Hi, everybody. Welcome to UBS Virtual CNS Day. My name is Ash Verma. I'm a biotech analyst here at UBS, and with us is next company is Neurocrine. And so we have Kyle Gano and Eiry Roberts from Neurocrine joining us. So, thanks for taking part in our conference.
Thank you, Ash. Really appreciate the opportunity to tell you a little about what's going on here at Neurocrine today.
Excellent. So yeah, I mean, we'll go through some Q&A. There are lots of investors and corporates are dialed in. We have around, like, more than 150 people signed up for our conference, and I'll do, like, the first 20 minutes of Q&A, then open up the floor to see if there are any investors or anyone who wants to ask questions on the open line. Otherwise, we can, you know, kind of continue the session and hopefully keep it tight to 25-ish minutes. So that's the game plan here.
Perfect.
So maybe I think it'll be helpful just to give, like, a very high level, you know, overview of Neurocrine. Most people would know Neurocrine by now, but just if you can give, like, a one-minute-ish introduction, Kyle.
Perfect. I'll start with that, and then we can jump in with questions, and the goal here is Eiry and I will tag team. So just a high level overview, we feel very fortunate to be in the situation we are here at Neurocrine. We've got a growing blockbuster in Ingrezza with a long-dated LOE. We've guided this year to $2.1 billion-$2.2 billion in revenue, which represents about an additional add of $350 million at the top end of that guidance. On top of this, we feel very confident in our second leg of revenue growth, which is crinecerfont and CAH. We received breakthrough designation in 2023 and look to file the NDA with the FDA in Q2 of this year.
Crinecerfont, we feel has the potential to be a blockbuster, to be paired along the side of Ingrezza in terms of the revenue potential, as a second leg of revenue for, for Neurocrine, with a commercial opportunity in the U.S. and Europe. I think in many ways, for me, it feels a lot like 2017 all over again, where we went through a period of years where there was tremendous value creation for the company and our shareholders. There are a couple differences, though. One is that second leg of revenue growth, which we didn't have in 2017 before Ingrezza was approved, and we have a very deep pipeline today, with a pipeline transformation that's undergoing, that's both exciting and differentiating.
We see the pipeline transforming from being a externally derived portfolio of assets to internally discovered programs, from small molecule to multimodality programs, looking at unvalidated to validated targets and symptomatic treatments to disease modification and cures. While we are in the early innings, we're beginning to see the signs of a high-value, sustainable R&D engine. Just a couple highlights there: we put five programs in the clinic over the past 12 months. We just started a phase II program in MDD with NBI-770. We have a line of sight to two gene therapy programs entering the clinic next year in GBA1-PD and in Friedreich's ataxia, and we have three phase II readouts this year that could lead to a registrational program in one or more programs next year.
So we're very excited to see some of the performance of these assets. I think we share, or say, related to the phase II programs, we share in the external environment's interest in the muscarinics, and one of those phase IIs is NBI-568, which is in a phase II study for schizophrenia. That will read out the second half of this year. And if that wasn't enough, we've got an M1/M4 dual agonist, that's just behind 568, that is NBI-570. And if that wasn't enough, we have an M4-preferring agonist as well, that's NBI-569, and an M1-preferring agonist, that is NBI-567. None of these orthosteric agonists require an add-back medicine to block peripheral effects. That differentiates our agonists over others that are in development.
The selectivity across the muscarinics, in terms of the subtypes and the selectivity of the brain over the peripheral circulatory system, are differentiating versus other agonists that are currently in development. And then just to round out the muscarinics, if all those agonists weren't enough, we also have a selective M4 antagonist that we're developing for movement disorders, which really leans on a lot of our expertise here at Neurocrine through Ingrezza. From a financial perspective, just quickly on this, we've never been stronger. We've got $1.7 billion in cash, durable cash flows, a very attractive P&L. Our capital allocation story is quite simple. We wanna choose those activities and those investments that will continue being a high-growth company, which means revenue growth, diversification, and a deep pipeline.
