions during the question-and-answer session. You may register to ask a question at any time by pressing the star and one on your telephone keypad. You may remove yourself by pressing the pound key. Please note, today's call will be recorded, and I'll be standing by if you should need any assistance. It is now my pleasure to turn the conference over to Todd Tushla. Please go ahead. Thank you. Good morning, and welcome to today's conference call to discuss the top-line results for crinecerfont in the Phase 3 CAHtalyst pediatric and the Phase 3 CAHtalyst adult studies. First, a few housekeeping items to address. Our agenda will begin with opening remarks from Kevin Gorman, our Chief Executive Officer, and from Eiry Roberts, our Chief Medical Officer. We will then turn the call over to our guest speaker, Dr. Richard Auchus, who will provide additional information and expert perspective on these phase III trial results. During Dr. Auchus's comments, you can refer to the supplemental materials, which were posted on the Neurocrine Investor Relations website earlier today. For those unfamiliar with Dr. Auchus, he is a worldwide thought leader in congenital adrenal hyperplasia. Dr. Auchus is currently a professor of Internal Medicine in the Division of Metabolism, Endocrinology, and Diabetes at the University of Michigan and serves as Chief of the Endocrinology and Metabolism section at the Ann Arbor VA Medical Center. Thank you for joining us, Dr. Auchus. Following Dr. Auchus's comments, we will move to Q&A, where additional members of the Neurocrine management team will be available, including Jean Chan, Vice President of Clinical Development, Endocrinology, and Clinical Team Lead for crinecerfont; Bob Farber, Vice President of Clinical Development and crinecerfont Program Lead; and Eric Benevich, our Chief Commercial Officer. Finally, during today's call, we will be making forward-looking statements. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to review the risk factors discussed in our latest SEC filings. With that, I am happy to turn the call over to Kevin Gorman. Thank you very much, Todd. Good morning, everyone. I really appreciate Dr. Auchus joining us this morning. We're quite privileged to be able to have him here and for him to give his views and answer any questions that you might have. I don't think I could overstate just what a terrific day it is for children and their parents who suffer from CAH. This data, once again, in the pediatric population, was just as outstanding as the data that we reported last month for the adult population. It is also, I think I can't say enough for the work that Jean and Bob and their teams have done over the past several years on this program. I'm not going to take up any more time here because we have a lot to get to. We really want to get to Eiry and to Dr. Auchus and then to your questions. Eiry, please. Thank you, Kevin, and a very good morning to everyone. It's really an extremely exciting time here at Neurocrine, given the breadth and depth of our pipeline. But today, our focus is on crinecerfont and the very impressive top-line data from the CAHtalyst Phase 3 pediatric and adult studies. I'm incredibly proud of the results generated from these studies, given the high unmet need that exists for children, adolescents, and adults living with congenital adrenal hyperplasia, and the many challenges and collective efforts it took to design and advance the CAHtalyst program, the largest global interventional studies ever conducted in this patient population. Firstly, I want to take a moment to thank all the patients, families, clinicians, and team members who participated in and continue to participate in the CAHtalyst program for their tremendous commitment and collaboration. In the CAHtalyst study, treatment with crinecerfont led to a highly statistically significant and clinically meaningful reduction in androgen levels when compared to placebo for CAH patients, with a magnitude of effect that was consistent across children, adolescents, and adult subjects. Patients treated with crinecerfont also achieved a highly statistically significant and clinically relevant reduction in their glucocorticoid dose while maintaining androgen control when compared to placebo-treated patients. In fact, a substantial proportion of both adult and pediatric patients treated with crinecerfont were able to achieve a physiologic glucocorticoid dose while still maintaining control of androgen levels. From a safety perspective, treatment with crinecerfont was generally very well tolerated, with few treatment discontinuations. The quality of overall trial conduct was also outstanding, leading to a very high completion rate for patients of over 95% in the adult study and over 95% in the pediatric study during the six-month placebo-controlled period. crinecerfont's mechanism of action as a selective CRF1 receptor antagonist brings the hope of a novel and effective way of controlling androgen levels in patients living with congenital adrenal hyperplasia. This hope was substantially confirmed by the results of both CAHtalyst studies, demonstrating that the androgen control achieved by treatment with crinecerfont allowed patients to reduce their glucocorticoid dosage by a clinically meaningful amount without negatively impacting control of androgens. The results of the CAHtalyst program show that crinecerfont, if approved, could fundamentally change the way in which clinicians manage the androgen excess experienced by patients with CAH. Potentially resulting in important improvements in clinical outcomes for children, adolescents, and adults living with CAH. The concurrent reduction in glucocorticoid to more physiologic doses could also result in meaningful improvement in the significant metabolic, bone, and other comorbidities experienced by individuals with CAH due to their lifelong exposure to the super physiologic steroid doses currently required to control the disease. I'm delighted to now hand the call over to Dr. Auchus, a renowned clinician in the field of CAH, who has dedicated much of his research career to understanding CAH and discovering ways to improve the care and outcome for patients living with CAH. We have had the privilege of working closely with Dr. Auchus for many years on crinecerfont and Neurocrine's previous CAH programs, and his leadership has been instrumental to the success of the CAHtalyst program. Dr. Auchus will provide more insight into the baseline characteristics of the patient population included in these trials, and context around the potential importance of these results provided today for patients living with CAH and the clinicians who care for them. Rich? Thank you, Eiry. It's great to be here. Thank you all for attending. My hats off to Neurocrine, for sponsoring this program, to my colleagues in pediatric and adult endocrinology throughout the world who have worked tirelessly over the last several years to do this, and to the patients and their families who participated. I want to call your attention to the supplemental materials, just to page three, to begin with, to just remind you what the problem is that we're dealing with here. In simple adrenal insufficiency, the adrenals don't make anything, and all you have to do is