Everyone, I'm Cory Kasimov, one of the Senior Biotech Analysts here at Evercore ISI, and it's my pleasure to host our next session with Neurocrine Biosciences. Thrilled to have the company's new, fresh CEO, Kyle Gano, as well as Matt Abernethy, the CFO, and of course we have Todd here with us who needs no introduction. So again, thank you guys for being here and taking the time.
Cory, I feel left out. You didn't make any adjective statement about me.
You're taller than what I was told.
You did say I was taller than you anticipated. Sorry.
You're taller than you are on Zoom.
Okay, there we go.
So there we go. All right, so with that, now we got that out of the way. I guess the first product I want to start off with is crinecerfont. PDUFA dates are obviously just weeks away, but it feels like the street is still largely overlooking this launch, at least based on the inbound questions we get for it. So maybe to begin, how big of an advance will this approval be for CAH patients?
Thanks, Cory. I appreciate the question. Maybe just to start, this is my first Evercore conference as a CEO, so maybe just a quick bit of introduction for me. I've been at the company for over 25 years in various roles at Neurocrine. I'd say for about the past 10 years I've been working in Business Development, so the things that are in the pipeline today, things that we've partnered, was largely done within my group over the past 10 years or so, which brings me to an interesting point. One of our earlier meetings today, we were speaking to some of the programs in the portfolio, in particular the muscarinics, and Abbott came up in the course of our discussions as it relates to a competitor program. And it just reminds me how long I've been in this business.
Fifteen years ago, I did a deal with Abbott in the Pharmaceutical area, and Abbott now, as you know, is a diagnostics company, but we partnered a program with Abbott back in 2010, and that became Oriahnn and Orilissa years later after we partnered that program, but it's amazing to see how things have changed that started at Abbott and now AbbVie, how things change in our industry in terms of peaks and valleys, ebbs and flows, and it just reminds me of how lucky we are here at Neurocrine with the medicines that we have, either near commercial as in crinecerfont's case or Ingrezza, and really an exciting time to be at Neurocrine as we think moving into 2025, so that's a little bit of background on me.
On your crinecerfont question specifically, I think a couple of things that are exciting about this medicine, and it really is tapping into the thesis of who we are as a company, starting with Ingrezza, developing first-in-class medicines, is that crinecerfont is a CRF1 antagonist. If approved, it will be first-in-class for CAH, Congenital Adrenal Hyperplasia. If approved, it'll be the first medicine for CAH in over 70 years. And we do think, like Ingrezza, crinecerfont's going to change the standard of care for patients. So what I think a lot of people don't appreciate fully is that as a disease state, it really is best characterized by one where the body is struggling to capture the HPA axis.
In the absence of cortisol, which is synthesized by a key enzyme in the body called 21-hydroxylase, there's no way to control the HPA axis within the body. And when you're not able to do that, what you see is high levels of ACTH that are uncontrolled over time. That leads to high levels of androgens that, again, that are uncontrolled over time. For the past seven years, the only way to control the HPA axis was to add back excessive glucocorticoids. And it results in this trade-off analysis that patients and physicians have to do for their care, where they either choose to control their androgens very tightly by using high-dose supraphysiological doses of glucocorticoids, or they back away from that and let androgens spike. And what we're able to do with crinecerfont is take back control of the HPA axis directly.
We operate upstream in this cascade at the pituitary where the CRF receptor is. And by doing so, we're able to reduce ACTH, control ACTH in target tissues and organs. That allows us to normalize the androgens, or at least bring them closer to normal, and reduce the reliance on excessive glucocorticoids. In fact, we're able to bring a good portion of patients back to the equivalent of physiological levels of cortisol ultimately when they're taking crinecerfont. So you put all that story together, and we're really excited about the opportunity that we have here, assuming the PDUFA dates later this month are favorable and we get approvals for the NDAs that are currently in review. We'll look on launching the medicine in early 2025.
What's the street missing, I think, is one of the key questions here. I would just put it simply as this: it's really hard to understand what the ultimate demand for medicine is going to be like this. When you onboard the medicine, it takes a little bit of time to down-titrate the glucocorticoid. When you think about explaining what the disease is, and then ultimately how would you onboard crinecerfont, I think there's a question of how is this ultimately going to be adopted in the real world. Now, in the clinical studies, what we saw is a significant reduction in androgens, a significant reduction in glucocorticoids.
