Welcome, everyone. Thank you very much for coming here this afternoon. You're gonna see very little of me, because you guys hear enough from me, I think over the years, and so we have an outstanding team and an outstanding agenda for today. As far as that team goes, you're going to be able to see all of the senior management team from Neurocrine is here. There's several that you've heard from many times before on our webcast. There's many more that this can be an opportunity for you to interact with.
But even more important, I think, is that you're going to get an idea of the depth that we have at Neurocrine, at least slightly get an understanding more of the depth we have at Neurocrine, because we've brought our senior leaders within the company with us here, who actually run the departments, run the programs, that are so important to us. So I really hope that you go up and avail yourself of talking with them today. Let's talk about how the day is going to go. We put together an agenda that I hope you find enlightening, educational. I hope you find today enjoyable, as we go through this.
What we've tried to do here is we've tried to give you the important information, the important topics that we wanted to get across, and after each one, have the opportunity for a Q&A session dedicated to that portion. But then at the very end, have a Q&A portion that all questions are welcome in that. Then what we'll do is we'll be ending the webcast, and we're gonna go into breakout sessions, and so you can then at that point be able to go talk to, as I say, the senior leaders within the company who run these programs, and you can ask more questions of them.
So when I said that we're going to be going over the major points, I wanna start out with first, here this morning, you're going to hear from Jude Onyia, who is our head of R&D. You're going to hear from him what we've been working on at Neurocrine for the last at least five years now in reshaping the R&D organization. But Jude's been with us for two years, and we thought we were doing a good job for that first three until he showed up, and then, wow, things really took an accelerant, and it's, it's been, it's been a joy to see what's gone on there.
And then you'll have an R&D Q&A with Jude, and Eiry, and Kyle, and Gerald Cheung, who is a distinguished scholar and fellow at Neurocrine, who runs a number of our programs, and Grace Liang, who is one of our resident neuroscience experts in the company. After that, we're going to go into CAH, and probably the most exciting, and the most important, and the most informative part of that session is we are so pleased and so indebted to a panel of that's going to be talking to you about CAH. And they're not gonna be talking about crinecerfont, they're not going to be talking about Neurocrine. They're going to be talking about CAH.
You'll probably meet for the very first time, a very delightful woman, who is, one of the oldest living CAH patients that is out there. We've been able to, talk with her, at Neurocrine a couple of times, and it's just been phenomenal for us. You're going to hear from a parent of a CAH child, and then we also then have two of the world experts, in, in CAH. And so that entire panel will be up here, moderated by Jean Chan and Bob Farber, who have run the CAH program here from beginning to end. Have a Q&A on that, and then we'll have that Q&A, as I say, for the entire company that follows.
And then we go into more detail in R&D, in your breakouts, CAH, and then crinecerfont in a breakout, and then psychiatry and our muscarinic compounds that we're going to go into there. So it's a full day. I hope it's gonna be paced well for us, and obviously we're gonna love your feedback, both you that are in the room and those that'll watch this on the webcast. We will, we will reach out to get feedback, so that we can do even better the next time. We are all going to be making forward-looking statements. There's some new information that I'll be giving and we'll all be giving today, so I would like you to read this quickly, and then go on to our latest SEC filings.
I think back about five years ago when that year of banking meetings, webcasts, that I said, "Neurocrine is going to look very, very different over the next five years than what we look today." And we were just getting an inkling that INGREZZA is a real important drug. We knew it was an important drug. We knew that we were going after an incredibly unmet medical need, but we still didn't know just how important the drug was going to be to Neurocrine, and how we were then starting to transform ourselves. And I think you would all agree that over the last five years, we are a very, very different looking company. That's where we are today. Over the next three years, Neurocrine will be transforming itself.
We've been working several years on this, but you are going to see just as dramatic a transformation in this company over the next three years as you've seen in Neurocrine over the next five years... You can read these things just as they are. We have a history of being able to discover, develop, and come, and get into in the marketplace with three drugs and, knock on wood, a fourth drug very shortly. And what I would like to give you a bit of news here today is that fourth drug, crinecerfont, the FDA just notified us that we have breakthrough designation for both the pediatric and the adult. So that's very important. Eiry will be able to discuss that with you in more, as will Ingrid, who's our head of regulatory. Fantastic news!
You're going to, as I say, hear from Jude about this completely new R&D engine. Well, it's gonna be new for you because this is the first time we really come out and present it. It's been something that's been building, as I said, for several years in Neurocrine. And you're going to hear more about our portfolio of muscarinic compounds, and a little bit of new news in just about 60 seconds. I put the word largest in front of there. So let's go to that pipeline. I usually don't like these big, busy pipeline slides, but there's a few important updates that are in here, and two of them that I'll go to right now is having to do with our VMAT2 franchise. As you know, we've been... INGREZZA has been an amazing drug, as I alluded to. It continues to be amazing.
We've got patent protection now out to 2038, as we've settled the ANDA litigations. But we have always, as Jude says, more, better, and we're introducing, after a number of compounds that we've been working on for a number of years, a better VMAT2 inhibitor than even INGREZZA. That's a lot to say, that there's a better VMAT2 inhibitor. Yes, it's early, but we've put this through its paces quite a bit, and this is more potent, and it offers us the opportunity to go into additional indications, additional different type of modalities with this. And as we look at this, we look at taking INGREZZA into the adjunctive treatment of schizophrenia, and we say that this could even be better there and beyond. So what we're doing is we're scaling down that ATS program. It's one trial.
It's going to give us, I think, terrific data with INGREZZA, but what it really will do is it's going to inform, and it'll be in the right time frame and cadence as that data comes out, to be through with the phase 1s, with NBI-890 here, and to be able to launch that program rapidly forward. I would also like now, that NBI-770, we said it was a, it was a proven mechanism in MDD. Trust us. But we didn't tell you what that mechanism is. Now that it's entering into phase 2, we're availing here today what the mechanism is. It's an NMDA and NR2B NAM. The important part of this story is, while that has been validated now in MDD by at least 3 other compounds, all of those were IV.
This is the first and only oral NR2B NAM, and I think that that gives us a very significant leg up in going forward with this, and it's gonna be starting its phase 2s. Finally, as I go through this, I said largest muscarinics. You've known about 568, that we have the M4 agonist in phase 2 clinical development, which has been enrolling extremely well. You know that we had 570, which is an M1, M4 dual. But what we have now is that we have a phase 1 ongoing now with an M4 preferring compound.
We have and also we're initiating a phase 1 with an M1 preferring compound, and in the next, let's call it three weeks, we'll be submitting the CTA, and then next year, early next year, starting the phase 1 program with an M4 antagonist. There isn't a muscarinic program in the industry to rival this. We're going to be able to take these and fully elucidate how this important receptor system is functioning in human diseases and which parts of the receptor system that we are going to drug appropriately, depending on the disease. That's all that I'm going to be saying. All of that will be gone into in more detail, and I'm not gonna try to give an introduction to Jude, A, because he likes giving his own introduction better than my introduction, so that's what he's going to do now. Thank you.
Dr. Gorman, thank you. Ladies and gentlemen, good afternoon, and thanks for joining us for today's Analyst Day. As I was preparing for this presentation on Sunday morning, my young high schooler popped into my home office and he said, "Dad, what's going on, and why are you talking to yourself?" I didn't realize I was talking to myself, but I proceeded to explain to him that I was preparing for this very important Analyst Day presentation. And he goes, "What's Analyst Day?" I explain, and he looks me right in the eye and he says, "Dad, all you have to do is to speak their language." I don't speak analyst, but I'll give it a try today. Okay.
What I thought I'd do is briefly introduce myself and also share with you, as Kevin pointed out, the exciting work we've been doing to transform our R&D organization in the last couple of years. I've been at Neurocrine exactly two years this month, and prior to that, I spent much of my career, 25+ years, at Eli Lilly and Company. At Lilly, I held several roles. The last 15 was one of the key leaders of the biologics research organization. 7.5 years leading the Indianapolis Biologics Research Organization as Executive Director, and 7.5 years as Vice President over all of the entire biologics research organization in both Indianapolis as well as in San Diego. In this role, I really was fortunate to lead or be part of a team that delivered well over 65 clinical candidates.
Okay, depending on how you count, 9 or maybe 10 of those are approved drugs today, 1 in regulatory review, and 3-4 that in phase 3 or phase 2, that I believe will be drugs in the next couple of years. And in aggregate, this includes a subset of game-changing, practice-changing medications for the patients that we serve. And, as the only contact sports I've learned to play, I'm passionate about drug discovery. For the incredible opportunity that it affords us to be part, small part of our patients' journey. And I joined Neurocrine to do exactly the same, perhaps better. Bigger, better, faster, and to be part of this incredible team, a team that has accomplished so much and is poised to continue to do so, and to be part of this vision of doing truly brave science for the patients that we serve.
Two years into it, I love it at Neurocrine, for there is a lot to love and a lot to be excited about at Neurocrine. Notable, and perhaps pertinent to today's discussion, as you heard Kevin, is that we are still one of the smaller biotech, truly biotech, companies with the deep scientific focus and the scale, the grit, and agility to do what we do very well. Honed over the discovery and development of 3 FDA-approved drugs, including valbenazine, and with valbenazine continuing to do very well, and with exciting phase 3 data that we just reported on crinecerfont in CAH, and as you heard from Kevin, a really extensive clinical pipeline that is poised to graduate a couple of launch products in the future. There's every reason to be excited, and we are.
Importantly, is that we have the means and the will to continue to build and to transform our R&D organization for scale, for sustainability, and for competitiveness. And so today, what I thought I'd do, a bit at a high level, is to share with you our innovation-driven growth strategy, our capabilities, and how... and the progress we're making in building the next wave of innovative medicines, and to bring to life our vision and our purpose of continuing to do brave science for the patients that we serve. And to this, our vision, R&D vision, is to really emerge as a true global leader in the neuroscience space. And the leadership, we believe, must be predicated in our ability to really sustainably advance a steady flow of innovative molecules to the clinic, through the clinic, and all the way to commercialization.
Judging from where we are at today and where we want to be in the future, we strongly believe that we have to increase our R&D productivity on a long, steady state, to be able to produce one commercial launch product every other year. To deliver to this long-term vision, in the short term, in the next 5 years, okay, we are building a robust R&D innovation engine that can rapidly and reliably deliver 4-6 development candidates a year in what we're sort of branding easily as a 25 or 20 development candidates over the next 5 years. This is through both internal and external innovation across a range of modalities, that steady state will then pay out this one, one product launch every other year.
Okay, given where we are, these goals are pretty bold and audacious, but are much needed... to secure the future that we seek. Begs the question: what is our strategy to do this? In terms of strategy, as Kevin pointed out, in the last, particularly in the last year and a half, we have focused on working on a strategy that will allow us to build that breadth as well as the depth, and transform our engine for sustainability. The fundamental tenets of the strategy is summarized on this slide, and they focus on strengthening our therapeutic areas, modernizing our capabilities, including horizontal capabilities that amplify the modalities. The thought is to shift focus and point that engine into a higher probability, best-in-class, and next-in-class opportunities that we believe we can win in.
And last, of course, is to deploy external innovation as an accelerant to amplify our R&D journey. All of this, of course, is towards delivering a diversified portfolio across all of our therapeutic areas and across the modalities. And it suffice to say that the guiding principle behind this strategy and our transformation agenda is really deeply rooted on a move, closer and closer to precision medicine, with a focus improving overall probability of success through a deeper understanding of diseases and the met needs that we work on, through a focus on clinical and genetically validated, targets. Targets that we particularly have translationally relevant endpoints that we can follow in the clinic. And where possible, we will pick targets that have shared pathophysiological mechanism across a couple of diseases, so that we can leverage this to build a pipeline into molecule assuming success.
For these targets, we will take a modality-agnostic approach, including exploring drug combos or intentionally designed, multi-targeted drug combos. As I pointed out, we've been working on this a little over a year and a half as a strategy. But this is no longer just a strategy and a vision, and a strategy on paper, for with every day, every month, our teams are bringing this strategy and vision to life. I hope I can share a bit at a high level, some of the elements of that. For this, what I thought I'd do is for each of the pillars of the strategy, I will double-click on it, with emphasis on where we've been, where we are, and a little bit of where we're going. The first being our therapeutic areas. So if you recall, where have we been?
Up until recently, we were a small molecule company with a big footprint in psychiatry and overweighted on, frankly, risky, novel, first-in-class targets. As we look in the future with an eye on leadership in neuroscience, we have gone back to really focus and sharpen where we play, how we play, and the core competencies that are needed in each of the core therapeutic areas. What this means for us is a focus, a rebalance towards areas of greater need, great areas of greater probability of success, and specifically, while maintaining a focus and a footprint in psychiatry, but to develop investments in neurology, neuroendocrinology, and to build an emerging franchise in neuroimmunology that is applicable to all of these therapeutic areas. To make this work, we have created a matrix therapeutic area units.