replace the cortisol and aldosterone deficiency, and we know pretty well how to do that. Most endocrinologists can do that pretty well. The problem with congenital adrenal hyperplasia is that there's a defect in one of the enzymes to make cortisol. So all that steroid flux, make a lot of cortisol, is diverted to androgens. So not only do we have to replace the cortisol deficiency, but we have to shut off the spigot. And in order to do that, we have to reduce ACTH production from the pituitary. The way we've been doing that for 60 years now is by giving more than a physiologic dose of glucocorticoids to provide negative feedback on the pituitary. And we know what that does. It takes about 0.4 milligrams of dexamethasone to suppress the pituitary, to about 32 milligrams of hydrocortisone or eight milligrams of prednisone. Now, I don't know anybody that wants to be on eight milligrams of prednisone for the rest of their life, and I know a lot of drugs that have been developed to take patients with rheumatoid arthritis and other diseases off that eight milligrams of prednisone by putting them on a safer drug. So what we have is a tightrope bed or a Sophie's choice, if you will, that we can't currently, with our armamentarium that we have, both replace the cortisol deficiency adequately and physiologically and lower the androgens. So we have to make a choice. We either give people too much glucocorticoids, and we know what that does in the long term, cardiovascular disease, metabolic disease, bone disease, hypertension, psychological effects, or we give them a physiologic dose and let their androgens rise, which causes infertility, tumor development, short stature, and other problems. So the mechanism of action of crinecerfont is directly on this pathophysiology to reduce ACTH production without giving people excess glucocorticoids. So the trial designs are on slides four and five, and so then on slide six is the baseline characteristics. Now, the Endocrine Society clinical practice guidelines for pediatrics recommends using hydrocortisone no more than 16 milligrams per meter squared per day. And that is distributed throughout the day, usually in three doses or sometimes more, in order to keep the androstenedione at the normal level. That's the biomarker that we use to tell that the adrenal androgens are well controlled. We also use 17-hydroxyprogesterone and other things. But as you can see, this patient population was already at the maximum dose, and they are still uncontrolled. We have a lot of patients with this problem. I think it was a majority of those patients who actually had the time and ability to participate in the study. For every one patient that you see in this trial, there's probably five-10 more who could have been in the trial, who could have benefited from this, but just didn't have the time and the ability to participate. If you look at the adult patients, they're on a pretty comparable dose of glucocorticoids, and their androgens are a little higher. So we tend to allow the adults to be in a little poorer control so that we don't give them even more glucocorticoids. So I think that's a pretty typical scenario that you see, that the adults tend to be in a little poorer control, to avoid the long-term glucocorticoids. In the adults, it's the long-term goal. In the children, we really try to keep things normal, and we will use more glucocorticoids, but we try to keep it under 17 milligrams per meter squared per day. So these people were not in very good control. Slide seven shows that the primary endpoint was met, with no question. The P values are all very, very small. I've not been involved in many studies where the P values were this small. On slide six, you know, the way the trial was designed, we added crinecerfont, and then in the adult study, we had a protocolized glucocorticoid reduction down to a goal of a physiologic dose, like we would in someone with garden variety adrenal insufficiency. The end part, the primary endpoint in the adult study, reaching less than 11 mg/m²/day and androgen control, that's the holy grail. That's pretty much normal. We are not able to do that now. You can see in the placebo group, there is a small number who probably were overtreated. Okay, so maybe there's about 15%-20% of people who we can control with a physiologic dose of glucocorticoid, at least for six months. We don't know about longer than that. 63% of the people who had crinecerfont added were able to maintain their androgen biomarker control at six months after starting crinecerfont. So that's quite impressive. That's something we cannot do currently with anything in our toolkit. Now, in the pediatric study, again, these children are already doing the best they can, and that's reflected by the fact that nobody in the placebo group could reduce their glucocorticoid. Okay, so when Mercury Morris talks about the 72 Dolphins, he talks about the 17-zero season. He says, "It's not about the 17, it's about the zero." And I think that this is really about the zero in the placebo group, that these people were already maxed out on everything they can and are still not controlled. That's why they're in the trial. The 30% that you see is the 30% who not only were in control, but who also were able to reduce their glucocorticoids to physiologic. We don't report the data, how many people got close to that or achieved one of those two endpoints. So this is something, again, that with our current armamentarium, we cannot do. So I, the other thing that's truly impressive is the fact that 97, 95% of people in both trials stayed through it. Very few dropouts, very well tolerated. People are motivated and looking for something better. So I'm just delighted to be a part of this study, and we're all, all of our investigators throughout the world are delighted to see the results. Thanks, Rich. We really appreciate that, and thank you for really bringing some very important additional context there. Just one word on the kind of next steps for us with this program right now, and then we'll open it up to your questions. So, you know, we obviously have the open label treatment periods for the CAHtalyst pediatrics and adult studies ongoing. We're working very hard so that we, what we shared with you today is probably about less than 10% of the data that will be generated ultimately from these trials. And we're looking forward to really having a much deeper and greater understanding of the overall value that crinecerfont can bring for patients as we delve into the deeper into the data over the next weeks and months. As we do that, we'll obviously be moving towards submission of regulatory dossiers in both the U.S. and Europe for crinecerfont. Equally importantly, working on full publications, we hope, in top-tier journals and presentation of the data to enable obviously more in-depth discussion of where crinecerfont can add value for children, adults, and pediatrics living with CAH currently. We will be sharing some additional information regarding the results as well from these studies at an analyst day that we'll be putting together in December, and we look forward to discussions at that point in time as well. With that, let me open it up for your questions, and we look forward to getting, delving