And I think from any parent, so just put it back to the patient now, any parent, if you said, "We can reduce your glucocorticoid dose for your child for their entire lives potentially by putting a new drug on board that is safe," I think every parent would say, "Absolutely, we would want that." How is it ultimately going to be adopted? It's going to take a bit of time, a bit of trialing, but ultimately we do expect that a large portion of patients will benefit from a medicine like crinecerfont. And as Kyle said, there's been nothing in this class for over 70 years, and they've just dealt with taking really high-dose steroids or living without control of androgens. And so there's been no alternative, no option. There's a lot of hope right now for patients, and it's something that we're quite enthusiastic about at Neurocrine.
Yeah, I think a lot of individuals in the area we get really fixated on understanding specific aspects of the data, but something that we all are able to understand is that high-dose steroids, they're bad for the brain, bad for the bones, and bad for the heart, and that's all something that we all recognize, and ultimately, patients are going to end up able to lower their reliance on glucocorticoids over time, and that's an easy story to tell.
Sorry, since we have 45 minutes, I'll say one last piece is on price. I think price is also a question. I think it's in current consensus. It's in the low $100s type range. What I've guided to is that the price point, when you look at small molecules for non-disease modifying rare diseases, the recent launches have been between $100,000 and $500,000. So we're, of course, going through the value work now to establish what the price point would be that would ultimately be adopted on commercial plans and then ultimately by patients. So that's one variable that, of course, shortly after launch, the street will know. Recent pricing of rare disease medicines have ranged between $300,000 and $600,000 and some. So I think there is support for the value, and there'll be support by the commercial markets.
Right. Okay. So we're eight minutes in, and I've asked one question, so it's probably good we had the 45. [crosstalk] But you did anticipate my pricing question, and I do think we are probably quite conservative there. So I think it's an important lever in the model. So the CAH population seems like it's pretty spread out. Does the team have a good idea on where these patients are located and how these demographics might impact that launch cadence you're talking about?
Yeah, so you have around 20,000-30,000 patients. They are spread out, Cory, to your point. And they're being primarily treated by the local endocrinologist. So these local endocrinologists will maybe see one to two patients in their entire career. So there's an aspect that that's a challenge to initial adoption. However, there are a subset of patients, call it 15% or so, that are being seen at the Centers of Excellence. There's 25 sites that we call Centers of Excellence or Centers of Almost Excellent as deemed by the CARES organization. And so that's where the initial concentration of adoption, I think, will be is at those specific Centers of Excellence. One of the good aspects of this launch is we've been able to put our sales force in place in July.
So they've been out for six months in advance of the launch, really just understanding how the disease is being treated, understanding where patients are at, even at the local endocrinologists. And they affirm what I just shared earlier is there is significant demand from patients. There is significant demand primarily from pediatrics and then secondarily women. So as you think about how does this translate to an adoption curve, I do think there'll be trialing at the Centers of Excellence specifically within pediatrics. I think that these clinicians will get used to onboarding the drug, and then how do you titrate the glucocorticoid on the back end of that? And then I think from that natural success, I think that then there'll be a good mouthpiece to those local endocrinologists in terms of how do you treat a patient with CAH.
These patients only come into the office one to two, maybe three times per year, so there's also that natural flow that will impair the launch. But coming out of 2025, we would expect there to be a very nice trajectory for this medicine.
Okay. This is the case with any novel therapy. The pre-launch educational efforts and everything are very important. You talk about having a field or having sales force in the field for the last six months or so. How's the feedback been both directly from the sales force as well as from your overall market research, and how does it differ between those Centers of Excellence and that broader community where they only see a patient or two in their careers? I mean, I would imagine any physician would see something like this, and when they haven't had a therapy for 70- plus years other than steroids, they would be excited about it, but are there any nuances in the feedback that you're getting?