These are best viewed as disease centers of excellence that are embedded in our functions, with a primary role of helping us sharpen our strategy and sharpen our execution in terms of where we play as to what's core, what's emerging, what's opportunistic, and what is out of scope, in terms of how we play, as in targets and pathways that we want to play in. As well as the core competencies as it relates to modalities that are needed to compete in each of these spaces. And to this, today, our core remain in neurology and movement disorders. We have emerging opportunities in epilepsy that will shape our resolve. And, as we look in the future, we will be opportunistic in neuromuscular, neurodegenerative, and neurodevelopmental diseases. In neuropsychiatry, our core will remain in schizophrenia and depression. We will be opportunistic in bipolar and psychosis associated with dementia.
Let me point out here, in neuropsychiatry, given the polygenic nature of psychiatric illnesses, and often the lack of clear pathophysiological mechanisms, here we will focus on only a handful of mechanisms, maybe three, maybe four, targets or pathways, ones that have clinical POCs that we will play to win in. In neuroendocrinology, we're building on crinecerfont. In CAH, we will expand our core more broadly into hypothalamic pituitary axis, and opportunistically, we are also looking for an opportunity for targeted entry into a subset, and I underscore, a subset of metabolic disease, as well as rare endocrine diseases, especially ones with limited recent innovation. In neuroimmunology, as you know, the neuroimmune axis is dynamically regulated in growth and in disease. Altered immunological responses exacerbate the pathology of many neurological diseases.
Here our focus is to target pathological immune response in neuronal diseases, as well as in neurodegenerative diseases. This brings me to our second pillar of the strategy, and that is modalities. It cannot be overemphasized that our ability to compete and win or lead in any space is really intimately linked with our ability to build, buy, rent, and have access to a multi-modality engine that will allow us to translate ideas quickly into innovative clinical candidates. On modalities, our strategy is rather simple, and that is to modernize our capabilities and to expand the range of therapeutic innovation that we participate in. As I pointed out, up until recently, we were a small molecule company. And let me emphasize, as a CNS company, small molecules is and will always be a key component of our toolbox, okay?
And consistent with that, first, we have been investing to strengthen our capacity and capability in small molecule drug discovery. Second, and concurrently, is we've also been investing in emerging and next-generation modalities that will allow us to participate in peptides, proteins, antibodies, and gene therapy. On gene therapy, I want to make a point. We believe that gene therapy will be a significant part of the future of genetic medicine. And consistent with that, in addition to building internal capabilities, early in the year, we announced an expanded collaboration with Voyager, and with that collaboration allows us access to industry-leading BBB-penetrant capsids that will give us the opportunity to create a competitive pipeline in gene therapy. Let me emphasize also, our investment in each of these modalities are relatively small compared to what you would see in a big pharma, but this is by design.
Equally by design is how we will boldly deploy, tactfully deploy these modalities on a select few of foundational, high-confidence, high targets that we want to compete and win in. Together, what this does, it gives us the optionality to pick and choose the right modality for the right target, for the right disease, and for the right patient. Over time, this will increase our probability of success and will also drive the productivity, it's already driving the productivity, that we seek. To that, I'm happy to report that in a little over a year and a half, we've gone from being ju st a small molecule company to really aggressively standing up these modalities.
As intended, these modalities are opening up tremendous opportunities across all of our therapeutic areas, and is allowing us to harness early ideas and translate them into a growing early phase portfolio. With the progress on the therapeutic areas and on the modalities, I think it begs the question: What is our innovation philosophy, and where are we pointing this powerful engine? To get to the future that we seek, we're taking a very pragmatic approach to innovation, one that is deeply rooted in the balance of exploration/exploitation trade-off. The exciting balance of looking in new places, as in first-in-class opportunities, and looking with new eyes in old places, as best and next-in-class opportunities. To this, we are deliberately rebalancing our portfolio, as you can see, towards genetically and clinically validated targets, high-confidence, high-opportunity targets that we believe that we can win on.
What this means is that often our lead generation strategies will focus on genetically and clinically validated targets, but to create a rich portfolio of novel, differentiated, patentable, best and next-in-class, high-value opportunities that we believe we can win in. Executed well, this will serve the foundation to drive our growth, including future investment in perhaps first-in-class riskier opportunities. To this, we've created, as you can see, a prioritization matrix. If you look to the top right quadrant, that will allow us to focus on these high-confidence, high-opportunity targets. For these high-confidence, high-opportunity targets, we will play to win with a robust strategy and a plan to differentiated outcomes. As needed, we'll buy multiple tickets, as in multiple shots on goal, follow-on, to ensure that we win in these opportunities.
Vital to this strategy is that we make molecule design, engineering, and optimization a core competitive advantage at Neurocrine. This is particularly important as we build out our biologics, umbrella biologics organization. And to this, at steady state, which we predict will be next year, our molecule design and engineering capability will be second to none in the industry, and we have deliberately hired some of the best talent to make it so. These molecule designers and engineers who understand the truth in these fundamental design principles of what is important to the patient, i.e., maximizing efficacy, safety, dialing in ideal like, drug-like properties, convenient delivery, but with line of sight from concept all the way to the clinic.
So this brings me to the last pillar of the strategy, perhaps obvious, but that is the power of external innovation, our ability to build, tune and torque and run our engine as fast and as aggressively as we've been running it, is intimately tied with having a world-class external innovation team with over 30 years of deal-making. We have seamlessly integrated internal and external innovation as a boundaryless source of ideas, enabling technologies, preclinical to clinical stage programs, and as always, are consistently looking for commercial product opportunities. With a focus overall on defining what we build, what we buy, what we rent, to amplify and accelerate our journey. And to make this work, we are agnostic to deal structure, and this is, allowing, has allowed us to optimally really balance our needs and interests with that of our partners.
As shown in the next slide, we relentlessly pursue external innovation to really meet and exceed the aggressive goals that we set. The point I want to make with this slide, if you look to the right, is the pipeline deals. The likes of partnerships or acquisitions from the likes of AbbVie, Sosei Heptares, Takeda, Xenon have been key to strengthening our clinical pipeline. Equally important, to the bottom, is the platform deals or modality deals with the likes of Voyager, Ascentyia, Biocytogen, Ablexis, Armea, and so forth have also been key to rapidly building up our early phase discovery pipeline. All of this, of course, is towards building a diversified portfolio across all of our therapeutic areas and across all of the modalities.
Well, with a year and a half into it, I think it's fair to ask the question: how are we really doing in terms of early phase pipeline? The simple answer is that we're off to a good start in creating the building blocks for the rapid and sustainable growth that we seek. In the last year and a half, we have delivered on 10 new development candidates, and importantly, these candidates are funding the flow and growth of CTAs and INDs in the clinic. This is also associated with the advance of our first biologics development clinical candidates, as well as, excitingly, accelerated timelines, an early measure of improving R&D efficiency. I want to pause here for a minute and make a point. I have not been at Neurocrine long enough, but I am told that this is the most productive we've been.
This is the first of the first of the first for us, and for a company our size, this is incredible productivity. But it's productivity we must now maintain and frankly, better yet, outperform. And important to that is that we're deliberately creating a portfolio, deep early phase portfolio, that will allow us to do this year-over-year, 2023, 2024, and beyond. This is a high-level snapshot of our current portfolio, focusing on phase I's. These are molecules that you've heard from Kevin, they're moving into phase I. All the way to the left, the standard about 27 exciting programs. My sincere apologies, but we've blocked out, for competitive reasons, some of the earlier programs. But except to make a couple of points, and that is, in a short period of time, we have transformed and strengthened our early phase pipeline.
Second, as called for by strategy, when you look at the colors, this is balanced across the therapeutic areas, as I pointed out earlier. This is also balanced across the modalities, almost a 50/50 balance between small and large molecules. This is overweighted on the clinical and genetically high-value, high opportunity targets that we believe we can win in. The last point I want to make is that, yes, while this is not perfect, we are confident that this is sufficient to support our short to midterm goals and this flow of really innovative molecules to the clinic. To that, I want to end on this slide that highlights some of our must-win focus areas. Okay? These represent proximal or primers of proximal opportunities to the clinic.
These select programs represent foundational programs that we're planning to win with a robust strategy and a plan to truly differentiated outcomes. Namely, to the left, first is VMAT2. Again, today, we're a leader in VMAT2, a leadership and experience that we're leveraging to really advance the next in-class molecules that will allow us a differentiated leadership position in both psychiatry and neurology. As you heard from Kevin, our first program, our follow-on program in 890, is a potent VMAT2 inhibitor that is poised based on the characteristics for both acute daily dosing as well as LAI dosing. And, behind 890 and poised is another even novel, even more potent, VMAT2 series. And even behind that is a VMAT2+ series. These are intentionally designed dual pharmacology agents that hit VMAT2, plus another target to provide differentiated position in both neurology and psychiatry.
For CRF1, again, building on crinecerfont, we see tremendous opportunities to advance additional best-in-class and next-in-class opportunities in CAH and the adjacencies thereof. For the muscarinics, as you heard from Kevin, again, building on 10 years of intense research and the internal expertise in muscarinics and Neurocrine, amplified by a partnership with Sosei Heptares, we are in a unique position to advance multiple flavors of muscarinics with our lead program, M4 agonist, NBI-568 in phase 2, NBI-567 M1 preferring that is initiating phase 1, NBI-569 that is in phase 1, M4 preferring, and a dual M1, M4, NBI-570 that is already in phase 1. And not to forget our internally developed M4 antagonist in NBI-986. Okay?
Lastly, of course, is gene therapy, and this is the opportunity to advance our first development candidate in GBA for Parkinson's and Gaucher, frataxin for Friedreich's ataxia. Behind these is we have exciting five additional exciting programs that we also believe will advance clinical candidates in a short period of time. The point I wanna make with gene therapy, again, is that the partnership, besides our internal build, the partnership with Voyager positions us to really take advantage of these industry-leading BBB-penetrant capsids. These capsids have incredible CNS tropism and transduction efficiency, and allows us a non-invasive IV delivery against these opportunities. Lastly, I hope this gives you, at least at a high level, the progress that we're making on talent, on capability, therapeutic areas, and the emerging early phase portfolio.
But let me end by impressing on you that what we're building or what we've built so far is a world-class R&D innovation engine, that we believe that person for person will eventually be one of the most productive in our industry. Okay? Yes, it's early days, but the strategy and investments are already delivering great innovation. It is the dawn of a new era in Neurocrine R&D. The foundation is laid. The pipeline is coming or emerging. Yes, we're excited, but we're even far more excited with where we're going. And with that, I will stop and invite some of the key leaders that have helped with thinking through and building the strategy to join me on stage for a quick Q&A. Eiry, our Chief Medical Officer, Grace Liang.
Grace is a VP Clinical Development and one of the core therapeutic area leaders in neurology. Gerald Cheung, a distinguished scholar coming up at Neurocrine. And Kyle, our Chief Business Officer. Kyle , where are you?
So Jude, thanks so much. You spoke analyst very well. You guys agree? He speaks Jude very well, and he's created a lot of substrate for us to build a foundation off of. So, can I open it up for questions? Todd and I will be going through. Brian, let's start with you.
Thanks, Jude, for that great review, and congrats on all the R&D progress. I was wondering if you could elaborate on the potential clinical as well as business advantages of using this next generation VMAT2. And I guess just how much do we know or how much are you learning about the interface between VMAT2 mechanism and the pathophysiology of schizophrenia that steers you towards leveraging a more potent next-generation molecule versus adjusting the dose or exploring other regimens with valbenazine?
I'll probably start, and I will invite Eiry and maybe Kyle to join in. So the thinking here is with the VMAT follow-ons is to really broadly creating an estate, okay, that gives us flavors that allow us to go beyond where valbenazine is today and frankly, beyond. Okay? And some of our early exploration in ATS will inform the ideal molecules and where they can go, okay? We are intentionally also designing based on the learnings we have molecules that even have... Again, in spaces we understand, we're designing deliberately plus strategies that bring in additional benefits that I'll probably not elaborate on for today. And so with this, we've got really the properties of this molecule is it's pretty potent, very low clearance, very low solubility.
It allows you QD, it allows you LAI strategies, and behind that, we have even far more potent, and we have plus strategies. We believe that these flavors, it's hard to predict which of these will be. It's early days, okay? It's hard to predict which of these molecules will be eventual winner in whatever indication, but we have the flavors. At least we are intending to build the flavors that will allow us to go with whatever we need.
Is this on or... Oh, this one's on. Okay, great. Thank you. So yeah, I think it's a great question. Thanks. And certainly it's an important question because valbenazine is an awesome medication. And you know, as a VMAT2 inhibitor, it performs incredibly well and very, very reliably, and we know about the simple dosing regimen and you know, the behavior we see in terms of efficacy and tolerability. So what that's meant for us is we've had to set the bar really high as we look at next generation molecules.
As Jude alluded to, we've been working in this area for a long while, and I think we're now feeling comfortable that we have a couple of molecules to bring forward, including some of the added pharmacology that give us an opportunity to add even more benefit to a broad range of neuropsychiatric and potentially neurological disorders as well. I mean, I think the first thing I would say is it mentioned in the slide the ability to have a long-acting intramuscular injection, and we know that in areas like schizophrenia and other neuropsychiatric disorders, compliance and adherence to medication is really difficult and challenging. We've seen with tardive dyskinesia, a very high compliance rate, for the long run, for INGREZZA, and that's been fabulous.