into some of these topics. At this time, we will open the floor for questions. Again, if you would like to ask a question, please press star one on your telephone keypad. You may remove yourself from the queue at any time by pressing the pound key. Once again, that is star one to ask a question. We'll go first to Paul Matteis with Stifel. Please go ahead. Hi, this is James on for Paul. Thanks for taking our question, and congrats on the data. Just wondering if there's any more granularity you can provide around some of the efficacy data. You know, specifically, we're curious what percentage of patients achieved androgen control. And then maybe just kind of second, you know, as we think about translating these data and thinking about these data in the real world, you know, why did you define a normal steroid range of 11 mg per meter squared? And, you know, I guess as we look across these measures of androgen control and steroid control, what kind of responder rate do you think would be considered clinically meaningful in the real world? Thanks. Okay, I'm going to answer the second question first and then refer back to the phase II data for a little bit about the granularity. So 11 milligrams per square meter per day, average person is about 1.7 square meters, 1.8. It's about 20 milligrams a day of hydrocortisone. That's about what we use now to treat people with garden variety adrenal insufficiency. People who are smaller, we try to get to about 15 milligrams per day. The daily production rate is about seven or eight milligrams per square meter per day, but you can't really achieve that because of the pharmacokinetics of the hydrocortisone tablets. So we wind up having to give a little more, get a little higher peak, to allow for a longer duration of action of the hydrocortisone. That's, I think, quite reasonable as a goal. I mean, we can quibble whether it should be 10 or 12, but that's about right. Now, if you look at the phase II data, pretty much, you know, at 100 mg twice a day, everybody responded. You know, I think, you know, that's so... I, and if you look at the four-week pediatric data, which was similar to the phase II trial, where we left the glucocorticoid dose the same, dramatic reductions in the androgen nine, when you just add crinecerfont. So we get the... Pretty much everybody responding. I don't know if Irene wants to say anything further. Yeah, no, I think Rich, you said it very well. The one thing I'll add about the use of the 11 milligrams per meter squared was obviously we had a lot of discussion with experts such as Rich and other individuals involved in the program, but also with the regulators. I think it was really important to get to a clarity of definition that was acceptable in the setting of this clinical trial, where we were obviously trying to also balance, in the first time this had been looked at in a phase III program, the risk of adrenal insufficiency, and we did not want to put patients at risk of that. So I think it was a fair balance in that regard, and we were absolutely delighted with how that worked out. I would definitely agree with Rich's point. We talked about the mechanism of action here being a direct mechanism on control of androgen levels. And so from that perspective, I think all the patients have the opportunity to have a response to crinecerfont. We have not seen evidence of non-responders in that setting. Obviously, it gives clinicians then the opportunity to have more flexibility in how they manage the glucocorticoid dosing on an individual patient, individualized patient basis, with the ultimate goal, as Rich said, of getting to that ideal scenario of just physiologic replacement. And I think we demonstrated in this trial that a significant proportion of the population were able to achieve that, even in the course of this clinical trial setting. Yes, in the adult study, the entry criteria were 14 mg/m²/day or more. So that winds up being about 30 mg of hydrocortisone, as I showed you, and they get down to about 20 mg. So that's about a 30% or a 10 mg reduction. That's pretty sizable reduction. Thanks for the color and congrats again. Thank you. We'll go next to Tazeen Ahmad with Bank of America. Please go ahead. Your line is open. Hi, good morning. Thanks for taking my questions. I just wanted to expand on the comment about quality of life endpoint. What are they? And, you know, how should we interpret them when we see them in December? And then secondarily, on the discontinuation rate, I think it was around 5%. How do you view that rate in the grand scheme of things? And is, was there a key reason why patients discontinued? Thanks. That's an incredibly small discontinuation rate for a one-year—well, for even the six-month phase. Again, I don't think I've ever been involved in a study of this size that has had that small of a discontinuation rate. And most of those discontinuations were because of, you know, people moving and things like that. There were no SAEs that were assessed as being related to crinecerfont, which speaks to the safety of the drug. The common adverse events were fatigue, headache, and coronavirus infection. You know, I think everybody gets those. And in the pediatric study, was headache, fever, vomiting, and upper respiratory tract infection, which again, children get. So, you know, it was pretty safe and the people talked with their feet, you know, they stayed in the study. So I think that was quite impressive. I'm trying to remember the other part of your question. Yeah, let me take that. We haven't talked a great deal about the quality of life endpoints in the study. And I think, you know, obviously as we dig deeper into the data and come forward with more information, we can talk more about that. The other thing I would say about the safety and tolerability is obviously this program comes on the back of us already having approximately 1,000 subjects having been dosed with crinecerfont over the course of the clinical program. And we have been extremely impressed by the continued fashion in which crinecerfont has been well tolerated. In particular now with the results released today, seeing that safety and tolerability profile continue into the younger pediatric age, down to an age of four, that were included in the trial. In terms of quality of life, we talk about quality of life for the patients, but I want to talk about burden of disease to the family. Okay? These parents have to split pills four times a day. Some of them have to get up at 3:00 A.M. to do this. Despite that, some of the children are still not controlled and having advanced bone age. What I think will come out over time is how the burden of disease on these families is alleviated by this sort of block and replace approach. By eliminating the concern that the androgens are going to rise by controlling that with crinecerfont, and then just replacing the cortisol deficiency, as we would in someone with simple adrenal insufficiency. So I think that in the pediatric population, since we remember we're presenting the pediatric results, I think that's a huge impact on this. I think in the adult population, it's about being able to find an endocrinologist who can take care of you. You know, I get people from all over the country that come to