We're gonna continue investing in Ingrezza, as well as supporting the launch for crinecerfont in both the US and Europe, and we're going to drive high-value programs that are in clinical development aggressively, meaning if there are multiple indications, we're gonna take those on in parallel, and accelerating our research efforts to make sure we get to phase II as quickly as we can. All these will be done with a lens on internal organic growth, using business development to fill in gaps and/or bring in those tools that will help our research team win. And then ultimately, if we, we continue down this strategy, we believe that we'll be well positioned to become that leading neuroscience company that we aspire to be.
So a lot there, very quick, but I wanted to jump into the questions and give you a kind of a 10,000 view of Neurocrine before doing so.
... No, this is great. I mean, I would say that your renewed focus on the pipeline and broadening of the opportunities has been very well received by investors. So, would love to talk about that a little bit as we go through. Maybe, like, starting off with Ingrezza, like, if I can just ask a high-level question. Just, I think, like, the diagnosis rate has improved quite a bit here from... You know, like, if you go back, like, six or seven years ago, you were in single digit on the diagnosis rate, and now, I think 35% is what you quoted more recently.
Like, is this going to be increasingly more difficult, or do you see there is a ton of room to increase either the diagnosis or the treatment rate to drive... continue to drive growth for the franchise?
Well, Ash, hi. First of all, it's very nice to be here. Thank you for having us. And, yeah, I mean, obviously, we're very excited by what we've seen with Ingrezza to date in tardive dyskinesia. And you're right, we're entering actually our eighth year after launch, and it's quite remarkable to see the growth that still is existing year on year for Ingrezza. And I think that is an indication of the fact that there is still a huge amount of unmet need in this, this space. And a lot of that pertains to the fact that we're still, you know, in baseball terms, in the second or third innings in terms of our ability to help clinicians diagnose and ultimately treat patients with tardive dyskinesia with the appropriate VMAT 2 in Ingrezza.
And so as you said, we started off, at the time that we came to the market, was just single-digit patient numbers being diagnosed. We estimate now that about a third of the marketplace is actually diagnosed. But of that... So that still means that two-thirds of patients who are suffering from tardive dyskinesia do not have a diagnosis of tardive dyskinesia, and therefore don't have the opportunity to have effective treatment. And even of those third that are, of the approximately 600,000 patients that are diagnosed, only half of those now currently get treated with a VMAT2 inhibitor. Despite the fact that in the recent APA update of the schizophrenia guidelines, VMAT2 inhibition was chosen and portrayed as the most appropriate treatment for patients suffering with tardive dyskinesia.
The reason for that really is that there's still a huge educational gap that exists, and so much of our education is focused on targeting clinicians treating these patients. And when we say clinicians, we're talking not only about psychiatrists, but about many of the advanced practice providers that have come into the psychiatry space over the course of COVID and prior to that. And so, we spend a lot of our time, both on the commercial side and on the medical affairs side, educating these advanced practice providers, be they nurse practitioners or physician assistants, who have full prescribing rights, because they really are focused holistically on supporting the patient, and we find that they're very keen to get that education to enable them to treat the patient effectively.
There's a lot of misinformation in terms of how clinicians are currently still taught to treat tardive dyskinesia. They follow these three Rs, either of reducing the antipsychotic medication, replacing the antipsychotic medication, or removing it entirely and using drugs like anticholinergics, none of which have any evidence behind them to support the treatment and effective treatment. And so we see a huge opportunity still for patients to be helped by Ingrezza as we continue that educational process, including, obviously, our direct-to-consumer advertising, which has been an important point of educating the public around the fact that there are opportunities that exist for them to get improved treatment and improved and appropriate diagnosis. So we're really in the early days. We also entered long-term care recently as a next tranche of potential opportunity for patients.
And obviously, with our Huntington's disease approval last year, there's another group of patients there that certainly could get significant benefit from Ingrezza as well.
