We can start? All right. Just wait for everyone to get in.
Good afternoon.
Good afternoon, everyone. I hope everyone's doing well. My name's Akash Tewari. I am a pharma and biotech analyst here at Jefferies, and I have the pleasure of hosting the Neurocrine management team, Kyle, Eiry, and then Todd's here as well. Kyle, why don't I give it to you for some introductory remarks, and then we'll get started.
Thanks, Akash, and thanks, Jefferies, for having us here today and tell you our story. I would say that at the outset here, we will be making forward-looking statements. I'd like to direct everyone to our latest SEC filings for our risk factors. With that behind me, I would like to also add that I'm still on my first tour here at Neurocrine. I became the CEO full-time in early October, so many of my conversations with investors and being out here on the circuit here is for the first time. So I thought it would be good to tell you a little bit about myself as we jump into talking about Neurocrine. I've been at the company for almost 25 years. A little fun fact for you in case we meet outside of here: I started as a summer intern.
So yes, summer interns can become CEOs at the same company. I've worked here in various roles over the years in many different capacities, either by title or indirectly trying to help out a small biotech company through rough times. And that's been a real hallmark of Neurocrine as a company that's worked through a lot of difficult challenges and shown a lot of resiliency over the past 20, 25 years to get to where we are today. And really, that's where I'd like to spend the majority of our discussion. You know, I feel like here we are in 2024, looking at 2025. It feels an awful lot like it was about seven years ago when we were launching our first medicine for tardive dyskinesia in Ingrezza.
We have a tremendous amount of growth ahead of us, and I'll tell you about that in just a moment, but I think it's built off of our previous achievements and our promising future ahead. For those of you that are unfamiliar with the company, we actually have three FDA-approved medicines out there, and when they were approved, they were each first in class in their own right. If we look at one of those, Ingrezza, specifically approved in 2017 for tardive dyskinesia, this is our growing blockbuster. We reported Q3 sales of $613 million in revenue. That's about 25% year-to-year growth, and that's pretty astounding if you think about being seven years into launch and still seeing that level of growth. We raised our guidance with that earnings of $2.3 billion-$2.32 billion for this year, with that same 25% year-to-year growth attached to that.
We're very excited about the growth opportunity for Ingrezza moving forward. There are about 800,000 patients in the U.S. with tardive dyskinesia, and we assume we estimate about 85% of those 800,000 patients are still not getting a VMAT2 inhibitor, and that's the mechanism of Ingrezza. A lot of work to do ahead and a lot of opportunity that remains. That's an important point to make considering that we still have patent life out to 2038. Fourteen more years of market exclusivity in the market that we hope to continue to grow and treat many more patients with tardive dyskinesia. This is a growth story, and we have another potential blockbuster that we see in the making here. We have crinecerfont in FDA review.
We have two NDAs right now in FDA's hands for two different formulations that treat a rare endocrine disease called congenital adrenal hyperplasia. The PDUFA dates for these NDAs are December 29th and 30th of this year. Assuming those are approved, we'll look to launch this in early 2025, and we're very excited about this opportunity just as much as we were with Ingrezza. This is a medicine that, if approved, will be the first new medicine for CAH in over 70 years, and I think that we're all very excited to have the opportunity to bring medicine to patients that will really change their standard of care. Like Ingrezza, crinecerfont will be a first-in-class medicine, and I hope you see a theme here in the types of medicines that we develop at Neurocrine. Behind crinecerfont, we have programs moving into phase III development.
NBI-845 is a program that produced very nice positive phase II data early this year in major depressive disorder. And we also have a selective M4 agonist, NBI-568, that will move into registrational trials next year as well in schizophrenia. We have the deepest muscarinic portfolio in the industry, five programs in phase I, and a very strong financial position. And that gives us all the incentives to invest further in ourselves. We have an R&D transformation that's undergoing right now. We've been a company that has leaned on business development quite a lot over the years to fill out our pipeline, to partner regionally where it makes sense, where we don't intend to have a footprint. And we're using some of our investments here that we're able to retain from Ingrezza to plow that back into ourselves and do more internally as time moves along.