see me because many endocrinologists don't want to take care of this disease because it's hard and because you can't accomplish both ends with the tools that we have right now. And this makes it easy. Anybody can give this dose and then replace the cortisol deficiency. They know how to do that, but it's very hard to control the androgens and to, you know, split the pills and give the bedtime doses and the right amount and so on. I think quality of life is one thing for the patients, but burden of a disease is a whole another thing. Okay. Thank you. Thank you. We'll go next to Brian Skorney with Baird. Please go ahead. Hey, good morning, everyone. Thanks for taking the question and congrats on the data. Based on the comments about the adults being sort of at baseline, a little worse off, I would have thought that would predict a lower rate of conversion to physiological doses. Across both studies, treatment infancy to-... to kind of happen. Can you just help us understand sort of the differences in adults versus peds patients or any parts of the trial design that sort of impact the lower rates of patient conversion to physiological levels in these two studies? Hey, Brian. Is it just that? Yes. Brian. Hey, would you mind repeating the question? You broke up, just a little bit, I think, at some key points of it. Okay. Yeah. If any differences in the adults versus the peds patients or the trial design that sort of impacts the lower rates of conversion of patients going to physiological glucocorticoid doses. There's just kind of a little bit of subjectivity here in weaning them down and maybe more caution about bringing the peds patients down. And, you know, just how do you kind of think about the open label experience? And would it imply that there'd be a much higher rate for a longer time to get these peds patients to physiological levels? Hey, Brian, there's quite a lot of questions in there, but, let me just make sure I understand and clarify. So is your key question about why the rate of getting patients to physiologic levels might be a little different between the adult. Exactly. And pediatric trials? Okay, with regard to the question around the open label, obviously, we have this—we're reporting the results of the six-month randomized trial. We have a lot, that very high proportion of patients continuing in open label, and we continue to, you know, see good tolerability. But we haven't dug into those data in the fashion that I think would be able to address your question there yet. But, so Rich, do you have a thought about this? Well, so there was a protocolized glucocorticoid reduction in the adults. So we sort of force down titrated them. In the pediatric study, they also had a schedule, but they were more flexible about reducing. They had to have normal androstenedione to go on, and we know that all these children had high androstenedione to be in the study. That's why the placebo group was zero, okay? So it was a slightly different patient population, so to speak, that in the adult study, there were some people who could have been in control, but you know, were taking too much glucocorticoid. That's the 18% placebo responders. In the pediatric study, everybody was being treated as intensively as they could and still not in control, so nobody could improve in that trial. And saying that 30%, remember, this is 30% that got to physiologic and maintained normal androstenedione. So we're not capturing those people who got close to physiologic, who got to 12 mg/m²/day and stayed physiologic, or who got to 11 mg/m², but were a little bit above physiologic. So that's where we have to get more granular, and that will be coming in the subsequent presentation. But that is a good question. Thank you. Thank you. We'll move next to. The only other thing I'd add... Sorry, Brian. Just to finish off the thought on that. Sorry, I was trying to turn my microphone on. The other thing is, bear in mind that this was the first time that any study of crinecerfont had been performed in children under the age of adolescence. We had a small cohort of adolescent patients that we had dosed in phase two, and that was the reason why we chose the sequence of endpoints for the pediatric study that we did, with the androgen control being the primary and the steroid reduction being a key secondary. Because I think we anticipated that clinicians would be more cautious and would require more flexibility in the reduction of steroids in this first study. And so your question about the open label is a very valid one. Your question about how that translates into real-world experience, and, now that we have such supportive data and the tolerability and safety profile being what it is, I think that we could, you know, we could certainly anticipate that they would look much more similar. There's no reason physiologically to believe that from a biological point of view, that the response to crinecerfont would be different in the different age groups. Thank you. We'll go next to Phil Nadeau with TD Cowen. Good morning. Congratulations on the data, and thanks for taking our question. One question for Dr. Auchus,Dr. Auchus, can you talk about how you would use crinecerfont in clinical practice? How would you use it in adult patients and pediatric patients? Which patients would be most appropriate for therapy? Thank you. Yeah. So, I think there's, again, from the adult studies, about 15%-20% who can maintain good androgen control with physiologic dose of glucocorticoids and probably don't need this. But the other 80%, they're either on too much glucocorticoids or they're on a reasonable dose, usually still above physiologic, and their androgens are a little high, and they don't want to take any more. And we allow that to happen because they're not planning to have children in the near future or things like that. I think I would offer it to any of those 80% of people. And I think in the pediatric population, you know, I can see several scenarios. Again, I think if a family has a choice between taking medication twice a day and four or five times a day, I think you're gonna say twice a day. And I think in the adolescent group, this is, you know, just like in type 1 diabetes, this is a situation where children tend to get into poor control, and then that mars them for the rest of their life. This is an opportunity to and, you know, during adolescence is a time when people are concerned about their looks and their weight and things like that, that glucocorticoids do bad things, too. So I think they, these families will welcome a way of being able to minimize the disease burden and and allow the children not to be exposed to high doses of glucocorticoids. Maybe one follow-up. There's concern among investors that payers are going to push back, that you're replacing largely generics, which, with what's likely to be a branded price therapy. How would you make the case to payers that the benefits here are meaningful and deserve to be paid for over the generic glucocorticoids? Hi, Phil. What I would just jump in here and say is that you know, now that we have actual data in hand from the adults and from the pediatrics, now you can really have meaningful conversations with payers. Having conversations with payers prior to this would - was