Yeah. Yeah, got it. All right. That's, that's great. And maybe, like, just, talking about crinecerfont, just switching gears here. I mean, in the... Like, you've seen some pretty good data on both the safety and efficacy side. Like, from your perspective, what is the potential, what are the potential, you know, focus areas for the FDA when they start to look at the application and, like, when we start to look at the, you know, kind of the launch and the, the ramp here? I mean, a lot of these patients sit, within what you could, you know, consider as, like, very core specialists.
How do you try to broaden the, you know, approach of your crinecerfont product towards more broader audience so that it can maximize the benefit of the launch early on?
... Yeah. No, certainly. So as background, crinecerfont is a CRF1 antagonist that we recently read out data from 2, the largest program actually ever performed in patients with congenital adrenal hyperplasia. And there were 2 key studies within that program, one of which was in adult patients and the other in pediatrics. So as a little bit of background on CAH, it is a rare congenital disease which is usually diagnosed at birth or shortly thereafter. And in the past, prior to around 60 years ago, it was universally a fatal disorder in individuals who were diagnosed with it, who had classic CAH, salt-wasting CAH. And then so it's also a treatment where there's been very, very few steps forward in terms of medication availability and new therapies for the last 60 years.
In fact, glucocorticoid treatment is really the only treatment available right now. And so these patients are very challenging to manage, and as such, in the main, they are seen within expert centers. And because given the lack of useful medical therapies here, physicians rely on the steroids to not only replace the adrenal insufficiency that patients have, but also to try to handle the excess androgens, which form another important part of the disease. And so it's really a place where there's an enormous amount of opportunity for new medication to add significant value for patients. So most of these patients, as I said, are treated in expert centers, and in fact, general endocrinologists today really don't feel confident managing patients with CAH, given the complexity of the disorder.
The good thing is that the patient advocacy environment here and patient support system is pretty strong, and as a result, the linkage between these specialist centers and patient advocacy and the patient community is pretty strong, particularly for pediatric patients and their families. And so as we get ready for our, hopefully, for our launch after successful approval and registration, we will be engaging first in the United States with this community, and have done actually for many years already in the context of the clinical trials, in order to start to educate clinicians first in those specialist centers, also in the setting of patient advocacy, and finally, then in the more general endocrinology community, as to how to manage these patients more effectively.
The great data that we read out last year, and we were overwhelmed by the nature of the data that we saw, both in terms of the efficacy profile of crinecerfont and the safety and tolerability profile, it far exceeded our expectations. I think what it's going to hopefully allow clinicians to do is have a much simpler way to manage patients with CAH by using crinecerfont to control the androgen excess part of the disorder, and therefore leave them able to just use the steroid treatment that they've used for so long to... as a replacement therapy for the adrenal insufficiency.
And so while all of our effort initially is really going to be focused in those specialist centers and supporting the pediatric and adult endocrinologists who treat these patients day-to-day, it does really provide the opportunity for that to go broader than, given, if this is successful in transforming the treatment of the disorder and making it a simpler thing for endocrinologists to consider.
Yeah. Yeah, that's great. So maybe, like, talking more about the pipeline, I mean, you know, Kyle also spent some time on this, on the muscarinic. I mean, you definitely have a pretty broad offering in terms of the pipeline that you're pursuing with lots of different permutation and combination. My question is like, I mean, so we know that there are two programs, like from your competitive standpoint, that are slightly ahead of you in terms of, you know, clinical development with Cerevel and Karuna. I mean, like, is there an early mover advantage that you think that you have to fight here with your competition? And does that make a big difference in this field from your perspective?
I don't know if you can give any examples specific to that situation. And yeah, like, would love to understand. I think you're looking at it more from like a not just schizophrenia alone, but like cognitive side of things also, right? From the muscarinic side. So if you can elaborate on that a little bit.
Sure. I think the exciting piece about being a company within this space is the opportunity to have a portfolio of assets that are from a mechanism perspective, validated, and gives you the opportunity to treat a range of diseases from cognition to psychosis. That's a very attractive area to be in, and knowing that we've got a lot of different flavors of molecules that will be investigated to understanding what pharmacological fingerprint, if you will, will be of greatest benefit in that spectrum of cognition to psychosis disease states is gonna be our challenge, and we're up for it here at Neurocrine over the next couple of years.