But I think as we go into schizophrenia and other areas, we can anticipate that that's likely not going to be as good. And so the ability to have a once-a-month or other treatment for patients, I think, would be a real differentiator. And then just one comment about the mechanism. I mean, we obviously know a lot about VMAT2 inhibition and the breadth of applicability of that mechanism across... You know, it's a presynaptic monoamine, a modulator. And whilst we focused a lot of our efforts until recently on the dopamine element of that and how it relates to the use of valbenazine in movement disorders and the effect we've seen there, we do know that, say, in patients with schizophrenia, increased presynaptic dopamine synthesis is an important feature for at least certain patients.
Applying that in combination with other pharmacologies really gives us an opportunity to potentially differentiate. At the end of the day, it's all going to come down to the clinical data that we can generate. Our goal is move molecules as rapidly as we can from our discovery preclinical setting into the clinic and enable us to put in place, through use of tools such as our PET imaging and other proof-of-concept-type studies, an ability to triage these molecules as rapidly as possible, pick the winners, and move forward with those to serve the diseases that have such unmet needs still. I mean, I don't know, Grace, if you have anything else or anything you want to say in that regard or Kyle?
We're done here.
Thank you. Brian, this morning.
Thank you for the question. Jude, I noticed on the slide deck under endocrinology, you had metabolic disease. I think your former employer has an emerging metabolic disease franchise. So I was just wondering where you kind of see the unmet medical need in metabolic disease, given your experience and all the research that you've done at Lilly?
Yeah, I'm glad. I see you noticed the Lilly pipeline in metabolic disease. To be clear, that's not what we're trying to do at Neurocrine. We are trying to be Neurocrine and focus on where we believe Neurocrine can lead and be competitive. The intent for us in metabolic disease is, we're really being opportunistic here to explore spaces where we can enter into subsets of metabolic disease. I can directly say we're not gonna do diabetes, okay? You never say never, but we're not intending to go do diabetes, dyslipidemia, frankly, NASH and osteoporosis, and so forth. That's not what we're thinking about. What we're thinking about is leveraging the when we have a molecule and a mechanism into adjacencies that represent subsets of metabolic disease, right? That's how we're looking at it.
You can look at CAH as having metabolic components and the adjacencies of CAH. You can also look at things like obesity, okay? Not polygenic obesity, but you have subsets, subsets of obesity that, given the tools, given the molecules, and given the legs, that are perhaps worth exploring these adjacencies.
Paul.
Thanks. That was, that was interesting. Just more broadly, you highlighted a couple of areas that were interesting that you're not at least obviously in right now in mid-stage development, like neuromuscular, neurodevelopmental. Do you feel like internally, you have all the right tools to address some of these indications? Like in muscle specifically, does Neurocrine have what they need in-house, or is this something you'd be working on with your BD team to access other technologies like, like oligos or things like that?
Yeah, excellent question. So when you look in these spaces, we have... Again, we're positioning it as being opportunistic. We do have molecules that we believe and capabilities that we believe that will present a space for us to explore. Without diverging much, well, some of the platforms actually give us a competitive position in some of these spaces, and so we're carefully exploring these. And as these programs mature, we'll share as much as we can.
... We'll take. Got me. I've been recovering from a cold. Good to see everybody. Todd Tushla, Investor Relations. Question on this side.
Thank you for providing the update, and congrats on all the progress. Jay Olson from Oppenheimer. Super excited about the breakthrough therapy designation for crinecerfont. And as Neurocrine grows into a global organization with a potentially global launch of crinecerfont on the horizon, can you talk about the steps you're taking to globalize your R&D? And maybe just to drill down on NBI-890, will that be a global development program? Is that part of your vision? And if so, how do you plan to make NBI-890 into a global drug? Thank you.
Do you want to start on the R&D?
No, you-
Oh, me. Okay, great. Yeah, thanks, Jude. Great question, and it is really exciting. We're very excited about the breakthrough designation for crinecerfont and that the opportunity that provides us for the first global set of submissions and hopefully ultimately approvals and launches for crinecerfont and CAH. You know, in terms of our organization, we've already been on a journey with respect to globalization. If you look at our clinical development, I would say for the last 5+ years, and even before that, actually, in Neurocrine's history before that, we've completed development programs around the world and including collaboration and partnerships with our colleagues in Japan as well. And so I think that. The natural progression from that obviously is as we move into the approval and commercialization process.
But it's also fair to say that if you look at our collaborations in licensing, research, and development efforts, we've, we've collaborated and partnered with other companies around the world as well, whether that be Idorsia or BI or other organizations. And so we've learned a lot from a lot of those collaborations and from a lot of our current clinical development. Specifically to NBI-890 and the VMAT2 inhibitor, I think given the breadth of the indications that are currently in scope and under consideration there, we do believe that there's an opportunity for us to provide value for patients around the world, and that will be a global clinical development program. At least in some of the indications that we undertake, where the unmet need is most.
And so I believe that will be our intent moving forward for almost all of our programs, actually, unless there's a very specific reason as to why particular regions of the world would not gain advantage or benefit for patients in that area. I know, Kyle, if you want to say anything else there.
Yeah, just maybe to add to that, you know, we did acquire a small company in the U.K. called Diurnal about a year or so ago now, and that allowed us to have commercial and clinical operations, a footprint there in the U.K., and it's something that we'll certainly look at building out with the right cadence for our other clinical programs that are in the pipeline over time. I think that would be useful organization that we can leverage there in Europe to help us do studies within the region. And I think that what we've seen today in neuroscience, you have to be able to do studies globally to get them you know quickly enrolled and hopefully in the hands of patients as quickly as possible. It's certainly something that we'll continue to do.
Next question on this side, Phil.
Thanks, Todd. Hi, Phil Nadeau from TD Cowen. A broader strategy question. We've seen other companies that have historically had a focus on neurology, decide that in order to have low-risk candidates in their pipeline, they had to move to adjacent areas. Sounds like Neurocrine is gonna double down on it with a focus largely on neurology. How confident are you that you can create a portfolio with a variety of risk profiles with that focus? And, did you consider looking at adjacent areas more aggressively, and why'd you decide to double down with the focus on neurology? Thank you.
No, we have carefully thought about really areas where the opportunities are, unmet, on unmet need exists. And second is also areas of greater probability of success. And if you look at today, for example, just pick these orphan diseases, the 7,000 orphan diseases that are out there. Okay? Depending on who you read, 20%-40% of them have neurological components. Many of these are pretty defined mechanisms that you can easily, in an attractive way, go after, and these will provide opportunities for land and expand into other broader diseases. And so we see the probability of success—opportunities are there, the probability of success is there, and it gives us all the opportunity to expand into adjacencies as needed, based on targets and pathways that we can go after.
So that's part of the thinking. One thing I'd add to that, too, is some of the challenges that we've seen with companies and neuroscience isn't necessarily the lack of targets and disease states to pursue. It's because a lot of the companies that are in the space are limited by access to monomodality. I think if anything I've learned over the years at Neurocrine and seeing our own challenges in certain targets and others is that it really is this concept of matching the right modality for the right target, and doing that allows you to maximize what's available out there in the biology to its highest extent.
I think that's where we've decided to focus our time and energy, is to give us the access to those modalities that will help us win on those targets that might be being pursued by others, but in an inefficient or inappropriate way.
... Hello, I'm Grace Liang, and I am, Vice President of Clinical Development, and also primarily involved in the neurology therapeutic area. So our thinking as we've developed the strategy over the past few years is, as Jude and Kyle have pointed out, to really find and define the right target for the right modality and the right population, and also the right outcomes. And the way that we're prosecuting that, in both being very careful about the targets that we select, is leveraging our deep, internal expertise already and our presence in the movement disorder space.
So we will continue to play there and look for high opportunity and high probability of success targets to work on, which we are currently doing, as well as, again, some of these new other, other indications in neurology that, again, have very, strong science and also, the potential for applying precision medicine techniques. And so how we will do that in the clinical setting is to really expand and deepen our use of translational experimental medicine approaches that are gaining traction in improving the success in the neurology space, as we've seen across our industry, and we've already deployed that in our early phase development program.
I'm happy to say, sitting alongside Eiry, that as you've heard, imaging modalities, electrophysiology, other digital biomarkers, and the list expands currently in biomarkers that are available to us that can, again, give us clear insight into the science and the feasibility of these programs moving into later stage.
Thank you. So that wraps up Q&A for this session. There's gonna be two more bites at the apple here after the CAH panel, as well as at the very end, a catch-all if you do have additional questions. What I'd have to say is, good job, guys. I know it's hard to get up and talk to analysts, but hopefully you guys found this insightful, and importantly for Neurocrine, it really builds an engine of sustainability. So I'm really looking forward to this team and how they're gonna continue to progress. So thank you, all. If you wanna give them a round of applause.
Housekeeping comment. That, that's the whisper that he was doing in my ear. The presentation will be posted around 4:00 P.M. today, so that'll be out there. Now, it is with great pleasure that I get to introduce Dimitri. Why is it great pleasure that I get to introduce Dimitri, and why am I introducing Dimitri? Dimitri, I will count as employee number 1 at Neurocrine. If you look at his HR form, it'll say something like maybe 3. But Dimitri and I actually was working with during the formation stages of Neurocrine. He has. We call him the godfather of Neurocrine. So he's been there for 30, going on 32 years. He, for the last, gosh, I don't know, 17 years or whatever, he ran all of our research efforts.
When you think of elagolix, or I should say Orilissa, Oriahnn, that's Dimitri. When you think of INGREZZA, that's Dimitri. When you think of crinecerfont, that's Dimitri and his group. So he has brought us all of those. I would say, of all of them, crinecerfont brings him the greatest joy. And why is that? Well, Dimitri's entire career, both prior to coming to Neurocrine, has been on understanding the HPA axis, hypothalamic-pituitary-adrenal axis, and understanding corticotropin-releasing factor's role in that. I've said a number of times, and it's the only time I think I come close to chest-thumping about Neurocrine, is that we know more about the HPA axis and CRF than any organization in the world, and that is due in no small part to Dimitri and also to Wylie Vale, who was our scientific founder at the Salk.
So Dimitri, you know, what Neurocrine was founded on, if you were able to look back into the original business plan of Neurocrine, it had out there as mission number one: to find orally active small molecule CRF antagonists, CRF1 receptor antagonist. That's what we were founded on. That's what we did. We put more CRF antagonists in the clinic than any other pharmaceutical company, initially for looking what was considered at the time that a CRF1 antagonist would be an antidepressant anxiolytic. Unfortunately, that didn't turn out to be the case. When that didn't turn out to be the case, most people would then say, if they've you know, put their entire life's work into that, that that would be very disappointing.
Their head would go down, and they would crawl back into the lab and try to be, you know, whatever, "What's the next target to work on?" Not Dimitri. Dimitri went on a walkabout, is what I'll call it... He said, "There's no way that this CRF system, as important it is into human biology, doesn't have a role in serious diseases." And he harkened back to what Wylie Vale had said to us right from the very beginning: "Really love the fact that we're looking at the central role of CRF in anxiety, depression." He says, "But please never forget that fundamentally, CRF is a hormone-releasing factor. It acts in the endocrine system.
It acts on the pituitary." So that's what Dimitri went out on his walkabout that he did, and he came back and said, "I met this guy, Richard Auchus," and it was life-changing for Dimitri. "I think I know what we're gonna do in CRF." With that, I'd like to invite Dimitri onto the stage to take you through a quick 32-year journey.
All right. Thank you so much, Kevin. Yes, I'm gonna take you through a 30-plus year journey of Neurocrine and the CRF program, and I was told to have 5 minutes, so buckle up. All right. Actually, the story starts in 1981. The peptide itself, CRF, was discovered by Wylie Vale by brute force. This was before molecular biology. He used 500 sheep hypothalami to isolate the peptide for CRF. But a decade later, Neurocrine was founded, and as Kevin said, we founded it on the platform that Wylie Vale had started at the Salk, which was the CRF program, as well as another platform from Larry Steinman at Stanford University.
The Wylie Vale lab, 10 years later, actually cloned the CRF1 receptor out of a single human anterior pituitary from a Cushing's patient. So that gives you the scope of 500,000 sheep hypothalami to get the peptide, one pituitary tumor with molecular biology to get you the CRF receptor. As Kevin said, we've been in the CRF field for a long time. Neurocrine was able to identify the second form of the CRF receptor, the CRF2 receptor, both in human and in rat, and we used that to begin our drug discovery program for CRF receptor antagonists. Now, the first exposure of a CRF1 antagonist in humans occurred in 1998. This was with our partner, Janssen Pharmaceuticals, and the Max Planck Institute in Munich, Germany.
We completed a phase II major depression trial in an open label manner and simply determined that this small molecule had biological activity. Since that time, there were a number of POC studies that were done with 3 different CRF1 receptor antagonists, all in diseases of the CNS, as Kevin mentioned initially, looking at generalized anxiety disorder, social anxiety disorder, PTSD, IBS, as well as major depression. But throughout that time of us working in the CNS area, Wylie always told us, "Don't forget about the HPA." So what we did in 2007, we actually did a study called a Trier stress test, and I don't have time to go into the details right now. If you're interested, I will go over it with you in the breakout.