a little premature. We did that anyway. But we're going to, we're gonna have more meaningful discussions with payers as we go forward, and so I think it's a little premature to actually talk about that now. Perfect. Thanks for taking our question, and congrats again on the data. Thank you. We'll go next to Brian Abrahams with RBC Capital Markets. Hey, good morning. Thanks for taking our question, and congrats on the data. I was wondering if you'd talk a little bit about your expectations for real-world patient management for, for patients who go on, on crinecerfont. How much education of endocrinologists do you think will be required, both around management and the risks that are associated with super physiologic glucocorticoids? How would the down titration take place in the commercial setting, just in terms of monitoring and doctor visits? Would these be-- Would you expect protocols that mirror what you had in these phase III, or would this be more at physician discretion? Thanks. Well, I do a lot of physician education now, and it's really hard now because of the tools that we have that don't work all that well. This actually makes it super easy. The block and replace approach, endocrinologists are used to doing that with Graves' disease, with adrenal cancer, you know, there's lots of scenarios where we do that. This will make it actually quite easy. I think what they're going to do is, like you say, pretty similar to the trial design. Add the crinecerfont, watch the labs. As you see the labs improve and the clinical findings improve, you start to wean down the glucocorticoids. You don't want to go so fast that you induce withdrawal symptoms. You want to know, you know, you want to make sure that they're still replaced. You have to do a couple of other things, like, for example, you know, we have to instead of just, quote, "doubling your dose," if you're only taking two doses a day of hydrocortisone, we now have to tell people to distribute the dose differently. We often have to raise the fludrocortisone dose as we reduce the hydrocortisone dose. So there's a few other things that we'll have to do, which is sort of similar to what we do with a patient with Cushing's disease after they're cured. So again, I think endocrinologists are more comfortable with it, but that's how it would be. We add the crinecerfont, start reducing the glucocorticoids to physiologic, monitor as you go along, both laboratory and symptom-wise, and then get to your endpoint, and then just keep going. Thanks. Thank you. We'll go next to Chris Shibutani with Goldman Sachs. Hey, good morning. This is Stephen on for Chris. Thanks for taking our question. I have a regulatory one. Can you talk about what alignment you've gotten from the FDA in terms of what they're looking for from an efficacy and safety standpoint? And is there more data that's necessary from the open label extension to, say, fulfill some sort of safety database? Thank you. Let me answer the last part first. In our discussions with the regulatory agencies, both in the United States and in Europe, we reached agreement around the patient numbers and numbers of patients to be included in the program that would be required to address the safety question. It's pretty consistent with what's required in a rare disease like CAH. I think we have confidence in that moving forward. With respect to the programs, we discussed with regulatory authorities around the world, and we did get alignment around the endpoints that would be important for consideration in both the adult and the pediatric population. I think it's incredibly, gratifying to see that we hit with such, highly statistically significant outcome on both primary and key secondary endpoints across the board, including other endpoints, obviously, that we're not disclosing it right now. We're very confident in the data package that we have, both from an efficacy point of view and a safety and tolerability perspective. Our next steps will be to engage with regulatory authorities to, in a kind of pre-NDA setting, as it's called in the, with the FDA in the United States, and obviously, we're moving as rapidly as possible to be able to do that. Got it. Thank you very much. Thank you. We'll move next to Carter Gould with Barclays. Please go ahead. Hi, congrats on the data. This is Leon Wang for Carter Gould. I guess another regulatory question or just kind of kind of what's your expectations on would you have had dialogue with the FDA by the time we get to your September December Analyst Day and have a better understanding of the path forward? And also for Dr. Auchus. M entioned about one of the benefits, being to the frequency of glucocorticoid use in patients. Now, on the Analyst Day or just at a later point, should we see greater level of granularity on kind of just measures such as this in terms of things that could potentially drive adoption? Thanks. It was a little difficult to hear the second part of your question. I must admit, I maybe need to ask you to repeat that. With respect to the first question, the regulatory path forward, I think we have confidence in the package that we have in hand right now. We had a lot of discussion with regulators prior to commencing this phase III program. And actually, in the way that the phase III program played out with the highly statistically significant efficacy outcomes and the safety and tolerability that we've seen to this point, we don't really anticipate surprises in the upcoming conversation. In with respect to the timing of that relative to our Investor Day, I really can't comment on that at this point. I mean, we're as I said, we're moving as fast as we can, and we're engaging in those discussions as rapidly as we can. Yes, I'm going to need to. Got you. Repeat that last part of the second part of the question because I, I couldn't understand that. Yeah. I was just curious about any other type of quality of life or any other type of things that you could show on the December Analyst Day, such as reduction in the number of times a patient takes glucocorticoids while they're on crinecerfont. Anything that helps on that that can help better frame adoption or compliance for these patients? Yeah, no, I don't want to set false expectations around that. In terms of information that we'll share towards the end of this year, you know, obviously, we will be continuing to dig into the data, but it will be more in line with what we're actually sharing today and a little bit of additional information there. And the primary reason for that is because we want to preserve the ability to publish this information in a top-tier journal in as rapidly as possible and also present the data. Because I think the full publication and presentation of the data is what's going to enable us to really understand the full value proposition of crinecerfont, and we do not want to jeopardize that. I would also just jump in, to say, Carter, that one of the things that, that we look at here that's so surprising, and Dr. Auchus said it just a little bit earlier, is 95% completion rate within this first six months. That's just incredibly high. Patients have to, and their families have to feel that they're recognizing a benefit and staying on the drug for, for the entire time with