I think to your question on KarXT and Emraclidine, and I'm probably gonna use the companies that are part of the new equation now and the old company names as well interchangeably, because I still haven't worked them through my thinking. But we'll talk a lot about Karuna, BMS, and Cerevel, AbbVie. But from our perspective, I think there's a lot of data out there that suggests, at least on the antipsychotic side of things, that-
... there's sufficient room out there for multiple players to win here. We see even second, third generation antipsychotics being blockbusters here, with advantages in the area of safety and tolerability relative to earlier versions of medicines that were in the same space. I think for us, we acknowledge that KarXT and emraclidine produced some really nice data in schizophrenia, and that we have to ultimately deliver for ourselves with NBI-568 later this year and see how our data package stacks up with these other molecules. I think that our approach when we think about differentiation is pretty simple, actually. Everyone that's here right now that's in this stage of development, phase two through NDA, is really looking at activating the M4 system, and we're doing so in completely different ways.
Much more different than when we think about the antipsychotics that are out there today that are branded and trying to differentiate these particular antipsychotics on more nuanced pharmacology. The three companies, Neurocrine, BMS, AbbVie, are, are looking at doing this completely different ways again. So you've got KarXT, that's a pan-muscarinic agonist that is one that has exposure in both the periphery and CNS. Obviously, the CNS piece is what you would want in this particular disease state. But to block some of the off-target effects, they add back trospium, which is a pan-peripheral muscarinic antagonist, and the match isn't perfect. So what you see is still xanomeline-driven side effects, and you also see some trospium-driven side effects.
That's gonna complicate what the ultimate label looks like, and also in, you know, just at a high level, the treatment of patients, because you're giving them two medicines instead of one. In the area of Cerevel and AbbVie with emraclidine, they have what you call a positive allosteric modulator. It requires cooperativity of acetylcholine, which is the endogenous ligand of M4. It's dependent upon acetylcholine to drive efficacy. On the other hand, our approach is, we, with our collaborator, discovered the molecules that we're developing now with the idea that we would build in the selectivity across the subtypes of interest and for the CNS up front. So we don't require the combination of a add-back type of approach here to block side effects.
The selectivity and potency is dialed in up front, which we think provides an advantage in terms of simplifying the treatment regimen for patients ultimately that need an orthosteric agonist. I think the question that we get most often is, "What do you think is the differentiation between your approach of an agonist with a PAM?" I think at this stage, you know, we still have to deliver our data. But with 568 and all of our agonists, we don't have a dependence on acetylcholine. We activate the receptor whether or not acetylcholine there is at sufficient levels where the M4 receptor is expressed.
And we don't require it to be at high enough levels to drive efficacy in certain other disease states that maybe these molecules haven't been tested in, for example, in ADP. So I think there's optimal room here ultimately for all these different players to win. Obviously, I think there's good precedents for molecules that are fast followers, that have a best-in-class profile to do quite well. And what we see out there right now are 30+ antipsychotics with over 70 million prescriptions in this space. And to be the third of a potentially new antipsychotic class is very exciting for us, and we think ample room for us all to do quite well out there.
Good, good. All right, so maybe we can open it up for questions from investors, if, Operator, if you can check.
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Okay, great. So I have a couple of follow-ups if you know, if you bear with me. So I saw that there is a you know, like, new mechanism that's being talked about in schizophrenia, this GPR52 agonist. And like, Boehringer Ingelheim did this you know, deal, like $700 million total, including biobucks with Sosei last week. And apparently, I think you have this mechanism too in your pipeline. There is some sort of like a patent filing that we saw from December last year. If you can tell us a little bit about this, like, what do you think of this mechanism in any. To the extent possible, you can shed some light on how is your molecule may be differentiated versus the competition.
I think that'll be, that'll be helpful.