Yeah, that's the feedback that we're getting from our teams in the field, at least. And if you talk to someone like Dr. Rick Auchus, who led our adult study, super excited to have something for the first time ever in his career to treat this condition. As I'm thinking about modeling too, he thinks that crinecerfont could be a treatment option for up to 80% of the patients that are out there. So everything that we're hearing externally has been positive. I think you're hearing that also in the sell side and buy side doc reports when you're talking to endocrinologists, particularly the folks that are at the Centers of Excellence. And it's going to be important, particularly one of the toughest parts about the launch is to reach these local endocrinologists who, as Matt said, only see maybe a handful of patients during their practice time.
And so they rely heavily on the key opinion leaders. But so far, everything we're hearing is good.
One of the nuances that I think comes through loud and clear in the conversations with the local endocrinologists is if they get a patient with CAH, it's not the primary focus of their practice. And there's a lot of tinkering involved in managing this disease. When you draw blood, how do you then translate that to tinkering with the glucocorticoids when you draw blood again? And there's an art to this. It's not a science.
So those local endocrinologists, and we expected this, but it's just reaffirming that when you talk to them about treating CAH patients, it's a nuisance/ they're intrigued by it. And so typically what they're doing is texting or messaging with KOL at the Center of Excellence saying, "What should I do? What are your suggestions? Should I switch up how they take the glucocorticoids in the morning or higher doses at night?
Spread it out four times per day, 3x a day." So there's a lot of tinkering involved, so one of the pieces that crinecerfont, our hope is, solves from this ultimately is that if you can get a patient more stable, there'll ultimately be less complexity in having to treat this patient.
I think that's the long-term hope that a local endocrinologist can effectively treat a patient with CAH. So that, I think, is one of the aspects that we're just continuing to learn, and then the importance of these Centers of Excellence and how reliant the local endocrinologists are on their ultimate feedback and how they advise.
I mean, I can tell this is going to be an educational launch so that we can grow some.
I think the interesting piece here on this, it just reinforces the benefit of being able to treat children at the youngest of all ages because that's where you start the tinkering today with glucocorticoids. If you're able to start them with crinecerfont at the beginning, then there's only one tinkering episode, if you will, that occurs at the youngest age, and they're able to just modify their treatment of these two different medicines ultimately as they age versus now, if you think about an adult patient coming in, they've already done the tinkering when they were first diagnosed many years ago, and now they're going to have to readjust their baseline with crinecerfont on board, so those are the things that we're working through, but it does speak to one of the many advantages of being able to treat children.
So you mentioned the prevalence numbers that are out there, and they seem pretty consistent. Do you think that's going to be the case as a new therapy gets launched into the market? Are these patients, have they been identified by ICD codes? Is it pretty well established, or do you expect it to maybe be like we've seen with a lot of other kind of orphan launches where it turns out to be kind of meaningfully larger than maybe we thought it was going to be?
Well, it's an interesting question. One of the things that just to help level set, there's really no traditional ICD-10 code specifically for CAH. There's ICD-10 codes that capture CAH as well as some other endocrine diseases, so it kind of muddies the water in terms of the number of patients that have been diagnosed.
That being said, the real advantages of CAH versus something like Ingrezza is there is a genetic test. Most babies are given that test when born each year in the U.S. It's more the rare case that you hear about someone that goes in their adolescence or in adulthood and then gets a diagnosis later at that stage. I think if you look at genetic studies, you triangulate based off of projections to that 25,000-30,000 number that we see out there. The next layer that you go to is those patients that are diagnosed. We know from the CAH advocacy group that they've identified about 68,000 patients and families with CAH, and that's something that you can lean on to start on out of the gate in terms of patients that are in the system and what they look like from a care perspective.
The next piece that you go to is you look at medical records, you look at interactions that physicians have had with diagnosed patients to understand what those patients look like. And you can actually get a feel in the claims databases about how many patients could be potentially out there. And of course, we also try to understand more beyond that just by working with the physicians, with the sales force that we have out in the field doing education now. All those things will help us ultimately when we launch. I think it will be really interesting to see if that phenomenon that we have seen with other medicines drive more patients to get a diagnosis and the number is higher than 25,000 or 30,000.
But right now, we're really comfortable with that dynamic and with the piece I think that you mentioned, Todd, that out of the gate, we think that 80% or more patients could benefit from crinecerfont.