But basically, it's a way to determine that blockade of CRF receptors at the pituitary level can affect adrenal steroids. With that, we filed our first IND for CRF antagonist in congenital adrenal hyperplasia in 2013. That was with our prototypic compound 860, that we had partnered with GSK in the CNS field, and we demonstrated in a phase I/II, a PK/PD relationship between blockade of CRF receptors in the pituitary and the change in androgens that we see from the adrenal gland. And then we met Richard Auchus, and at that point, we did a single-blind, placebo-controlled study in CAH patients, and we demonstrated a relevant androgen reduction with a CRF receptor antagonist. Crinecerfont IND was filed in 2016, and shortly after that, we completed a phase II proof of concept for crinecerfont in the treatment of CAH.
Our first adult patient for a phase 3 study was dosed in 2020. Shortly after that, we dosed our first pediatric patient, and recently in 2023, you've all seen the data that, Eiry and the group will go over in a minute, but it was very positive data in both adults and in pediatric CAH patients. So to summarize our entire history of CRF, our R&D efforts have not only spanned the time frame of 30 years, but we've spent a lot of time looking at the spectrum of the CRF system. Not just with the GPCRs, the R1, R2 system, but also with the neuroendocrine peptides that are part of the family of CRF. These would be the urocortins. Again, all credit goes to Wylie Vale here. They discovered these peptides. They are bioactive peptides, both in the brain and the pituitary.
They have their own biology that we could explore. As well as there's a binding protein out there. This is a binding, a soluble binding protein in the periphery and in the CNS that binds up CRF and urocortins. So there's a lot of opportunity here still, as Jude mentioned, in this whole CRS, CRF area. But just focusing in on the antagonist for a second, I told you that our first compound, the first compound that went into humans, was 775. That was with Janssen Pharmaceuticals. That went to phase II. We had four additional compounds with a very large GSK collaboration that we did, looking at a variety of compounds in all the disease states that I told you about in the CNS, and we finally have crinecerfont, which just completed our phase III trials.
What we're very proud of at Neurocrine, I think over the time that CRF has been discovered since 1981, five of the compounds that have made it to phase 3 or further are have been associated with Neurocrine, and we're really proud of that fact. So thank you, and I'll be around later if there are any questions. I'll turn it over to Eiry.
Thanks, Dimitri. You know, it's really humbling actually, when you look at that history and see how much work and how much effort over so many years goes into getting us to where we were this year, and our ability to read out the data from the crinecerfont Phase III program in CAH, in adults and pediatrics. I'm gonna spend just a couple of minutes up here doing a very brief overview of congenital adrenal hyperplasia, because the most important part of this discussion around congenital adrenal hyperplasia today is for you to have the opportunity to hear from our panel that represents both individuals who've dedicated their whole lives to treating patients with CAH, and individuals who have been living with, or supporting and advocating for patients with CAH throughout their lives as well.
But just let's take a couple of minutes to talk about CAH itself. So CAH, congenital adrenal hyperplasia, is an inherited disorder that leads to a defect of a key enzyme in the adrenal, that is responsible for producing glucocorticoids. As a result of that defect, patients with congenital adrenal hyperplasia suffer from adrenal insufficiency, and have to take glucocorticoid doses, hydrocortisone or equivalent, and usually aldosterone, throughout their lifetime to prevent adrenal crisis, which is a life-threatening part of the condition. The problem with CAH, though, is it's not just a disorder of deficiency, it's also a disorder of excess. Because of that key enzyme deficit in the adrenal, the precursors of glucocorticoid are shunted to produce excess androgen or male hormone levels.
So patients with CAH not only need treatment for their adrenal insufficiency to prevent them from having adrenal crisis and adrenal deficiency, but they also require treatment to treat those high androgen levels that they have. And in order to treat those high androgens, what we have to do is we have to shut off the ACTH drive that comes from the pituitary to the adrenal. Now, the big problem in CAH is that for the last 60 years, the only way we've had to do that is by using steroids. And so we have essentially a sucker's choice or a Sophie's choice, or a very difficult situation that we all have to deal with in terms of understanding how to help patients with CAH. With those steroids, we can either just treat the adrenal insufficiency.
We give physiologic level of steroid, we treat the adrenal insufficiency, but then these patients run very high androgen levels, and as a result of those androgen levels, they have disorders of growth, abnormalities of bone, and many of the other issues that you see on this slide, represented by the high ACTH and androgen excess, including tumors and things that lead to infertility for patients in adult life. So the other choice we have, is we can give really high doses of steroids and try to suppress those androgens. And if we do that, then we run all the risk of what happens when you give high-dose steroids to patients for the duration of their lifetime: cardiometabolic disorders, hypertension, osteoporosis, bone fractures, and many of the other neuropsychiatric and neuropsychological issues that go along with excess steroid use as well.
So it really is an environment right now, where the treatment options that we have available to us just don't solve the problem for us, and you're gonna hear that more from people who are actually living with this disorder day to day, as we get to the panel. Now, crinecerfont provides a very different opportunity here, because what crinecerfont does through its antagonism CRF1, is it actually directly impacts the pathophysiology of CAH, and it does that and reduces the androgens directly. So that has two big impacts for us. It allows us to balance a situation where we don't have androgen excess anymore, and that means we don't deal with the issues associated with androgen excess for these patients.
But it also allows us to reduce the amount of steroid that we have to use, so that we're getting to a stage where we're just replacing the deficiency. So that's why we were so excited with the crinecerfont data that we saw, and that's why I think as we think about breakthrough, as Jay mentioned earlier, you know, it, it re-emphasizes again for us an acknowledgment of the seriousness of this disorder, the nature of the unmet need here, and the opportunity that we have with the data that we have in hand to hopefully make a difference for patients living with this disease on a day-to-day basis. So with that, with that in hand, I just wanna take the opportunity to introduce our panel, and to start by introducing and calling up to the stage, Dr.
Robert Farber, who is Vice President of Clinical Development and is the team leader for our crinecerfont program, and Dr. Jean Chan, who is an endocrinologist and the VP of Clinical Development in Endocrinology for us here at Neurocrine. They will introduce you to the remainder of the panel. I hope, and I know this will be a highly informative and very inspiring session for you. Thank you.
... All right, we're all comfortable, assembled here. All right, excellent. Okay, so this segment, we definitely have just, Jean and myself have a great amount of pleasure and privilege to have this esteemed panel in front of you all today. They, this is a panel that definitely doesn't speak to analysts, so earpieces will be required. We are gonna hear really the human element here that's hopefully going to come through, and we have worked very hard to keep this as a discussion-based as possible, and everybody up here is gonna be speaking from the heart. So I hope you'll join me in welcoming them and supporting them in this. So the panel actually consists...
It's a multidisciplinary panel, actually, a lot of different perspectives and levels of expertise standing or sitting in front of you now. Two of them are CAH clinicians, and they actually happen to be two of the world's experts in congenital adrenal hyperplasia and its treatment, and have done a lifetime's worth or a career's worth of research on CAH. You'll get the adult and pediatric perspective from Doctors Richard Auchus and Dr. Kiki Sarafoglou. And then we're also joined by a patient advocacy leader, Dina Matos, from the CARES Foundation. And then rounding out our team up here, we have two members of the CAH patient community.
We have Leslie Holroyd, who is our adult CAH patient, as well as Alex Dubois, who is a caregiver and actually the mom of an adolescent boy with CAH. So again, we're gonna kick this off with a question. I'm imagining that there will be other... you'll have opportunities later on to ask some additional questions. But we're really going to again keep this right at the level of trying to understand kind of the day-to-day that these individuals experience and have experienced for their lives. So, I'm gonna hand it off to Jean.
Great. So first of all, maybe, we can have the panelists just give a very brief introduction of themselves.
So I'm Rich Auchus. I'm a professor of Medicine and Pharmacology at the University of Michigan, home of the number one Wolverines. Go Blue! And I'm a steroid biochemist, so I do basic clinical and translational research, and I see adult patients with CAH.
I'm Kiki Sarafoglou. I'm a professor in pediatric endocrinology and also the Department of Clinical Pharmacology at the University of Minnesota, and I see patients with CAH, pediatric patients mostly, but I also transition my pediatric patients to adults, and I follow them throughout their life.
Hi, I'm Dina Mattos, and I'm the Executive Director of CARES Foundation. So CARES is an acronym for Congenital Adrenal Hyperplasia Research, Education, and Support Foundation. We are the only organization in the U.S. solely dedicated to the CAH community. We were founded in 2000 by a family whose child was diagnosed and didn't know about the disorder or had any resources. But we're also representing patients globally. We have members from 70 other countries across the globe, and we're a founding member of CAH International, a new collaborative of CAH organizations and smaller support groups.
Good afternoon, and my name is Leslie Holroyd, and I am a patient with classic congenital adrenal hyperplasia. I was born in 1957, so I'm 66 years old, and I was born in England at home with a midwife, when very little was known about CAH. I came to the States in 1991, and I joined the CARES Foundation in, I believe, 2014, and that was the first time that I'd spoken to anybody regarding CAH. And so, I look forward to sharing some further information about myself.
I'm Alex Dubois. I am the mother of a soon-to-be 16-year-old teenage boy, who was diagnosed through the newborn screen at birth with salt-wasting congenital adrenal hyperplasia. So I'm a mom, but I'm also an advocate, and I've been part of the CARES Foundation for about 15 years now. So happy to be here to share my experiences with you all.
Well, I just want to extend my very deep thanks to all of you for taking time out of your busy days and schedules to come here, share your stories, share your thoughts and insights. And maybe I can just start first with a question to Dr. Auchus. As an adult endocrinologist, when you have a patient, a adult patient, that is referred to you with CAH, can you tell us a little bit about what that interaction is like?
... Right, so at first I have to get a sense of if they've received good care in the past. If they come to me short and overweight, I know that their pediatric endocrinologist didn't do a great job. What comorbid diseases they have, either related to their disease or unrelated to their disease, and then what they're like as a person, what their goals are in the near future, if they're trying to raise a family or whatever. Are they in school, and so on. Then I try to find out if they've seen any other adult endocrinologist before me, and that's usually an awkward situation.
Because they'll be telling me what their other person told them, and it's often wrong, or how they tried to manage them, which was often not very good. And so we try to piece that out. You know, endocrinologists fix things. You know, we know how to manage things. We cure disease. We have good treatments for a lot of things. We can replace this, we can replace that. Most endocrinologists do not like to take care of CAH, and it's for the reasons that Eiry pointed out before, is that we really can't make things normal with the drugs that we have currently. You have to kind of make a decision.
Either you say, "I'm gonna give them a physiologic dose of glucocorticoids, as I would treat someone with garden-variety adrenal insufficiency." And then I know their androgens are gonna be high, but at least they won't have the complications of the glucocorticoids. Or you say, "I'm gonna control their disease by giving them a lot of glucocorticoids, and I know that that's under control, but then they're gonna get the diabetes, the bone loss, the muscle weakness, the psychiatric disease, and the long-term complications of that." And there are endocrinologists in one camp, and there are endocrinologists in the other camp because of how they were trained by some other endocrinologist who only saw one or two patients in his entire career.
I think, you know, we have to kind of get a sense of what compromises we're willing to do under the current situation. I hope that I don't have to have that conversation in the future, based on what we've done so far.
Great, and actually, I'd like to kind of extend some of that conversation about the adult experience with CAH to Leslie, and invite Leslie to kind of share a bit about your story. You know, how you learned that you had CAH, maybe even retrospectively, some of the things that you had to deal with and learn about in your journey.
Okay. Well, as I said earlier, I was born in England in 1957, and very little was known about CAH. And so, for the first two years of my life, I lived in the hospital because it was easier to keep me there because I was so unstable. And my mother was not a very well-educated woman, and so she just couldn't grasp the concept of, you know, that I needed medication three times a day, and, you know, she had to watch me very carefully, in case of adrenal crisis. So it was easier just to keep me in the hospital. I was began on hydrocortisone, and I've taken that most of my life. There's never been another medication that's really helped to control anything.
Even with all, I've been on it for 66 years, and I am now dealing with the long-term chronic steroid therapy. You know, I have insulin resistance. I, unfortunately, I'm not osteopenic. I have no osteoporosis, but I do have all the metabolic problems that go with chronic steroid therapy. And so, you know, I'm here today to just really learn about, you know, the new medications that's out there now, crinecerfont, and I'm excited that hopefully this is something that will help me. I don't have good control right now of the androgens. I am short, I am obese, so I am dealing with all that, you know, just as a result of the steroid therapy. And yeah, so.
Maybe, Leslie, if you could talk a little bit about your experience with the healthcare field.
Right
... and dealing and managing the condition.
Okay. When I was quite young, I did have an endocrinologist who did, you know, help with my initial care. But then as I was a young child, I was only managed by a PCP or a GP, as we call them in the U.K. I did not have an endocrinologist at all. I guess either there wasn't one available. I'm not really sure. But just to go back slightly, when I came out of the hospital, after living in there for 2 years, I went back to the care of my mother. But because she was basically non-compliant with me, I was removed from her care for neglect, and I was placed in the care of Children's Services until I was 18 years of age.
So once I was placed in the care of Children's Services, they did—I did get better care. They, you know, followed me closely with the primary. I still did not see an endocrinologist, and I went all through my young adulthood with no endocrinologist. I didn't know—I knew nothing about stress dosing. I knew nothing about carrying an emergency injection. To be truthful, I didn't know what I had. I grew up with a lot of secrecy and shame, and nobody explained anything to me. And I did not learn that I actually had CAH until I joined the CARES Foundation when I was 57 years old. Up till that point, I knew my adrenal glands didn't work, and I took a medication 3 times a day, and that was just so that I wouldn't die.