I think you'll see some of that in our pipeline starting next year. We were really focused on expanding our reach into different disease states and different modalities moving forward, and that's what you'll see. That's offering patients not only medicines that treat the symptoms, but offering disease modification and curative therapies. A part of that is moving into different modalities, as I mentioned. That'll be a big part of what we have for next year entering the clinic, in particular two gene therapy programs that we will be developing for GBA1 Parkinson's disease and for Friedreich's ataxia. On top of the pipeline, we talked about our commercial products, the R&D transformation that's underway. We're as strong as ever from a financial standpoint.
We have about $1.7 billion in cash and growing over time, and that's going to give us a lot of ability to invest in our commercial products, Ingrezza and hopefully crinecerfont next year, and then bring forward our late-stage assets to commercial as quickly as we can. I think with that, Akash, I'll stop there. We can take some of your questions.
Sounds good, and it's great to hear you're a former intern. As was I at ISI eight years ago, so.
There you go.
Not the CEO of Neurocrine, but okay. Let's start off with maybe just Ingrezza. And you know, I think the street was nervous because we were all sitting here tracking IQVIA data and thinking, and this was not only a dynamic in Q3, but even Q2, where it felt like you're looking at Austedo XR. It seems it's seemingly taking share. And I remember talking with Todd, and Todd's always so calm and relaxed. It makes me feel good. But I could sense your team.
Kind of your thing.
I could sense your team is very adamant about two things. Like A, that kind of 60/40 market share holding up, and then B, don't read into this IQVIA data too much. You know, talk to me about what the dynamic that's going on here. I mean, I'm sure you're getting this question a lot. Why has there been maybe a divergence between what we're seeing with scripts and then, more importantly, what you're actually reporting on revenues?
Right, so I think on the third-party syndicated data, I mean, we all know that's projected data. So in any given quarter, there could be noise around the modeling that was done for those prescriptions that were tied to that quarter. So we always caution people not to place an over-reliance in terms of it projecting onto a model. We appreciate that people will continue to do that, and you know, for the most part, it's been directionally accurate in terms of the relative positioning between the two products. I will say, if you just look at the total category, you know, I reported our growth this past quarter and what we see for this entirety of the year. The market opportunity for TD continues to be very robust.
And the way we would see the market right now is both products, ourselves and deuterated tetrabenazine, are enjoying great growth in this category. We will see on a quarter-to-quarter basis, there may be times where we outgrow them and they outgrow us. I think we do see with the XR formulation of deuterated tetrabenazine that it has benefited Teva over some period of time as they've launched that product and done well. But still, as we stand here today, there's over a million prescriptions of Ingrezza written since 2017, and we continue to be the market leader. And if you look at the differentiation that we have as a product for tardive dyskinesia, it's over multiple areas. When we think about safety tolerability as a broad category, valbenazine is a very selective VMAT2 inhibitor. There's no off-target effects.
We know very exquisitely, very specifically how the medicine is used in different patient populations, which is very favorable in terms of its profile. There's a more favorable DDI profile as well. When we think about efficacy, you can look at the labels of the two products. We see that Ingrezza has a fast onset of action, very good profile and efficacy overall in terms of placebo-corrected AIMS scores and magnitude and effect that differentiate Ingrezza as well, and then last but not least, even though we see a once-a-day formulation with deuterated tetrabenazine, valbenazine or Ingrezza doesn't require titration. And we have a novel sprinkle formulation that is out there that came out in the summer timeframe to help those patients with dysphagia, which we know is also differentiating, so we really like what we have with Ingrezza. We expect the market to continue to grow.
As I mentioned, we're investing heavily here, and with 14 more years of market exclusivity, our expectation is we're going to continue to grow the market.
Understood.
I'll just quickly add. So a couple of years ago, we started to provide annual guidance for Ingrezza, and we were hoping that would take some of the angst out of the marketplace in terms of looking at IQVIA or Symphony, but we know that's going to happen. So with that being said, on an annual basis, our revised guidance is in the range of $2.3 billion- $2.32 billion. And in the category, that's about 60% share.