Right. Okay. Just a couple more on CAH, and then I promise we'll move on. Given everything we've talked about so far, what do you see as the biggest risks for the launch outside of people sitting in seats like mine, getting out over their skis in terms of early expectations, but more fundamental risks to the launch? What do you see them as?
I think commercial insurance access is going to be one of the initial hurdles that we're going to have to get through. This is going to be a high-priced medicine in a class where there's not a lot of patients, and so it's on us to ultimately ensure that where we price it and ultimately getting it on formulary is going to be a key aspect, so with that comes, you write a prescription. What's the experience going to be of that clinician getting that ultimately to patients, and so if there's these commercial insurance challenges, having things like a quick start program or an early patient assistance, free goods program is going to be something that we're focused on out of the gates because it may take a couple of quarters to ultimately get this medicine on formulary.
So that's one that we're spending a lot of time with and understanding what are some of our risks and how can we ultimately mitigate that. I think the second piece is just purely just going to be that basic blocking and tackling. Once a patient is on medicine, how do you ensure that they stay compliant to that medicine? And then what's the relation to the glucocorticoids? So I think that KOLs are going to be incredibly important in this regard. I think our specialty pharmacy patient service hub is also going to be an important element of engaging with patients throughout this entire journey.
But I know we've dedicated a lot of real estate to this, but I would just say thank you for doing that because this is a meaningful launch for patients and then also a meaningful launch for Neurocrine and really diversifying our revenue base and helping another subset of patients out there.
Yeah, my only other two cents on this, Matt, is on the patient front. We talked about the most motivated patient group will be the kids and their parents and then women of childbearing years. I think the tougher part will be the older patients who are in their 60s who have only known one way of treating this condition, and you're going to have to fight that complacency to help them understand that there is still a benefit in being able to control your androgens and reduce the level of glucocorticoids that you're going to take over your lifetime, so that's going to be tough.
So we're going to get to the pipeline in just a few minutes, but as it kind of is interrelated with this, assuming this is approved later this month, would you look to keep the PRV you'd get, or would you monetize it?
Yeah. That's a great question. We've seen some of the dollar values go up on some recent PRVs. I think right now, let's get approval. That's a good question to ask on the other side of that. But we do have some programs in phase III right now or moving into phase III, 845, and 568 that you could think about potentially using that to accelerate review. So I think we'll get the approval hopefully later this year and get the medicine launched, and then we'll have that good discussion internally.
Okay. And then the last thing I want to make sure I work this question in because there was quite a bit of buzz earlier on in the summer about potential competition in this field down the road. Natural way to distance crinecerfont from competition would be to have longer-term data demonstrating meaningful benefits and everything else. So along those lines, any just sort of broad-based thoughts or specific ones on how this competitive kind of landscape could evolve over time?
Well, I think touching on a point there, we do have our Open Label Extension program still ongoing. We had over 95% of the patients that were in the placebo portion of the phase III's rollover to the open label extension. We think that's going to be a valuable source of long-term data that no one has.
We're currently looking at the data and when we'll have that over time. But right now, that's a study that continues to run, and we're going to learn a lot about the disease state in the care of patients with crinecerfont as that study continues. In terms of the competitive standpoint, I'll go back to my opening remarks. We operate upstream in the HPA axis. The competitor in the space, Crinetics, which we know very well and respect that team there. In fact, I've worked with many of the people there at Neurocrine many years ago. They work and operate downstream in the HPA axis on the ACTH receptor. We think that we have a better approach to this in the sense that we're able to control everything from the pituitary down, including ACTH and the androgens.
We believe also that normalizing these two elements of ACTH and the androgen is the key for long-term care of these patients versus putting them into a state where they may have very little to no androgens. That's not one that we aspire to our patients to have and think that can be deleterious over the long run. Androgens actually serve an important role within the body. So I think that time will tell. We have a nice first mover advantage, if you will. I think three, four, five years on the market before another medicine would come in there, whether it's Crinetics or any other programs in this disease state that may come down the road. But ultimately, where we land today is that we've got great efficacy data. We have great safety and tolerability data in over 1,000 patients, well over a year on crinecerfont therapy.
If we do get approval later this month, we'll have an indication statement that allows us to treat anywhere from the youngest of children to adults and two formulations to match the needs of these two different patient segments. And we think that really puts us in a nice leadership position.