That's how it'd been explained to me. And, you know, there was no internet then, there was no way of me finding any information, there was no medical textbooks I could look at. So I just had to take the word of the doctor, my primary, and I guess he didn't know a great deal either, because I was very mismanaged. As I said, I'm short, no attention was paid at all to my height. And as I got into puberty, no attention was paid to the potential of, you know, children fertility, as because either they didn't know or they didn't choose to share that with me. And so as I grew into adulthood, I still did not have an endocrinologist. I did not get an endocrinologist until I joined CARES Foundation when I was 57.
Up till then, I'd just been managed by PCPs, and I would just get blood work here, there, and everywhere. So basically, I've been mismanaged most of my life, and I'm paying for that now dearly. So let's see.
Thank you so much for sharing that story. That is really incredible. And maybe, given the substantial impact that this condition had from the very beginning, maybe we can turn to and get the pediatric perspective. Dr. Sarafoglou, you're a pediatric endocrinologist at a major tertiary referral center. You follow a lot of pediatric patients with CAH, both locally as well as patients coming from all around the country. Can you just tell us some of the reasons why patients or children are referred to you?
A lot of children that fifty percent of my practice are from children that they are referred from across the country. And a lot of them are coming because they are either having growth failure because of a treatment, or they have growth failure, in a way, they have growth acceleration and because of undertreatment. And a lot of them also, they have virilization. So that means girls can have virilized external genitalia, but also the boys can virilize, so to the extent that you can have a 40-year-old boy that has the genitalia of a 13- or 14-year-old boy. And all of that, the excess androgen exposure can have a detrimental effect on their final adult height. Because what that means, they have lost years of growth.
Because if your skeletal maturation, for example, is 10 years when you are a 2-year-old, you have missed 8 years of growth. So it's a disease that, you know, we as researchers desperately need adrenal therapies, other therapies to control androgen excess, but without having to compromise by over treating our patients.
Mm-hmm. Yeah, thank you for that, Dr. Sarafoglou. You know, I'd be very interested, Alex, you know, you are a mom who heard the diagnosis shortly after birth because it was through genotyping. How can you kinda describe that initial impact that had to your life and kind of learning... You know, I know you've learned a lot from the pediatric experts and endocrinologists, and of course, with the CARES Foundation, a lot of the issues that diagnosis and impact that diagnosis had. Can you share with us a bit about how that kind of unfolded?
Yeah. Absolutely. So, as I said, our journey started almost 16 years ago. We had two boys, ages 3 and 4. We were getting close to Christmas. It was December 22 when James was born, and we'd brought him home. It was terrific. You know, we had three healthy boys. We were getting ready for Santa to come, and he was a bit of a sleepy baby, was a bit jaundiced, but again, so busy, just seemed like sort of a normal newborn thing for any of you who have children, know those first few days and weeks, you just really don't know what to expect. So went through Christmas, and day after, he was 5 days old, got a telephone call from his pediatrician.
Answered the call, and she said, "Your son has tested positive for congenital adrenal hyperplasia." Said that quickly. "Could be a false positive. You could go in tonight to maybe further do tests to confirm the diagnosis, or you could wait till tomorrow, whatever you'd prefer." So, of course, again, any of you with children know you don't really wait when you're given news like this. So quickly went in to the children's hospital. We're in the Boston area, still are. And he went through a battery of tests, blood's drawn through the skull, any which way they could get it. And after a day, they were able to confirm the diagnosis. His sodium had dropped tremendously, potassium was through the roof, and, you know, it was a scary situation.
Fortunately for us, Massachusetts did have CAH as part of the newborn screen, so we were able to confirm that diagnosis. We were assigned an endocrinologist who quickly put him on his regimen of hydrocortisone and fludrocortisone, which he still stays on to this day. And it's, you know, it's been tricky. He does see his endocrinologist regularly. He gets regular blood tests. We just make sure that his growth, through doing the bone age scans, is keeping up with where he should be. So we're very fortunate. I mean, we have had really good care and people who understand, but even with that, you know, there are limitations. And his endocrinologist, who, you know, I absolutely respect, but also does not have many patients with CAH.
Primarily, she manages patients with diabetes, and so she'll sometimes, knowing how active I am with CARES and in the CAH community, will ask me, "Well, what's new in CAH?" when I go to visit, which, you know, is fine. I mean, she's absolutely a great clinician and knows what's going on, but sometimes you feel a little bit you know, alone. And, and for that, very grateful for CARES Foundation for introducing us to others in the community and for Neurocrine, too, who has been a fantastic partner to our community, and we couldn't be more excited about this new treatment.
All right, and maybe I'm gonna shift to Dina. Because, Dina, you often find yourself at the intersection of the healthcare providers and the experts that you're gaining information and knowledge from, and hopefully able to translate that for the patients who reach out to you. And can you tell us a little bit about your experience with fielding these various bits of information that come in?
Well, I always say CARES, the work at CARES has been the most rewarding but also the most challenging, because of the patients and how diverse they are and how different the challenges are for some patients. It's a very different experience for parents of a baby or a young child versus an adult. So, when a child is first diagnosed with CAH, we often get a call or an email from parents, sometimes weeks or even months later, because they've been grappling with this diagnosis and trying to understand what it is, because often they've never heard of CAH.
So for new parents, the first or one of the first things we say to them is, "Congratulations on your baby." And they're shocked that we say that to them, because, for them, the birth of this child has been earth-shattering, and it's been a life-changing experience. So that's the first thing we say to them, and then, they wanna know, "How long is my child gonna live? Is my child going to have a, quote, unquote, normal childhood? Are they going to be able to play sports? What are... What's their life going to be like?" And fortunately, we can assure them that with good care, they can have a pretty normal life, but, you know, there are things that they have to, be mindful of. And I think reassuring for parents is also to talk to older CAH patients.
We were at a conference. We had a conference several years back, and we had a 22-year-old who spoke about his experience. After he spoke, there was a line of... We had another session going on in another room, and there was a line of about 50 parents waiting to talk to him.
Mm.
But we connect them with older patients. We have support group meetings with experts, but also with their peers and patients who are living with the disease. So we're able to reassure them, but not everyone has access to good care. And the other thing is that up to now, there haven't been any new products on the market, any new treatments. For over 50 years, we've pretty much had the same treatments for CAH. So they're adequate to keep these patients alive, but they're not optimal, and we need to do better for these patients. So Kevin said we weren't gonna talk about Neurocrine. We have to talk about Neurocrine, because what the work that Neurocrine is doing is going to be life-changing for these patients, and some don't even know it yet.
Now, for the older patients, many of them have been reserved to the fact that they're just gonna have an awful life. They don't feel well, they have osteoporosis, they're overweight, they have diabetes or all the other comorbidities associated with their steroid treatment. And then some of them who are fortunate to have good care and access to some of the clinical trials and the new treatments that are being developed, you know, do have hope for a better life. I think what's most troubling to me is the fact that you have patients like Leslie and even younger patients who wanted to have a family and have a normal life, and they didn't have that opportunity.
I met a patient who Leslie knows, about two years ago, who was born with atypical genitalia, didn't have surgery, which is, you know, a controversial area, but she wanted to have a normal life and a childhood, and she came from, you know, a large family, but she did not have that opportunity. So we need to talk about, you know, some of these issues, but we also need to work together to improve the care for these patients. So I'm grateful for all of you who are here today, who've been contributing to what I hope will be a better quality of life for patients with CAH.
May I add something?
Yeah, please.
Dina mentioned about fertility. Yes, I did want children, and when I was about 18, I believe, I went to my PCP. I wasn't having periods like all my friends in college, and,
... I didn't understand why, and so I went to see my PCP, who referred me to, I don't know, a geneticist or a fertility expert. I don't know what she was. But, she basically told me, "You cannot have children. You should not have children. If you do have children, your child will probably die, and why would you want to pass this on? And you should just forget about it." And I believed her because I had no other reference. There was no support system, there was nobody I could contact, and, nobody seemed to care about, you know, my fertility issues. And, so it's extremely important that, you know, with treatment, that, you know, we can now-- and there's many, many CAH women now have children, without any problems, you know, if they're receiving good care.
So clearly I wasn't, and that is a regret, I must admit. So-
So can I interject here? So, I have about a dozen CAH patients that have had babies in the last couple of years, and I have other women that have had the same experience as Leslie, that they were told by their private doctor that, "You can't have children." And I wanna remind you that a diagnosis of infertility creates as much anxiety for a patient as a diagnosis of cancer. Okay? There's only one other disease that's close to that. So this is not a small matter. And I also wanna remind you that the men also have probably worse problems with fertility than the women because the androgens from the adrenal short-circuit the signal to the testes to make testosterone and sperm. So both the men and the women, if they're poorly controlled, are going to be infertile.
The choice that we currently have is to give them diabetes, bone loss, muscle wasting, or fertility, and that's really not an acceptable choice at this day and age.
Great. So, thank you for that. And, Dina, some of the words that you were saying kind of brought me back to conversations that we've had for a few years, at least now, around the level of awareness and education, and how educated actually the patients and caregivers that come to you. I mean, obviously, initially, they probably come to you with a whole lot of questions, but they clearly are a group of patients that are thirsting and hunger for for new knowledge. And what I would like to ask really of the entire group is those opportunities to harness, you know, either coaching for, you know, like Alex, new moms.
Leslie, I know that you do a fair amount of coaching with adults who are, you know, sort of trying to get a much better understanding. And of course, Doctors Auchus and Sarafoglou, serving on various panels, helping support groups. Can you talk about kind of how that goes and how the patients, how receptive they are to those educational opportunities?
Well, I will say that especially parents, they become very well-educated very quickly because they have to be. If they don't have access to a good CAH expert, they're often telling these doctors what they should be doing. I have a mom, actually from New Jersey, who has a girl with CAH. I think she's about 10 now. And she was going to an endocrinologist who was managing her child not well, and she was doing a lot of the educating. And I kept saying to her, "You have to go to so and so." And she finally did after about four years. She called me crying. She said, "For the first time in my life, I felt like a truck was lifted off my shoulders because he understood what I was talking about.
I didn't have to teach him." So parents become very well-educated by necessity, right? The adult patients often come with a lot of comorbidities and issues. They've either been misdiagnosed with PCOS or and have done research on the internet, and they say, "Well, I think I may have CAH. Can you refer me to an expert?" So once they find a community that is supportive and that understands them, they are willing to go that extra step and then become advocates for, you know, new treatments, for better care, for more education. And that's, that's what I see our, our role. I mean, we still have a lot of work to do in terms of education of the community in general, but also other practitioners who are treating these patients, often at the local level, and think they're doing a good job.
But again, they're not optimizing the care for these patients, so we have to do a better job of doing that and, involving them in, you know, clinical trials at the local level, because not everyone has access or the availability, whether it's, you know, job-related or something else, to travel across the country.
I think, you know, a lot of times people are told, "This is the best that we can do," you know, and then, you know, and you just have to acquiesce with that.
I would just say for my son, I mean, what I've always wanted to do is just to provide him with the tools to be able to, at one point, and it's not too far from now, be able to care for himself and really understand what's going on in his body and what an adrenal crisis or an impending adrenal crisis may be. So we've been able to do all that we can in terms of providing him with those rescue medications and working with his endocrinologist to get to a point where he's well managed, but it's not perfected by any means. And so for me, as a mom, and us as a family, to be able to know that there are more options coming is reassuring.
For us, just to know that his care could be more optimal moving forward is a great thing to know.
So the other issue we come across, and I'm sure Dr. Sarafoglou has seen this, is when children go to school, the issues that arise from that, because, you know, parents are nervous, and they talk to their school administrators and teachers about the possibility of an adrenal crisis when a child gets ill, and they don't understand it, and they're frightened. So they don't wanna deal with it. Especially in a private school situation, they don't want to accept these children because-
Mm
... they are concerned about the liability. And we tell them, "Well, it's just like a child, you know, that has to carry an EpiPen. You just train these people." But because there isn't that knowledge of CAH, and, you know, these kids look perfectly normal most of the time, so I often refer to CAH as an invisible disease, because often they look fine, if, especially if they're under the care of an endocrinologist who has at least some knowledge of CAH, but they can crash very quickly. I was telling this story earlier. We had, one of our children, adult children...
I'm sorry, one of our young children with CAH, who was about six or seven at the time, we were at an Endocrine Society meeting, and the mom came to volunteer at our booth, and he was running around and was excited to pass out pamphlets to the doctors, and all of a sudden, he just fell to the floor, and he was having an adrenal crisis. So, again, education and better treatments, and I know that Neurocrine isn't working on this now, but we need, you know, treatments that are really going to contribute to a better quality of life for these, you know, children and these adults. Children don't wanna go to the nurse in the middle of the day because they feel different, right? And that affects them psychologically and, you know, their behavior.