Understood. Exactly. And you know, over the last two years, particularly post the pandemic, you've talked about the investments you've made in long-term care facilities. And I think you've said that it could be like maybe 10%-15% of your share growth over time. It's interesting. On the Q3 call, you also upped the prevalence estimates for tardive from, you know, 600,000 to 800,000. A, what drove, you know, on a Q3 call for you to suddenly up your TD estimates? What are you seeing on the market? And then number two, how much of that is driven by increased visibility in those long-term care facilities? And generally speaking, how should we see that segment of the business grow over the next few years?
Maybe I'll start with the epidemiology piece. When we first launched Ingrezza for tardive dyskinesia back in 2017, we came out with a number of about 500,000. That was at a very low, the lower end of the band that we had estimated to be the actual prevalence. A couple of years later, we upped that to 600,000. And they really haven't said anything. We haven't updated our work until very recently this year. And what's happened over that timeframe is still very robust growth within the antipsychotic space. So it continues as a market, a class of therapeutics to grow in the single-digit type of growth rates on an annual basis. That's multiples above the growth rate of the general population.
So I think for us, when it comes to the epidemiology, it was just about the right time to update our current number on that, given that the antipsychotics continue to grow quite significantly. And the work that we did this year on the overall prevalence was a little bit more robust because we have more data than we've had in prior years. So we felt confident that this 800,000 number, while still on the lower bound of the region, or lower bound of the prevalence estimate that we have, is a more realistic number of the actual number of patients that are out there today.
The correlate to that, or the continuation of that, is that we had a pretty good estimate of how many patients that have been diagnosed over the years, but with a higher prevalence number, it tells us that overall our reach in the total market is not as high as we thought. So when I say 85% of the patients with TD not on a VMAT2 inhibitor, that's with that 800,000 number in mind. So it is a market that is continuing to grow. And I think what you see there is our reflection of that with our prevalence number. And then when it comes to how that pulls through our commercial thinking, you know, ultimately, the number of antipsychotic prescribers continues to expand with that increased prescription volume.
We also see growth in different segments of the market, to your point, Akash, in terms of what we see in long-term care. We needed to reach those new prescribers both on the psychiatry side as well as those that are working in long-term care facilities. That can only be best done by expanding your sales force.
Understood. Maybe just lastly, you have next-gen VMAT2 inhibitors in development. And I feel like there's multiple angles, right? A, you've run a lot of studies with Ingrezza in other indications, you know, adjunctive schizophrenia. And maybe we haven't seen the success there as we've seen with tardive dyskinesia. So A, are the next-gen VMAT2 inhibitors going for indications where you've already tried Ingrezza and you feel like maybe a more potent molecule would have success, and maybe that's where Ingrezza maybe faltered? And then number two is potential long-acting formulations and the ability to convert, you know, over time a significant portion of this market into an LAI-type dynamic. Talk to me about what are the options with your next-gen VMAT2 inhibitor programs. I think you're going to have data next year. How should we be thinking about this?
Yeah, I think with Ingrezza and valbenazine, the generic name, we've primarily focused on movement disorders. That's always been the target basket of indications that we wanted to pursue. After the tardive dyskinesia indication, many of you may recall that we spent a number of years looking at different studies and different age groups within Tourette's. And we didn't get the right profile that we're looking there to ultimately advance that to an approval. So we discontinued development in Tourette's, but then we picked up a program, a development interest in Huntington's chorea, where the mechanism has been validated. And we did get an approval for that a couple of years ago. And those are the two indications that Ingrezza has today. Subsequent to that, we started a program in the dyskinesia associated with cerebral palsy. That's a phase III study that's ongoing right now.
Hope to have data on that next year. The last one goes back to the schizophrenia application. As you mentioned, the adjunctive setting, that's what we call the ATS study. We have a single phase III trial that's ongoing right now. The idea here is that this is a different population than we see with movement disorders. Given the different needs and wants of patients and physicians within this class, what we've tried to do is use valbenazine to learn about the opportunity in schizophrenia and take those learnings and use those for the follow-on molecule, which is NBI-890. The adjunctive treatment of schizophrenia study will read out next year. That will dovetail nicely into the completion of the phase I work for 890.