Yeah, let me just say, Ash, that we really respect your team from the perspective of going all the way down in the patent filings. That's... I like that approach. In terms of GPR52, we've had a number of programs and have a number of programs in a lot of different areas right now here at Neurocrine, probably not surprising to most of you. One of them is in the GPR52 space. We see an interesting profile here from the perspective of both cognition and psychosis as well. I would just say it's probably pretty early days, too early to really comment on our approach or Boehringer's approach on this particular target, but certainly we'll follow it. There's been interest in this target in with other companies over the years.
It's been a difficult one from a medicinal chemistry perspective... but we'll look at how the program evolves here over time, and once we both have clinical data, I think that would be a good time to follow up and have a question how this might work ultimately in schizophrenia and how the programs might differentiate.
Yeah. Yeah. And then maybe the two MDD assets that you have, like 845 and 770, anything that you can elaborate on that? Like, what is? I mean, it's a pretty crowded space. Like, what is. Like, how are you trying to position them? What's the kind of value proposition here?
Eiry, you wanna take that one?
Yeah, that'd be fine. I mean, I think, although there are obviously a fair number of companies and medications already approved in the depression space, we know that the vast majority of patients with major depressive disorder don't gain full relief from currently available treatments. And in fact, you know, in the last years, it's been very much an area of adjunctive treatments in depression or additional and new approaches to treatment-resistant depression or inadequate response to treatment in major depressive disorder. And so, both of these compounds are focused on that in inadequate response to usual treatment setting.
Essentially, they both are aimed at trying to achieve a more rapid onset of antidepressant effect, a little bit ketamine-like in terms of the approach, but without some of the challenges of ketamine's use in that setting. Taking 845 first, this is an AMPA potentiator. Some of the mechanism of action of ketamine is presumed to be through AMPA mechanisms, and as a result, what we're looking at is a molecule which potentiates the AMPA system, downstream of where ketamine is usually acting, and that is being studied as an oral treatment. We read out a study in the pretty near future, actually, in the first half of this year, in major depressive disorder, looking at the 28-day MADRS scores in that proof-of-concept phase II study.
The other mechanism, NBI-770, is one that actually has been validated using intravenous approaches, parenteral treatment. It is an NMDA NR2B NAM antagonist, and those molecules have struggled with therapeutic index and therefore have not been able to go forward to any great extent into later-stage development or to become useful medicines. We have an oral approach to this target. We're just actually starting two parallel phase II studies, a phase II proof-of-concept study and a phase Ib, essentially, proof-of-mechanism study. And so, once we have the data from those study, we'll be happy to talk about whether or not we've been able to validate this target further using an oral approach.
Yeah. Yeah, got it. And I have one, like, follow-up question from an investor. So, just, you know, just inquiring about the plans for Efmody. So, when you have crinecerfont and Efmody, and if the Efmody also becomes successful in this ongoing phase II study, and if you're able to bring that to market, like, what is the plan? Like, would that be kind of like complementary to crinecerfont, or would that be its own, like, separate treatment option?
So as I mentioned earlier with crinecerfont, what we're hoping to do is change the paradigm of treatment and the paradigm of androgen control in patients with congenital adrenal hyperplasia. Even in the face of doing that, though, these patients will still suffer from adrenal insufficiency and will require some glucocorticoid therapy. So Efmody, as you know, is a modified glucocorticoid therapy that is intended to mirror the diurnal rhythm that's seen in normal cortisol release better than other available steroids that are on the market. It's already marketed in Europe for treatment of congenital adrenal hyperplasia, and we will be, first half of this year, reading out two additional studies, a phase II study in CAH for Efmody and an adrenal insufficiency study.
Once we have the data from those studies, we will decide on the next steps in the United States. And obviously, you know, I think that will be important for us to see in terms of determining what's next for Efmody in the US.
Yeah. All right. Great. Thank you. Thank you so much for your time, Eiry, Kyle. This was super helpful. Yeah, 30 minutes went by pretty quick.
Mm-hmm.
So, good luck with all the, you know, the pipeline and all the exciting programs that you're working on, and I'm looking forward to staying in touch.
Appreciate it, Ash. Thank you.
Thank you. Thank you.
Yeah. Have a good one. Take care. Bye.
Bye.