such a small dropout rate. Yeah, and even the people. Great. Thank you. On the placebo, whether they know it or not, are staying in so they can be on the drug in the open label phase. You know, I mean, that's quite... You know, because people who aren't reducing their glucocorticoid might feel like they're on a placebo, you know, so, but everybody's staying in the trial. Excellent. Thanks. You're so welcome. Thank you. We'll move next to Anupam Rama with J.P. Morgan. Hey, guys. Thanks so much for taking the question, and congrats on the data. One for the company and one for the KOL on the line. For the doctor, based on what you know from the phase II experience and kind of the top line for crinecerfont and CAH, would you have any hesitation using this product as a chronic therapy long term? And then for the company, just on Analyst Day, is it safe to assume that in conjunction with Analyst Day, we might get the anhedonia and focal onset seizures proof of concept data as well, or could those come ahead of Analyst Day? Thanks so much. Well, you know, as far as safety, I mean, safety, it's very clean. I have no hesitation about using this drug, and I'm not just saying that because I'm here and I've... You know, they've sponsored the study. But I can tell you that the patients want to stay on the drug. Yeah, in terms of Analyst Days, we're going to cover a variety of different topics across our entire pipeline, which, as you can see, is evolving and has a lot of excitement around it. In terms of data, I don't want to set false expectations that we're gonna have a big unveil event at Analyst Day. It's really to deep dive really deep into our existing programs and to get a even deeper look into what we're doing in the preclinical space. And so you'll meet Jude Onyia and be able to get some insight there. So we'll provide more detail on what we're going to cover at our Analyst Day when we have our earnings call here in a few weeks, but stay tuned. The only thing I'd add, Anupam, just to be clear, is that we don't have any delay on our FOS or anhedonia programs. We're completely on track with the commitments that we've made around sharing data in the fourth quarter around those programs. Thanks so much. Thank you. We'll move next to Mark Goodman with Leerink Partners. Hi, thanks. This is Madhu for Mark. Just curious if being able to treat patients younger than four years old is a goal, and if so, could you talk about what that might entail in terms of future studies or data generation? Thanks. T hanks very much for the question. The trial inclusion criteria allowed for patients to be enrolled down to the age of two. It just so happened that the 100 patients included in this trial ranged from ages four to 17. You know, the design of the trial and the inclusion criteria going down to two reflects the fact that we don't really expect there to be a difference in crinecerfont response or treatment tolerability between two-year-olds and four-year-olds. We obviously are interested in understanding the potential for use of crinecerfont in even younger children, since this is obviously a lifelong disease. Obviously we'll be in discussions with regulators and other key opinion leaders about how to pursue that. Thank you. Thank you. We'll go next to... Sorry. We'll go next to Danielle Brill with Raymond James. Please go ahead. Hey, guys. This is Alex in for Danielle. Thanks for taking our question. Congrats on the data. Just wanted to dive in a little bit on some of the details of the other clinical outcomes. We're just curious about the median glucocorticoid dose reduction, particularly in the adults, and also curious when in the trial patients were able to achieve physiological glucocorticoid dose. And then, just if you have the data available, curious about any of the color on some of the secondary endpoints, blood pressure, glucose tolerance in adults, and bone health, final adult height and peak. Thanks so much. Thanks for the question. I think I mentioned earlier, you know, we are to walk that line right now between sharing information that we hope will be useful for people to understand our level of excitement around the information that we've seen right now from these trials, but also preserve our ability to publish in journals and presentations. So we aren't actually sharing those types of information. What I can say about the steroid glucocorticoid reduction is, and Dr. Auchus alluded to this earlier, is that in the adult study, there was a protocolized almost a forced down titration of steroid dosing between weeks four and 12 in the study. It was somewhat similar, although not protocolized to the same degree in the pediatric study. So if you're looking for a timeframe around which we were seeing a reduction in steroids during the trial, that would be it. But with respect to secondary endpoints, the clinical outcomes, obviously, we're delving deeper into that, and when we publish the data in its entirety, we'll be able to talk more about that. I think if you're asking about the clinical practice, would people do it at that rate? I would say they probably go a little bit slower than that. So, you know, in a trial, trying to get everything done in a six-month window, we may have gone a little bit faster than people would normally do. You usually see these patients every three months in pediatrics, every six months in adults. But I think, you know, it doesn't quite matter. We were able to do this in a large majority of the adults, in that very short period of time, which sort of attests to the potency of the drug on the target. And as Eiry was saying, you know, we're, I know you're investors, but we're scientists, and we, you know, we are really gratified that the science played out here. That we understood that all the years that we've worked on the pathophysiology of this disease and the mechanisms, and then trying to figure out the targets, and it worked out. So, you know, we really want to make sure that the science is followed through, so that we can, you know, present this to the scientific community in a way that is proper. Great. Thanks so much. Looking forward to the additional data. Thank you. We'll move next to Charles Duncan with Cantor. Hey, yeah, good morning. Thanks, Kevin and team, for taking my question, and congratulations on the results. I had a question for Dr. Auchus. I'm going to ask you to speculate, Dr. Auchus, but, yeah, and I understand you're a scientist, but please, if you can answer, it'd be great. I guess if we had asked you a week ago what the response rate that you would have liked to see, would it be less than 30% or north of 30%? I understand this is clearly versus zero, clinically meaningful, but what would you have liked to see? And then the second part of the question is, with ongoing dosing, you know, this is a milestone analysis. Given the mechanism of action, would you anticipate that that response rate would grow, further diverge, and deepen, or could there be a loss of efficacy over time? Thanks. Let me answer the second question first. The disease is called congenital adrenal hyperplasia. Part of the problem is that the ACTH is not only tropic, that is, it drives steroid production, but it's trophic. It drives adrenal growth. These people have large