We need, you know, better tools for them to be able to manage their own condition as they get older, like Alex's child. They need to be aware of the condition, and that happens with, you know, someone like Dr. Sarafoglou, when she talks about the transition from child to adulthood, and then Dr. Auchus is picking up from there. Because often the parents, they're helicopter parents who are managing these children's care. They're setting alarms to make sure that they're taking their medication on time, and then they go out on their own to work or to college, and in the last, I would say about five years, we've lost four young adults to adrenal crisis because they weren't compliant.
So... Oh, yeah, please.
If I can just add on to that. In 2015, talking about awareness and education, in 2015, I had a major surgery, and I was at a big teaching hospital, and it was all over my charts that I was adrenal insufficient. I did not have an endocrinologist. I did not have a protocol from my doctor. I assumed that they knew what to do. And it was about 2 or 3 days after the surgery, I was unconscious, and my husband happened to say to the nurse: "Oh, are you giving her steroids?" And they said: "What are you talking about?" Now, I did mention to the anesthesiologist prior to surgery, "I need to have a stress dose." And he goes: "Yeah, yeah, I understand, I understand." And I believe I got one before, during, and after, and after, nothing at all.
So two, three days later, I then went into renal failure. My kidneys shut down, and I was about one blood draw away from dialysis and ICU, just because I assumed that they were doctors, this was a teaching hospital, and they should know, but clearly they didn't. And, you know, I carry much guilt about that. I feel just as responsible, even though they should as well, that they should have known when it says, "adrenal insufficiency," all over your records, that I would need, you know, some steroid treatment afterwards. So I just wanted to make that point about awareness and education.
Can I add something?
Yeah, absolutely, Dr. Sarafoglou.
Yeah. So I agree that's a problem. Kids going to the school when they go to the school, that the nurses are afraid. So what I try to do in my clinic, as they are newborns, I create an emergency care plan where explicitly states what the parents need to do, if the kid has a fever, how to oral stress dose them. Then a plan how what the emergency room doc needs to do if they see the child with CAH. And also, I have a plan if the kid has surgery, that it's, you know, outpatient surgery, what kind of a stress dosing he needs versus when he has an inpatient hospitalization.
My coordinators, every six months, they re-review the letter with the parents and the kid, because eventually they are going to be the ones who are going to tell the doc, the physician who is going to do surgery or any other procedure: "There is an emergency care plan. I want you to follow the emergency care plan," because otherwise, what happened to Leslie?
... Yeah, Kiki, can you talk a little more about the burden of disease in this situation? Like, when you have a kid and you're, how often a day do they have to take medication? How often do they have to come to the clinic? How often do they have to have their labs checked? How often do they have their bone density, their height, and you have to titrate their medication, and how much does that take? And then Alex can-
Yes
Follow with that.
Yes. I have to say that the burden of disease is large for the parents because, particularly for the kids that grow, and develop, and go through puberty, you just need to make sure that they are well-controlled, and you need to make sure that the androgens are reasonably controlled. I mean, like Rich, I have come to accept that my kids, no matter how many doses they take throughout the day, they're going to have elevated androgens between dosing or. And particularly during the early morning hours, when the androgens are the highest. So what I try to do is, I tell the parents, "Well, you know, in order to be able to control your androgens and also make sure that I don't over treat you, we will need—I need to see you at least 3, 4 times a year.
We will need to have labs between, and sometimes... And not sometimes, always, after I do a dose adjustment." And in order to get them to buy in, I tell them why. I explain to them that the hypothalamic pituitary adrenal axis is very complicated, it's very dynamic, that the androgen levels fluctuate throughout the day. That, also, physical stress, the time that they took their dose the night before, or the time they took the dose before they came to see me, that can affect their androgen levels. And when I see them and measure their androgen levels, that tells me what their androgen levels are at the time I see them, but it doesn't give me an idea what the androgen levels are throughout, the day and the night. So these are the... I have to live with these shortcomings.
I tell the parents, "These are shortcomings, and I would try throughout the journey to help you manage the kid the best I can." Also, dosing. I, you know, a lot—most of my kids are on 4 times a day, and I have some that they are 3 times a day. The reason is, I have... I'm lucky that I collaborate with the College of Pharmacy at the university, and we were able to do pharmacokinetics and cortisol pharmacokinetics and pharmacodynamic studies to over 90 kids. And what we saw is that hydrocortisone has, we know, has shortcomings because it has short half-life. So when you take the pill, it stays in your system for 5, 6 hours, and then it's gone. Well, in children with CAH, it's even shorter.
So what we saw is, after 4-5 hours, the medicine was gone, and then the androgens rebounded. So then we developed a model, an integrated PKPD model, and our colleagues in Europe have done the same. And we saw that even 3-4 times the dosing still leaves the kids exposed to androgen, high androgens throughout the day and throughout the night. So telling that to my parents or sharing that with the parents, you know, understanding the complexities and the burden of the disease, they become more compliant, and they become more involved with the care. So but they know from the beginning that it's difficult.
Do we have time for Alex to-
Yeah, I wanted to make sure, yeah, I'd like Alex to be able to-
Yes.
Yeah.
Great, now I'm wondering if he should be on four times a day. So all to say, you know, I speak to a lot of other parents, and I will say that one of the frustrations, and maybe it's not a frustration, but just a question, is I talk to others in terms of: "What is your son or your daughter on?" And I really have never heard that he or she is on the same as my son. So just goes to show in terms of, like, every, you know, hydrocortisone, but whether you're two, three, four times a day, what does that look like? And when it comes to stress dosing, which is when there's a physical stress, trauma to the body, we need to double down, triple down on the hydrocortisone. That, too, I've heard double, I've heard triple.
So all to say, there's many ways to take control, and to be well managed. And, you know, I always question what exactly is well managed. I'm not sure I totally know what that looks like yet, or if I ever will. But James, right now, is on medication twice a day for hydrocortisone and once for his fludrocortisone. And a quick story is, I, when he was probably eight, we were at a CARES conference, and Dina saw him and looked at him and said, "He, he looks Cushingoid. You better go back to the endocrinologist." And sure enough, I did, and she looked, and she said, "Oh, I think we'll reduce to twice a day." And she now has put several of her patients on twice a day because of that.
So you know, it's interesting, and it's constantly looking at those bloods and the blood results and making sure that we're just, as Iris showed, we're looking to make that seesaw really not going one way or the other, but maintaining sort of that control.
Uh-
What I would like to say, I agree 100% with you that every kid, what we know is that there is so much variability in the glucocorticoid receptor response and also in the clearance of hydrocortisone. So you can have kids that they require high doses because they are glucocorticoid insensitive or because the medication is cleared out of the system like it's nothing. But also you can have kids that they may be on twice or three times a day, because if they do PK/PD studies, they're going to find out that they have very slow metabolism. But the majority of the kids, they are not slow metabolizers, they are somewhere in the middle. So not everybody is the same. So for some kids, twice a day may work, but most of the kids, three or four times a day, or even more.
This has been exceptionally informative. We are so grateful for the time that this panel has shared with us today. Our heartfelt thanks, Gene and myself and Neurocrine for what you've done today. Really appreciate it, and thank you all.
You've done all this-
Everybody should stay up because we're actually in a few minutes gonna have the opportunity to open the floor for your questions for the panel. But excuse me for having my back to you guys. But I just wanna add my own thanks. Thank you so much. It is so powerful to hear from you guys, and it really is the reason we come to work every day and the reason I know that Dr. Arcas and Dr. Serafica will come to work every day, is just to hear the stories and to hear, you know, the unmet need and how we can hopefully help with that.
I'm gonna spend just a couple of minutes doing something that I will never tire of doing, which is sharing with you the data from our crinecerfont phase 3 program in pediatrics and adult patients, and just going over the trial design very briefly, the key results that we share with you, and actually giving you a little bit more of a taste of a couple of the results from the trial, that we'll be kind of showing today. So first, just to reiterate the trial design for both adult and pediatric patients. So very significant similarities between the phase 3 trials in adults and in children. We essentially have this 6-month or so double-blind period comparing crinecerfont to placebo in terms of treatment.
There's a 4-week assessment built into the front of that in both the adult and pediatric studies that looks at the ability for crinecerfont to control androgens in the face of stable steroid dosing. And then, following on from that, in each of the trials, we have a potential down titration of the steroid dosing, so that at that 6-month time point, we're able to look at a placebo-adjusted impact of crinecerfont on reduction of steroid dose. Following on from that, we have open-label data that focuses on many of the endpoints that I know people are interested in: quality of life, clinical endpoints of relevance as they speak to metabolic, bone, and other issues. And then we have still ongoing an open-label extension that will continue until the medication is hopefully available commercially to patients.
The same, again, looking at the pediatric trial design, I kind of went through this with both trials at the same time. Very similar, and both trials agreed with the agency in terms of their ability to be sufficient to define the efficacy, tolerability, and safety of crinecerfont in that patient population. Just very briefly hit on the, what I just spoke to, the similarities between the trials. We also get questions a lot of the time, 'cause the data and the outcomes from the trials are not identical in terms of what we saw for efficacy. And so why is that? And some of that is due to the differences in the trial design itself. So the key endpoints focused on androgen reduction and steroid dose reduction with androgen control. That's very important.
So you only really get to count steroid reduction for these patients if it's associated with maintenance of androgen control. We had the same definition of endpoints across the trial, same target dosing. We had the six months randomized placebo control, and I mentioned that the first month was steroid stable, looking at androgen levels, and the next five months, active steroid reduction. The crinecerfont dosing in both studies was BID oral and was targeted to achieve a similar exposure across both the adult and the pediatric population. And we have clinical assessments throughout the program, related to the potential impact of steroid or androgens. Looking at the differences between the trial, and this is one of the very, very key differences.
In the adult study, after week 4, there was a targeted down titration of steroids that was focused on optimizing the steroid dose and trying to get as many patients as possible to physiologic steroid dosing, which was defined as less than 11 milligrams per square meter per day. It didn't actually take into consideration the degree of androgen control in those adult patients at that point in time. That came later in the trial when we were seeking to optimize both androgen and steroid dosing. The pediatric trial, though, was different because it was the first time we'd done this type of trial in the pediatric setting, and so the clinicians were given a lot more leeway and were asked to only really down titrate steroids if the androgens maintained control.
This was done both from the perspective of the efficacy, but also, to deal with this issue that we've heard about a lot, about the fear of adrenal crisis and the fear of down titrating the steroids too rapidly and therefore pushing patients into adrenal crisis. So that was one of the big differences we saw. Let's look at the data. This is first of all, the baseline characteristics. I just wanna make a few key points here. First is, we hear sometimes: "Well, this is really only a disease that has a negative impact on females." That's not the case. We know there's unmet need across both female and male individuals. Rich and others spoke to that right now. And it was really good that we had a balance of gender across these studies.
Also, very importantly, that the age range of patients included in the program was very broad, from 4 years old to 58 years old. Now, one thing I wanna say about the baseline glucocorticoid dosing here. The dose in the pediatric study of 60 milligrams per meter squared per day is the very highest dose recommended by the Pediatric Endocrine Society as an appropriate dose to give to children with this disease. What you see from this slide, though, is even in the face of that highest level, as the mean dose of hydrocortisone that was used in this study, the androgens were still out of control. So the individual still had a mean androgen level in that pediatric setting of about double the recommended. Same is true on the adult side.
High-dose steroid use, 2 times physiological, thereabout, raised androgens even higher in that setting for those adult patients. Look now at the body mass index. We see even from the very early age group of children here, subjects are overweight. They're already dealing with some of those metabolic issues, and it gives you an indication, again, of the overtreatment associated with the steroid here and the burden of disease that these individuals are living with.
Then finally, I think in the context of this trial, we saw a really, really high rollover and completion rate and rollover into the open label study, which we took as an evidence of the fact that this was a protocol that was well designed by our colleagues up here that were involved in that generated a high-quality study, but also the tolerability of crinecerfont and the unmet need and the desire for these patients to have access to an alternate treatment. I wanna spend just a minute talking to you. This is new data. These are data we have not shared before, looking at the androgen reduction here.
So first of all, if you look at the degree of androgen reduction in the adult study, we already shared the fact that the androgens were raised in these patient populations, even in the face of high-dose steroid use at baseline. We saw for adults, about a 45% reduction, and in the pediatric study, a 54% reduction in mean androgen levels at that week 4 on stable glucocorticoid. That's a substantial and meaningful reduction. If you look at the placebo patients, and this is the most important line on this slide, is that even in the face of stable steroid treatment, and those steroids were high doses, these patients increased their androgen level during the first 4 weeks of the study.
And so when you then get to the placebo-adjusted androgen levels, that's why you see such a significant, and clinically and, statistically significant change from baseline. And you see that in the context of being very, very similar to what we saw in our phase 2 program when we looked in the open label setting. This last slide you have seen before, which talks about the glucocorticoid reduction in this patient population. And I think, what we, what we see here is a substantial proportion of the patients on crinecerfont achieved that physiologic, dosing level of glucocorticoid with androgen control, 63% in the adults, thirty percent in the pediatric.
Much of the pediatric difference that you see here, I think, is driven by the trial design and the nature of the trial design, but it's also really important as we look at the difference between the trials, that 0% of patients in the pediatric trial that received placebo were able to get close to physiologic levels of dosing of steroids. So it's very clear that these patients are poorly controlled, and that in the presence of placebo, it is very difficult to get to a different level of control here. Again, a very significant P value, highly statistically significant, and a placebo-adjusted difference across the studies that is very similar.