And hopefully, we'll be able to figure out what the best path is forward for that molecule, which has different physicochemical properties than valbenazine. In particular, it is much more potent and has the chemical structure that affords it to be more formulated into long-acting injectable. So here, these are things that would be attractive in larger disease states where compliance is an issue, things like compliance and other psychiatric disorders that we see common with antipsychotics. And what makes us believe here that there might be an application is that at the heart of the mechanism is we're depleting the presynaptic cleft full of dopamine. And that's the same process by which antipsychotics achieve their efficacy by blocking dopamine on the postsynaptic dopamine receptors.
So we'll see how that all plays out, but that's the mechanistic underpinning of why we think VMAT2 inhibition might have an alternative role besides the movement disorders.
Understood. Now, I have a question that, you know, it was interesting when the multidisciplinary review for KarXT came out. And you know, I think when we were looking at those phase II data sets and then even Karuna's data set, there's a perception, okay, well, Neurocrine didn't have a dose response, but these other programs did. And it was really fascinating to me because they actually had an exposure-response relationship even with Karuna's drug. And what you saw was that the idea that even KarXT had a clear dose response isn't necessarily true. And this is actually something Karuna said for a while. Like if you have AEs, it's probably a sign that you have adequate PD effect. So this will get theoretical, but when you look at emraclidine's failure, how much of that do you think was maybe not titrating, right?
Where maybe they thought there's a clear dose response with their drug, but in reality, and obviously their phase III data didn't show that. Do you feel like part of the reason why they had the effects as they did is because they didn't necessarily assure that patients had adequate PD exposure? And then number two, when you think about your phase III trial design, right? You've talked about the ability, maybe we'll titrate, maybe we don't. What would your base case be right now for your phase III design? Do you think titration is important for this class?
There's like five questions.
Yeah, that's right. Let me start just by the comment around the Cobenfy or KarXT. I mean, clearly you have two medicines there. You have xanomeline and you have trospium, both of which have a relatively narrow therapeutic index because of the breadth of their activity. One as a, you know, pan-muscarinic agonist in xanomeline and the other as a peripherally acting antagonist. And so it's not surprising that there's a need for titration potentially there and that the tolerability is different across different patient groups. I'm not sure you can read that through to either emraclidine or to 568. With respect to the emraclidine data, I mean, obviously I believe we were disappointed, obviously in terms of for patients particularly, based on the previous phase I data, phase I- B data that had been published and presented.
The program that ran in phase II-B was very different from the program that had been run in phase 1-B by Cerevel, both in terms of the number of studies, number of sites, the number of patients included, and actually the way in which those studies were run. And so I think there are many, many reasons that I'm sure AbbVie will dig into to understand what the true cause of that failure was. For us, in terms of the M4 selectivity and M4 mechanism, it doesn't detract from our belief that that is a very valuable potential path forward in the treatment of schizophrenia. I think as we saw in our phase II data, we ran an adaptive trial design to assess a broad dose response.
It is not at all unusual in our history and in the history of this field that you don't get a clear dose response in psychiatry. I think it's more unusual to have a medication in schizophrenia or depression that has a clear dose response. And so we were very confident with even the 20 mg dose going in and subsequently higher doses that 20 mg was a sufficiently high dose to start the trial with. These are acutely unwell individuals, and we needed to go in with a potentially efficacious dose at the lowest of the doses tested. That was supported by preclinical data and from our pharmacodynamic findings in phase I .
And so what we demonstrated there with the 20 mg dose level was a very encouraging efficacy profile and a clear tolerability profile that was consistent with the ability to move forward into phase III. We saw efficacy and change in the PANSS scores as early as week one, statistical significance and separation from placebo at week three, and that carried on through to the end of the trial at week six. And so with that all in mind, we're going forward to the FDA within the next couple of months for an end of phase II meeting, and we will plan on a simple, straightforward psychiatry schizophrenia phase III registration path with the embedded in the 20 mg dose as the core dose that we wish to go forward with.
I'm sorry, one to one.
One to one randomization, not two to one randomization.