adrenals. As you get people into good control, there is atrophy of the adrenals, and there is less tissue to make steroids. Yes, I think there is definitely the possibility that over time, that disease control will actually improve, and I don't anticipate escape from the drug. Again, I think the fact that 95% of the people are staying in this study is, you know, attest to the safety and to the, you know, continued efficacy of it. The other point, you know, again, yeah, like you say, zero in the control group. So, the 30% is the people who met both endpoints. I mean, this is a- Yes. Very, very strict composite endpoint. I wouldn't, you know, I think the benefit, the number of people in the crinecerfont arm that benefited, we are doing that, and we will be doing that analysis for the subsequent publications. I wouldn't say that I had a preconceived notion of that. I'm more interested in more granular information of how many people experienced some benefit. Again, if you just look at the four-week androstenedione, where you don't change the glucocorticoid dose, and you look at the reduction in the androstenedione, it's pretty profound in the crinecerfont group. I think that tells you something about how many people benefited from the drug. Helpful. Thank you. Thank you. We'll move next to Jeffrey Hung with Morgan Stanley. Please go ahead. Hi, this is Michael Riad on for Jeff Hung. Thank you for taking our questions, and congrats on the compelling data. We had two questions. The first for Dr. Richard Auchus. Since pediatric patients are in a critical window where you can prevent abnormal development and things like virilization, do you think most, if not all, the peds can derive a clinical benefit, regardless of whether they achieve that physiological dose? Well, right. I think, I think yes, exactly. I think getting the androgens under control, even if the glucocorticoids are somewhere between that 11 and 17 mg per meter squared control, you know, that's a win. Especially, the people in this trial were uncontrolled. Just achieving control and getting in that window, that's a benefit, for sure. Perfect. Thanks, and then maybe a follow-up for the company. When could we expect to see data on testosterone levels, particularly in females? Is this something we could see at the Analyst Day in December, or is this more likely to be included in the publication? Thanks again. More likely to be included in, in the publication, Michael. Perfect. Thanks. Very helpful. Thank you. We'll go next to Laura Chico with Wedbush. Hey, good morning. Thanks very much for taking the question. I actually have two for Dr. Auchus. So I just wanted to clarify, first, what do you see as the critical time point for intervention among your CAH patients? I just wanted to clarify the need in both the pediatric and the adult setting. And then also, just another clarification, relative to your currently managed CAH patients, how closely does the CAHtalyst trial population kind of mirror those patient characteristics? You know, this is a chronic disease. There is no window of time, and just like all chronic diseases, if people get out of control at any time, the men develop adrenal rest tumors. If they develop adrenal myelolipomas, if the women have uterine problems, that's going to have an impact further on. If they're overtreated with glucocorticoids for a period of time and they don't meet their peak bone density, or if they lose a substantial amount of their bone density or develop diabetes, that's going to impact the rest of their lives. There is no window. It's a chronic disease. So, and then the second part, how do these reflect? Actually, pretty reasonably in the adult trial, and I don't take care of children. Dr. Sarafoglou does. But, but you know, saying that about 15% are reasonably managed and the rest of them need something else, I think that's pretty close. Thanks very much. Thank you. We'll go next to Ash Verma with UBS. Hi, congrats on the progress here. I have two questions. Just on safety, anything you can share on the few serious adverse events that you saw in the study? Can you remind us how concentrated is the endocrinologist audience where bulk of these patients are? Thanks. Let me take the first one. We, we saw very few serious adverse events in the trial, none of which were deemed to be related to crinecerfont. Then on the second question, centers of excellence? Yeah. Sorry, so the second question was how many centers of excellence? Sorry, is that what your question was? Yeah, anything that you can help to frame how concentrated the physician audience is and whether or not it would be helpful for you to access the market when you eventually launch. Okay. Well, I think what I was one of the points we try to make is, yeah, there are not a lot of places that specialize in this, and it's hard for people who don't live near one of those to get good care. And one of the advantages of a drug like this is it makes any endocrinologist able to take care of these patients by doing the block and replace approach. So you reduce the problem by adding crinecerfont to one of just replacing the adrenal insufficiency, and anybody can do that. So I think it actually, you know, although there'll be a need for certain issues in terms of tumor formation and fertility and you know any kinds of surgeries that they might need, that there will be specialized centers. I'm looking to retire at some point, and so I actually need some people to be able to take care of these people locally. Sure. I mean, from our checks it. Hey, Ash, we gotta go to the next question, Ash. Yeah. Okay. Thank you. We're gonna follow up. Thank you. We'll move to our next question. Comes from Malcolm Hoffman with BMO Capital Markets. Hi, guys. Malcolm on for Evan Segerman, and congrats on the data for both the adults and pediatric patients now. I just wanted to ask, how does this pediatric data today position Neurocrine against other competitor CRF1 antagonists, like Spruce's agent? Obviously, you guys are ahead of Spruce's development, but how can investors think about how this data may differentiate crinecerfont versus their agent? Thanks again. Yeah. You know, I think what we're doing here today is talking about some just outstanding data on top of last month's release in the adult population, which was equally outstanding. We've set the bar now, I think, for the treatment of these patients. And so talking about other competitors, I would just let their data speak for itself, and then you and the scientific community can then look as data comes out and compare and contrast both. Thanks, Todd. Let's go to the next question. Thank you. We'll go next to Ami Fadia with Needham. Hi, good morning. Congrats on the data, and thanks for taking my question. I had one for Dr. Auchus. Can you talk about what might be the trigger for a patient to have that conversation with their physician on changing or exploring kind of a different treatment if they are generally well controlled or if they are not well controlled? So is there a specific metric or a specific test that sort of triggers that conversation? And then if you could sort of differentiate how that conversation might go between an adult patient and a pediatric patient. Thank you. Well, I think, you know, in