In addition, and what we look forward to sharing as we go and publish these data next year and present them, is for those patients who didn't get to physiologic levels of steroid reduction, we saw very meaningful and substantial changes in steroids right across that population of patients, in the vast majority of patients. And so, it really speaks to the strength of the and the value of the the crinecerfont brought to these individuals in this trial. Overall, when you think about safety and tolerability, crinecerfont treatment was generally well tolerated. There were very few serious adverse events and none deemed related to crinecerfont. You see here the most common adverse events during the adult and pediatric studies.
In particular, and of relevance, I spoke to it a little earlier for the pediatric study. There were no safety concerns in this portion of the study associated with adrenal crisis. So overall, I think a very robust set of information that we are taking forward to the agency. We already talked about the Breakthrough Therapy designation, and we look forward to submitting our NDA next year, and following on from that, submitting outside of the United States for crinecerfont as a potential treatment for androgen control in CAH. With that, I'm gonna hand over to Matt, who I think we have a few minutes left for a more general Q&A from the floor, right?
... Yeah, absolutely. Thank you, panel. You guys were amazing, and thank you for sharing the story. I got good feedback from several of you. The only negative feedback was about Michigan, so I think that's a good thing. So, I'm gonna start off with Paul.
Thank you. Sorry, I'm knocking bottles down over here. Thanks so much. So I was really struck by the caregiver's story and the patient's story, and it was just amazing to me how much challenge there is with your care at, you know, an excellent academic center and then, you know, in kind of more of a community setting. And it made me wonder and want to ask a question to the two specialists, you know, how much education is this gonna require from Neurocrine to generate adoption of this drug? And, you know, in our shoes, right, we're trying to not just forecast how broadly a drug's used, but also how quickly it's adopted. What kind of advice would you give to us for thinking through the key considerations here? Thanks.
So, as I mentioned, at least from the adult endocrinologist perspective, they don't like managing this disease because it's complicated, and it involves a lot of titration. But if you think about this, this actually makes it simpler to manage the disease because the concept is block and replace, and endocrinologists do that in a lot of other diseases. Graves' disease, you know, we give methimazole, and then we add thyroxine, and then everything's easy. So I think actually people will latch on to this, pretty quickly because it gives them, an easy button to press, and then they don't have to worry about, you know, titrating. I just give them whatever glucocorticoid. They, they know how to do that. They know, but they don't know how to control the androgens. So if you provide them with that, it'll be a lot easier.
So, and this is not a complicated dosing schedule either. It's, you know, either 200-- well, you know, in the adult trial, it's 100 BID or 200 once a day. So I mean, I think it will require a little bit of education, but, you know, I gotta say also, at the Endocrine Society and the AACE meetings, this has been a hot topic because, you know, it CAH in adults is sort of a new disease, because, you know, people like Leslie didn't exist 50 years ago because we didn't have hydrocortisone to keep them alive. So as we've gone through these last couple of decades, the data from England, from the consortia in Europe, and from the NIH, have sort of taught us what CAH in adults is like.
Our first look is not that great because we don't... You know, we weren't really sure what we're doing, and we didn't really have the tools to do this. But it is improving, as like Sweden now, you know, three-quarters of their women are trying to have children now, which it used to be 25%. So it's an evolving situation, but I think actually this will make it easy to educate them.
I think it's the same for the pediatric endocrinologists, too. I think it would make it easier because right now, we don't, we use hydrocortisone, and still we have to compromise, accepting higher levels, and then we have to wait for the side effects to develop. I have to wait until the skeletal maturation of the child is advanced before I can do something. You know, I use an aromatase inhibitor. It's not the best, but that's what is out there. Can you imagine if you are able to use a CRF antagonist along with hydrocortisone before the side effects develop? Then, as an endocrinologist, as Reed said, you just focus on replacing the missing cortisol, because also cortisol is important, has other biological functions, helps with our blood pressure, helps with our glucose.
Nowadays, we are focused on androgens, and we try to neglect hydrocortisone and try to keep it as low as possible because we don't like the side effects of excess glucocorticoids. I think it's going to make it easier.
The next question comes from this side of the room. Unless you want me to sing.
You can sing for us. Hi, Mark Goodman from Leerink. Dina, can you tell us how many patients you have in the CARES Foundation, adults versus kids? And then second question is just for the physicians. Seems pretty obvious that all the patients should be on crinecerfont. Can you talk about what types of patients should not be eligible, are not eligible, should not be on the drug? Thank you.
Well, I can't talk to that. I'll let the experts talk about that. But in terms of the patient population, so we have over 8,000 members right now. It's still a larger pediatric population because, as Dr. Auchus said, we didn't have treatments for CAH, you know, 50+ years ago, so patients like Leslie did not survive. But also, we did not have newborn screening, and we are fortunate now in the U.S. that we've had newborn screening starting in 2000. So, and there are other countries around the world that still don't have it, but, you know, we're, we're working with them, and there are several organizations working with them to, to, have newborn screening added to, to the panel.
So, it's still primarily a pediatric population, but because of, you know, one, the internet, and people are looking up CAH and some of the symptoms, and also because now we have treatments like hydrocortisone, but we also have, again, importantly, screening that is resulting in positive diagnosis of CAH. Before that, patients were dying, and it was attributed to SIDS or something else. But now, by the advent of newborn screening, they are being tested and diagnosed, and they're also now, you know, it's been about 20 years since we had newborn screening in the U.S., so they're now young adults and older adults with CAH.
The number, the 8,000, five years ago? I don't know. Do we know that, how much it's grown?
Well, what was that number? I think about five years ago was probably 5,000. Mm-hmm.
The only thing I quickly was gonna add is that, you know, I'm not sure exactly what percentage of the overall CAH population that, that exists, but there's a lot of excitement within the community for these new treatments, particularly this one. And as you can tell, many of us, most of us, are true advocates, and so I think it's a bit of a push/pull. I mean, I think there's gonna be education to the physicians, but there's gonna be a lot of us going to our physicians and asking for this. So the more that CARES puts that out, which we are doing constantly, I think the better it will be for everyone.
You were asking about the number of patients that might not benefit from addition of crinecerfont. You know, in the placebo arm, it was about 15% of people, and that's been my experience, that, you know, about 15% of the adults can be well controlled with a reasonably physiologic dose of glucocorticoid, about 15%, and probably everybody else is gonna benefit from it. Now, I don't know about pediatrics.
I think similar percentages, and in fact, I believe I would feel very comfortable to start kids that they are older than two years on crinecerfont. I will wait to have some studies on younger kids before I will commit to it, but more than two years of age with not acceptable levels of control, I won't have a hesitation to start them.
I committed to him first. Sorry.
Thank you. There was a lot of talk about the misdiagnosis. How much is the misdiagnosis at this point? Do you think with the new treatment, there could be more patients coming out, which were misdiagnosed?
Okay, let me address that because I, you know, we have been talking about what's called classic congenital adrenal hyperplasia. So there's classic and not. The way to think about it is severe and mild. Severe means you are cortisol deficient, you can have an adrenal crisis, you need daily hydrocortisone replacement. The non-classics are the ones who are often misdiagnosed. Dr. Sarafoglou has identified some kids that were missed in the newborn screen, which is not supposed to happen, but it does. That's not what we're talking about. We're talking about the non-classic women. Interestingly, that's probably the most common genetic disease in human beings.
It's about 1 in 200, but we don't diagnose any more than 10% of those women, because they're, you know, again, either misdiagnosed or they're not severely enough affected that impacts on their life, and that's not the group that was studied in the crinecerfont trial.
I just wanted to add something about. So for parents, a lot of them think that giving more medication is better, and they wanna constantly stress dose their children. If they're, you know, having a test in school, "Should I stress dose them?" If they're going to the dentist, even if they're not, you know, just having a cleaning, they constantly want to overmedicate, which, you know, we now know that, you know, contributes to, to a bunch of other issues. But, I just lost my train of thought. But in terms of the adult patients, and Dr. Auchus is on a lot of our support group calls, and the non-classic patients, they're like: "Well, I should be on some medication," and he often will say: "You've survived this long without it.
You don't really need it, unless you're trying to get pregnant or something else," but they want to be on medication because they think that's going to provide a better quality of life for them.
Yeah. That's a topic for another day, about the non-classic patients.
We've got one time for one more question.
Hi there, Evan Segerman from BMO. So you were talking about newborn screening and, you know, starting kids at age two. I know that we don't have data in younger patients, but what would you wanna see from a trial in patients younger than age two? And I guess, what is the trigger point to getting a patient who is two-year-olds, who is two years old, on therapy?
On therapy with crinecerfont or-
Yes, exactly, Crinecerfont.
Yeah, well, poor androgen control. But I would like to see some safety data. Because, you know, it's very hard to go to the parents of a newborn baby and say: "I want to start you on crinecerfont." And then they will say: "Okay, is it safe? What-- You know, what studies are out there?" So I have to be honest and say: "Well, you know, in older kids, you know, kids older than 2 years of age, yes, there is, there are no side effects." But, you know, I think may not be, but we would need to have studies. So I really think a small study looking at safety 0-2 years may be something that we should think in the future.
I guess, just follow up there, what do you need to see to start a two-year-old on therapy, or do you start all your patients who are two years old? Or would you?
Oh! I mean, you know, all kids, the majority of kids, they're going to have elevated androgens. That's, we have accept that, is what we look is to what degree, and then we look at clinical signs and say, "Okay, the growth is good, there is not advancement, so we can accept that level of androgen. Because we, you know, I don't know what is optimal. I use a threshold, say, less than 50, it's okay, but it's based on what? On clinical signs, pretty much. But if I have a way to control the androgens without increasing my dosing, I will do it.
Because I have kids that they are well-controlled, well-controlled, I've seen them in the clinic, no problems, and then at 7 years, let's say 7 years of age, they have a bone age, and all of a sudden it's 10. And I'm, you know, I'm like: "How this happen? I see them frequently, the levels are good. Why all of a sudden it's elevated?" Well, it's what we said before, that you have no matter how many doses you give, you're going to have elevated androgens throughout the day and especially during the early morning hours. And that is eventually is going to catch up, and it's going to affect the skeletal maturation of the kid. So instead of waiting, why not then say, "I am not accepting 50. I want my kid to have good normal androgen levels." That's how I will start crinecerfont.
In fact, I can do that without increasing the glucocorticoids, because as Reed said, glucocorticoids have side effects in kids, too: obesity, weight gain. Then what will happen is all these side effects set the ground for comorbidities in adults. That's why I will use crinecerfont even before symptoms develop, because I know that they have elevated androgens no matter what I do.
So, thank you, panel. It's amazing to hear, you know, your life's work and how you're helping patients. And, you know, it's just a joy to work for a biotech company that actually, you know, is in the process of helping many different patients, including the CAH community. So thanks, guys. I know, some of you probably want to get a drink right now, after getting done with the panel, but, they will be around in the breakout room. We will be able to have a continued dialogue with CAH. But thank you guys, for all you've done. Thank you. So, next up is gonna be Dr. Gorman. He requires me to call him Doctor.
And then we're gonna have a bit more Q&A, just open any business questions that you guys may have, and then we'll go into some breakout sessions. So we probably have about 20 more minutes.
I'm gonna try to figure out, and forgive me if I don't—this doesn't come out the right way. But every time I get to meet a CAH patient, parent, it's a blessing that CRF didn't work in depression. And I mean that sincerely in that it has really given us this opportunity, for these patients and these healthcare providers. Key milestones, that we have in 2024 and longer term. So let's look in that short term that we have coming up. You can read them here. Things that we didn't talk about today is 5 phase 2 programs that are going to be reading out, next year. So we, and we're really looking forward to those. Are they all going to work?
That, that would be ideal, but we know that would be beating all the odds that exist out there. Advancing the 5 phase 1 programs that we showed on the first slide that we've going through. Highest on the list is submitting the NDA for crinecerfont in adult and pediatric indications. We are going to be working with the FDA closely in order to get that done as rapidly as possible with the highest quality dossiers possible. We didn't talk about valbenazine here at all, and we have an oral granule sprinkles formulation that we have a PDUFA date coming up in April. That actually is very important for Huntington's patients and many TD patients because of the inability to swallow.
So being able to have that formulation is gonna be great for them. And then as Jude was talking about, continue to invest in and continue to perfect that drug sustainable R&D engine. But really, it's the longer term that I was hoping that we could get across here today. Getting crinecerfont widely available both here in the U.S. and across Europe in 2025 and 2026. That's goal number one of what we've been talking about here.
I'll go down to the very bottom bullet that we have on here, is the fact that we have INGREZZA and market exclusivity in 2038 in order to continue to drive the education, which we've been very successful in doing with the TD population, and I know we're going to bring all that learnings into the CAH population, but we have market exclusivity into 2038 now. Many of the phase I clinical programs that you've seen here today, those 20 development candidates that we want to be putting in through 2027, over the next three or four years, those are going to be turning into phase II and phase III programs at a higher rate than what Neurocrine has ever been able to do before.
It is then to have, as Jude spoke about, a sustainable R&D engine that will continue to have these development candidates, continue to have these phase I compounds coming in, continue to have that roll through, such that at a minimum it will be 1-2 mid- to late-stage clinical readouts each and every year. That's what the future looks like for us. I think that we're uniquely positioned as a neuroscience company to be able to do this, and so I'm really looking forward to the next several years that we have. Do we have any time for some general Q&A?