Yeah, and actually to that point, you know, there is speculation, patient expectancy, you know, there were maybe pauses in the trial during COVID for emraclidine. When you think about the conduct of that study, maybe there's not a read across in the mechanism of action, but let's think about placebo. What can you do to ensure that you're not going to have such a historically high placebo rate? And what gives you confidence you can pull that off?
Yes, I mean, the oversight of trials in this space is critical, and having sufficient involvement from the company at the site level to ensure the quality of both the patients that are being selected and also the quality of the data that's being generated on an ongoing basis is critical. We have built the team that already did that in the phase II setting. And if you see from the phase II data that we shared, our placebo response was a little higher than had been seen in phase I- B by the other companies. And I think that is reflective of expectation bias. That may be changed a little differently now with the emraclidine data, to be honest. But embedded in our running of the trial was a very clear and direct oversight.
And we were pleased with that placebo response because it did allow us to substantially differentiate on the drug effect, even in the face of a somewhat higher placebo response. So as we move forward, we'll be employing all the learnings that we gain from our phase II environment, plus also obviously what we learned from the field to ensure that we have the appropriate oversight, the simplicity of the trial design, and that we're working with high-quality centers in order to deliver.
Understood.
Maybe just to add to that too, I think if you look at the comparison that Eiry had made for emraclidine from phase I-B to phase I, the phase II trial that we conducted was more phase III-like. We had 210 subjects in the study. We had 15 sites. And you can see that that is almost nearly what Karuna had in their phase II and III studies. So that's something that is easier for us to be able to control rather than going from such a small study to such a large study. And those are all things that will build into our management and oversight thinking for the phase III study.
Understood. Maybe just lastly, you know, and I wish you guys did this more. You didn't publish a lot of data on the M4s. I was sitting here trolling patents, which, you know, can sometimes blow up on you. But are you going to release more data on the M4? I certainly think there's an appetite for that. So in terms of releasing more data, the Healthy Volunteer study, the dose response going up to 20 mgs on EEG or other metrics, will there be more disclosures on the M4 next year and when?
Yeah, I think we're figuring out the right venue to disclose more data, additional data on the muscarinic program. I would add that also goes for the NBI-845 program and MDD. So stay tuned on that. There are a couple of different things that we're thinking about. But my guess is we'll focus our attention first on getting the phase IIIs up and running. And these are going to be the same team members that put together a publication or a presentation that we'd be sharing. So we do want them to focus on getting the phase IIIs up and running. And then once they have that in a good spot, we'll look at having some of that data put out there.
Understood. You mentioned you have a very broad muscarinic portfolio. I mean, you have another pretty intriguing drug, which is a selective M1, M4. So you could have a cognitive benefit. And then theoretically, you may not have to dose patients with trospium. Can you talk about, A, what data we're going to be getting out of that program next year and how de-risking is that going to be for investors in terms of, are you getting into the brain? Are you going to be selective enough from a safety profile? And then number two, why you feel confident that you're going to have a profile that doesn't need to be dosed with trospium?
Sure. Maybe just to take the second question first. One of the things that Nxera did very well in the early stages of development was they were able to identify sites within the M1, M4 receptors that were conserved that are not conserved in the other subtypes, and their chemistry was based around this conserved region of the target, so actually, when we think about all the muscarinics that we have in our portfolio, they're only flavors of M1 and M4. They don't hit any other subtypes. So no M2, no M3, no M5. And it's not even close. It's 100-fold different. So when we think about our dual NBI-570, it really only hits M1 and M4. So you need trospium if you hit M2, M3, M5. We don't have that issue here.
The other thing that Nxera did a really good job of is that they created molecules that preferred getting in the CNS versus the periphery. So a lot of those peripheral effects that you worry about with xanomeline as well are not a factor here. So we're very excited about the profile that we have in this molecule. The next step would be to see the phase I data that we have probably end here in 2024 or 2025. We'll lead to a study in schizophrenia patients subsequent to that. So stay tuned.
Understood. Fortunately, we're out of time. I wanted to ask on crinecerfont, but I really do appreciate it. Thanks so much for the time.
Okay, it's a coffee.