the pediatric study, in the pediatric era, it would be that you see the child and you say, "Well, you know, the labs don't look good. His bone age is advanced. We, you know, we could add—We could have you wake up at 3:00 A.M. to give him a fourth dose of glucocorticoid, like some of the parents do, or we could add crinecerfont." You know, I mean, so whenever the child is having physical and biochemical evidence of poor disease, advanced height velocity, advanced bone age, poor laboratory biomarkers. And already, like the patients in this trial, already at about the maximum dose of glucocorticoid, that would start that conversation. Many of the new adult patients I see are either floridly Cushingoid on dexamethasone for 10 years, and wondering why they bruise all the time, and they can't lose weight, and that the doctor told them that their bone density is low. Then we have the conversation. "Well, you know, we can adjust your glucocorticoids and try to bring them down. Then we'll have to add something back," and so on. You know, that would be a time when I see people that are overtreated or the people who come in and they're in terrible control. They haven't had a period in five years, and their androgens are very high. I say, "Well, I could add some prednisolone or methylprednisolone to your regimen." They will... You know, you negotiate with patients these days. You don't tell them what to do. You know, they say, "Well, will I gain weight on that? What else will that do?" Or, you know, "And what, what are the side effects of that?" That's when you have that conversation. So you have a conversation whenever somebody is not controlled on a fairly physiologic dose of glucocorticoids, and that's the majority of these people. Thank you. Thank you. We'll go next to Mohit Bansal with Wells Fargo. Great, thank you for taking my question, and congrats on the data. One question from my side for doctor. How should we think about the long-term, in the OLE trial or even longer-term benefit in terms of lowering the glucocorticosteroids? Because do you think with the biomarker improvement, you should stabilize the steroid dose, or you expect it would come down further from here? Thank you. Again, I think with the adrenal atrophy that occurs over time, the disease generally becomes easier to control. I mean, I know this in people who have been taking dexamethasone for a long period of time. If you switch them to a very low dose of hydrocortisone, they often maintain control for a while, but then eventually, their disease deteriorates because their ACTH rises, and their adrenals grow, because they don't have something that's controlling that ACTH. And that's what crinecerfont would be able to do. So I think you can maintain control in the long term. You know, whether you could play with the dosing regimen and so on, sure, that's a possibility. This is only six months data. Did that answer your question? Yes, it does. Thank you very much. Okay. All right. Thank you. We'll go next to David Amsellem with Piper Sandler. Hey, thanks. This is Tim on for David. Just a few from us. First- How should we think about the commercial implications of 30% of patients getting to daily steroid burden at physiologic levels? Now, recognizing you'll have more meaningful conversations with payers soon, how do you expect payers to respond to that 30% result? Second, do you have any updated thoughts on pricing now that you have the full data set in hand? And last, do you foresee more of a receptive audience in pediatric and adolescent patients, given the obvious issues, you know, associated with long-term steroid usage in that population? Thanks. Yeah, hi, I'll take your questions, I guess, in reverse order here. So, you know, I'll start off by saying that, and I think we highlighted this early in our commentary. This is a patient and family community that hasn't had any significant new treatment options in decades, and there's significant unmet need. And it's a tight community. And so, you know, we expect that as these data become available, and as we start the process of education and outreach to the various stakeholders, that there'll be significant interest. But obviously, you know, we have additional work to do, as Eiry said, there's an ongoing open label study, studies. And so, you know, we need to wrap up that process of completing the data acquisition and go through the regulatory next steps. You know, you asked about payers. You know, Kevin commented that it's early yet from a pricing and access perspective. We have had some initial conversations, and I can tell you that payers recognize the significant burden imposed by chronic high-dose steroid exposure and the consequences of that. And so, you know, we're going to continue to have conversations with payers as we. Let's take one last question, please, Phil. Yes, sir. We'll go next to Sumant Kulkarni with Canaccord. Please go ahead. Good morning. Nice to see these data, and thanks for taking my question. Sorry if I missed this, but could you share any differences in the specific dose of crinecerfont between adult and pediatric patients? And do you think that might have had any impact on or not, on the efficacy or safety results you saw here versus in adult patients? It's a great question. Thank you for that. The way in which the trials were designed, we had done a lot of work looking at the pharmacokinetics exposure and clinical pharmacology aspects of crinecerfont in both adults and in children and adolescents before going into the study. We designed the program and the dosing in a way that the relative dose and exposure received by individuals would be the same. Whilst obviously the dose used in the pediatric study was somewhat lower, we had calculated and confirmed that that translated to the same degree of dosing as was seen by the adults. Got it. Thank you. You know, we're looking forward to seeing, like, the PK/PD correlations in adults versus children. That's the science that we have to do. So, you know, there may be differences in exposure that we're not aware of. So, yeah, it's a good question, and I don't think we've ever hit the maximum dose, right, you know, in either population yet. Yeah. Absolutely. Tolerability standpoint. Correct. Yeah. Well, I thank you all for your questions and your attention this morning. I hope you, as I, every time I get to listen to Dr. Auchus or talk to him, I learn so much. And so again, we're very, very fortunate to have had him today, and I have learned quite a bit. I would say one of the things that I hope you picked up on is just the excitement that all of us in the room here have with this data set. We are not going to be the rate-limiting step to bring this medicine to all the patients and their families suffering from CAH. We're going to work as fast and as hard as we can in order to get our regulatory documents together and to submit around the world. So I'm looking forward to talking to you all in about a month or so on our earnings call, and then very much looking forward to our Analyst Day in December. So thank you all for joining us this morning. And again, just a great day for CAH patients and their families. Take care. This does conclude today's call. 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