Yeah, we're gonna try to fit in 10-15 minutes of general Q&A, so-
Before we start that, I was very pleased to see, and someone that you'll want to talk to here, is one of our board members here, and it's Gary Lyons, the founding CEO of Neurocrine. So you get both bookends of the 32-year history of the company here today. So how about, from the management team, those of us who are normally on the earnings call, why don't we start out with us coming up here and grabbing a seat? While they're doing that, why don't we get started with questions? Believe it or not, they can walk and talk.
I can walk and talk, for sure. All right, Brian.
Thanks. Just maybe a couple of questions on crinecerfont, filing and data. Can you maybe characterize how the dialogue—what the dialogue's like with the FDA, what the gating factors are for the NDA submission, and whether or not you plan to request and are expecting a priority review? It looks like, I guess, the timeline for potential approval is 2025, so just curious if that's suggesting a mid-year submission and priority review, or perhaps a standard review, but an earlier submission. Then maybe just separately, can you talk a little bit about the change in in androgen levels that you saw in the placebo groups despite the stable glucocorticoid doses? And I guess, was that a mean or a median, and were there any outliers?
How would you, I guess, explain some of that, that variability? Thanks.
Yeah, sure, can answer those. The first one I'd say is that, it's been a really great journey with the FDA and with the regulators, around the world. And I think we're at a point now where there's a very clear recognition of, the severity of this disease, the unmet need, and I think a recognition, at least in the US, with the interaction we've had, of the, the strength of the package of information that we have. So with all of that in hand, obviously, once we had the data in the US, we, applied for breakthrough designation with those data in hand, and we were delighted to have that, to find that out just now.
We are on track to be able to go forward with a submission next year in both adults and pediatrics to the FDA, and with the European submission sometime thereafter, delayed to some degree following on from that, as is usually the case in Europe. We will be asking for Priority Review. I think that's appropriate, given where we are, and obviously, the FDA will opine on whether that's appropriate from their perspective. So it's been a great journey, actually, and I think we've learned a lot together with the regulators as we've gone through this program. And then the androgen control.
I think what is most striking is what we heard over and over again on the panel about how difficult these patients are to control on a day-to-day basis, and that, you know, the snapshot you get of androgens one day in the clinic is not what's happening to androgens over the period of time. I think that came up very, very clearly in our trial, where we had patients in the trial, both adult and pediatric, who came in on very high doses of steroids, and then but 1 month later, on placebo for that 1-month period, their androgens were higher than they were when they started, and so this is not a disease that's easy to control.
That actually reinforces even more the importance of a therapy like crinecerfont that can control those androgens directly without the need for then the supraphysiologic steroid dosing.
And, and just to be clear, at that four-week time point, the glucocorticoid dose was held, you know, constant from the beginning, so that, that was consistent. So I think, next up, Jeff Hung, and then we'll go to Ami.
Thanks, Jeff Hung, Morgan Stanley. You have multiple M four agonists. Can you just talk about the rationale for the M four antagonist and what indications might be best treated with that mechanism? Thanks.
I'm gonna let... Where is Kyle?
There's Kyle.
I'll let Kyle answer this one.
I have a microphone. I can answer.
I'd first start by just reminding folks here that, you know, we've been in the muscarinic space for over a decade, and we've played both sides of the target, both on the perspective of an agonist and an antagonist. We've found many of the same challenges that others have had in this space, mainly the balance between potency and selectivity across the different subtypes. When it came to the agonist, we have had discussions with Sosei Heptares over the years, Heptares before they became Sosei Heptares, and we've really liked the approach that they've had on it and feel very fortunate to be working with them in this space, and their approach was quite novel versus how we tackled the target and others.
We think that's shown and paid off dividends here with multiple different flavors of different M1 to M4 agonists from a selectivity perspective and a lot of things in between. In terms of the antagonist, you know, we're a movement disorder company, so looking at targets in the space that might afford us an opportunity to play in different movement disorders, an M4 antagonist gives us that opportunity through medicines like Artane, for example, that's a pan-muscarinic antagonist. Its effects are thought to play through M4, and you can go do your homework on Artane and see what and how that's used in various types of movement disorders. And what we think here we have is a well-behaved molecule that will allow us to treat a variety of different types of movement disorders.
I think we haven't really settled where we're going to land on that yet, but we'll acquire our phase 1 data and use that to inform a phase 2 program.
I would, I would only add. I yielded to Kyle on this because Kyle has lived that 10 years of history on the muscarinics and knows exactly where we've been and, and where we're going. Regarding this molecule, just to add, very well-behaved molecule. A very good performance in our in vivo pharmacology models, as well as also we do. This is one molecule we also have, at least in non-human primates. We have PET data that will inform an accelerated path in the clinic.
Yeah, the only thing I'd add is I think we would consider that muscarinic antagonism is a validated target in treating movement disorder. It's just Artane and other similar molecules; they're just not well-tolerated enough, and the side effect profile that they have is pretty significant in terms of cognitive impact and other side effects. So I think the really key question for us is to work out very early in the translational medicine space that Grace alluded to: Does M4 selective antagonism maintain the efficacy in movement disorder whilst not incurring some of the other side effects that are seen with the pan-antagonist?
Hi, this is Ami from Needham. Thanks for taking my questions. I've got two. Firstly, just on the CAH study, if you looked at the pediatric patient population, they saw greater reduction in androgens compared to the adult study. But when it came to the reduction in corticosteroids, that was about 30%-
Mm-hmm.
... compared to about 63. Was that something to do with how the study was designed, and what might we be able to see in the real-world setting there? And then I've got one more, different topic.
I mean, yes, is the answer to. I do strongly believe that it was in part due to the trial design. And I think I alluded to the fact that the way in which the steroid reduction was done was different from the adult to the pediatric study. In the adult study, it was a forced down titration, essentially, to try to get to physiologic in as many patients as possible, and that's really why you saw a proportion of the placebo patients being able to get to that. Because it didn't take into full consideration androgen control at the point in time of those steroid reductions. Where we got to the androgen control piece was later in the study when the steroid dose was being optimized, and we haven't reported those data as yet.
In the pediatric setting, it was very much focused on reducing steroids only in the face of good androgen control at that visit. And so I think you saw a more conservative approach to the steroid reduction, and also that means why none of the patients on placebo managed to get to that physiologic level, which reflects the poor control of the disease. I think in a real-world setting, there's really nothing to suggest that the biology associated with a CRF1 antagonist and its activity would be different in pediatrics from adults. And so I think in a real-world setting, it will look more similar as people become more comfortable with the steroid reduction in pediatrics, particularly in light of the fact that we saw so few, actually 0, issues with adrenal insufficiency and adrenal crisis in the context.
'Cause that was the other thing I think clinicians quite rightly would be worried about in that pediatric setting, is not exposing subjects in the trial to a risk of adrenal crisis.
And maybe perhaps a very quick one, just with regards to the muscarinics. You're spending a lot of time and effort behind kind of that broader sort of franchise. There are a couple of other products in the market that are in later-stage developments. What is likely to be different in Neurocrine's approach that allows you, enables you to win in this market over time? Thank you.
Do you wanna start, Kyle, or do you want-
Sure.
I don't mind. I can start, yep. Clearly, I think the first really important thing is this is a validated mechanism now. I think M4 agonism in the treatment of psychosis and schizophrenia, and first with the KarXT molecule and then secondly, with obviously Cerevel's molecule. I think we're gonna see different data from each of these approaches. They're very different approaches. The Karuna molecule is a pan agonist and obviously uses a peripheral antagonist to deal with the side effect profile that was unacceptable in the context of just using that original agonist alone. And, you know, they have good phase 3 data going forward, will get approved, I'm sure, but... Well, I'm not sure. I believe.
I believe, and I believe that will be important for patients with schizophrenia. There's still a lot more opportunity for different approaches there, though. And, you know, Cerevel's molecule is an allosteric modulator, a PAM. It requires acetylcholine to be present in order to be effective. Our approach is a direct M4 selective agonist. And we think that that's a very reasonable approach, and we are intending now to test that approach and look forward to getting our data next year. At the end of the day, it's gonna depend on the clinical data across these programs. And so it's hard to speculate the differentiation and clinical strength of our NBI-568 molecule until we see our data next year.
But I think the biology and the biological reasoning is very sound in terms of the fact that there will be different profiles across the molecules.
So more to come on the muscarinic. We have a full breakout session that Samir and Jas will be able to to talk through. It's obviously a class that we're very interested in, and more will come out with time. But now, Dave Gardner with Rock Springs.
Thanks. This one's probably for Kevin and Jude, and Roumeïum, looking at your name tag there.
Roumeï.
You had some pretty prolific pipeline slides, Jude, up there, and then you had a slide about external innovation, and I'm curious with how prolific the pipeline has become. Can you, can the organization, like, reasonably have capacity to take on meaningful development stage, you know, compounds coming in externally via acquisition?
So I'm gonna, I'll take the first stab at that. It's a very fair question. What you're going to is just basically how we're going to do capital allocation. We make trade-offs all the time, currently with our pipeline, both the clinical pipeline, preclinical pipeline, and also within the research group. We don't get to always do all the things we want to do, so, we're very data-driven. All right? So we do have capacity as currently in our clinical pipeline for, let's say, what you're asking about is a more mature, clinical program to be coming forward. We do have capacity to do that right now without having to make any real wholesale changes in there.
But I think that, because capital allocation is something that we review not just with the management team, but with our board, every single quarter that we go through, we have the discipline that we will make those decisions, but it'll all be data-driven.
The one thing I would add is, besides capital allocation, is that we've deliberately integrated internal and external innovation, such that strategically, you're trying to play off and balance where the gaps and needs are. What we can't, where we have gaps, internal, external complements, and vice versa. And so this has really been, at least in the last year and a half, intentionally using external to fill gaps that we have in internal. We've recruited experts, okay? Again, if you look at successful companies, you're as good as your internal organization is. Having a strong internal engine with the right expertise really informs how well you can identify good opportunities and bring them in strategically. And that's what we're trying to do. Tazine.
Okay, great. Thanks. Real quick question from me. So, Eiry, just what you mentioned before about, Neurocrine's view, that certainly crinecerfont is worthy of getting a priority review. It's heavily unmet need. But what's your current view about, FDA wanting to hold an ad com? Because no new drug has been approved in this space for 50 years, as was said earlier, and this is also a new mechanism of action. If an ad com is something that you would be expecting, do you think a priority review would allow enough time to get that done?
Yeah, I think it's a really great question. We are obviously preparing and planning for an ad com in case there is an ad com. And we will be well prepared for that. And I actually think, you know, having heard the group of individuals here as well on our panel, we, you know, welcome the opportunity to continue that educational process if it's in that setting. As I said, we will apply for Priority Review. It will be up to the FDA really then, whether they believe this is worthy of Priority Review, and also whether they think in the face of the data that we're demonstrating and their recognition of the unmet need and the seriousness of the condition here, whether an ad com is necessary or not. But we're just gonna make sure we're ready.
Tazine, just to add on to that, it. This is the first medication in 50 years.
Mm.
INGREZZA was the first medication ever for TD, and there was no ad com. The division, they're a different division, neurology, but they felt that they had sufficient expertise internally in order to make the call.
So, last question, and then Kevin will wrap it up. Sumant.
Sumant from Canaccord Genuity. Thanks for taking the question. So you've clearly done lots of work on Spinraza. We've heard powerful patient and caregiver and foundation, you know, perspectives on the product. How do you expect payers to react eventually when the product is approved?
Yeah, so the first thing I'll say is that, it's early days yet. We're only, what, six or seven weeks out since we announced the top-line results. Obviously, we've done work to understand, the point of view of payers, but preliminary work using a target product profile. Now, you know, very pleased to say that the actual clinical profile that emerged from the registrational studies is actually better than the TPP that we had done initial testing with. So we have to go back, and we have to sort of revisit what we think, how that's gonna translate into a label, and then how that's going to translate from a payer perspective. It's not just the commercial team that's doing this work, it's also the medical affairs organization, the health outcomes group.
Ultimately, what we have to do is to be able to tell a story of value, clinical and economic value, and I think we've got a really good story to tell, because of the unmet need and because of the clinical profile that emerged. I will say, however, that we also have done some focus groups with payers, and I was surprised at how savvy they were about the negative impact of long-term, high-dose exposure to glucocorticoids. So, you know, obviously we need to, you know, flesh that out and help them understand and appreciate the full impact of CAH, the deficiencies with the current standard of care. But they were a little bit more attuned to it, a little bit more educated than I had expected going in.
As we get closer to launch, certainly we'll have more to share in terms of what our market access strategy is. I can tell you that our payer account teams, our field medical teams, will be in front of those payers in advance, helping them to fully appreciate not just the burden of illness of CAH, but the paradigm shift that's coming.
So with that, I think we are done with this kind of open presentation, and I have to echo what Jude said a couple of times here. Any organization, but particularly within biotech, you are only as good as your people. We have a lot of our people here. I would really encourage you to go to the breakout sessions, engage them. I think you'll find that the quality of Neurocrine management that's here is o utstanding. Thank you very much for your attention all day.