Okay. Great. All right. So now finally, moving on to Ingrezza. Maybe to start there, can you just update us on how the sales force expansion is going and the impact that you're seeing in the marketplace?
So the sales force expansion's going well. We completed it this quarter. So there's always noise around an expansion. There's disruption that occurs to the organization, the sales organization in particular, as you bring people out of the field to train and then put them back out, in particular the new folks.
We'll start really seeing the payoffs of that occur around the middle of next year. Why I say middle of next year is we all know that Q1 is a difficult quarter for specialty products as you go through the reauthorization period and reset that happens each year. I really expect to see our efforts here really pick up in the Q2 timeframe of next year. What do we look for? What we look for is call frequency to go up with the sales force. That ultimately translates to, in a fashion that we know pretty well from a timing standpoint, NRX is increasing as well. There's kind of a leading indicator there and then the ultimate lagging indicator, which is in prescription volume increase.
The real rationale for the sales force expansion really goes back to just reminding of the success that we had in Q3. We saw sales revenue for Q3 of $613 million. Seven years into launch, that's 25% year-to-year growth. It's such a robust marketplace for us and even our competitor. Both brands have grown quite significantly over the past seven years. And on top of that, we've been working for several months updating our epidemiology within tardive dyskinesia specifically. Now, for those of you that don't know TD, tardive dyskinesia, it's a movement disorder caused by the long-term use of antipsychotics. And interestingly enough, the growth rate of antipsychotics doesn't track the growth rate of the general population. In fact, it's multiples higher.
There were 75 million prescriptions written last year of antipsychotics, and it continues to grow, not in terms of the number of indications they're being used for, but the number of prescribers that prescribe them. We appreciate all that, and we culminated this knowledge base into an update of our epidemiology that increased the TD market from 600,000 to 800,000. While we've been making great strides diagnosing patients, what it meant is we're a bit off on the number of patients that are actually on a VMAT2 inhibitor today, and that's the mechanism of Ingrezza. Only about 85% of patients with TD are not on a VMAT2 inhibitor. We've made some strides, but we've got a lot more work to do. With that work comes all the opportunity. With the great Q3 sales, we increased our guidance to $2.3 billion-$2.332 billion.
If you marry that to the growth opportunity that remains, we think this is a good time to expand the sales force to increase ultimately the awareness of the disease, which will translate to improved diagnosis down the road.
Corey, I joined the company seven years ago, and most of the conversation was around elagolix for endometriosis and what that royalty would be. I think peak for Ingrezza at that time of launch was maybe $400 million or $500 million. Sitting here thinking about a $600 million quarter, a multi-billion-dollar medicine, and I think one of the key stats is 8 in 10 patients are not being treated with their tardive dyskinesia. A significant market opportunity ahead. Everything that we can do from a promotional sensitivity perspective, that call frequency that Kyle mentioned, is extremely important. It does take a little bit of time to kick in, but ultimately, what you're looking for is an NRX per rep that gets back to where people were prior to the expansion. As Kyle said, that is typically a Q2, Q3 type timing.
So it is amazing that seven years in, still growing 25% year- over- year, and yet it's still 8 in 10 who are not getting this type of product. What needs to happen to get that so it's 5 in 10 or some other much smaller number? And where do you think it ultimately could get to?
Yeah, it's an interesting question. I mean, hindsight's always 20/20. And if you knew what the market could be at the time of launch, we probably would have started with the sales force size that we have today because it really does require that type of reach and frequency to drive awareness and diagnosis. And by that, over time, what we've seen in terms of how we've utilized the sales force is the prescriber base has gotten larger, wider, broader. So to keep up the same type of call frequency for the physicians that are prescribing, you need to have a larger sales force. The other piece that we've done and seen over the years is the value of calling on physicians within long-term care facilities.
That's something that's an inch thick and a mile wide in terms of how much coverage you need to get out there and speak with the physicians that are in these long-term care facilities. Over 1,500 in the U.S. I think the sales force allows us to do that now in a more meaningful way and with the frequency that we need to break through some of the headwinds that we see in the TD category. In terms of where we can ultimately get, obviously, we're not going to be able to treat all patients with TD. I think that you look at other chronic diseases.
I think you could certainly multiply or get a multiple of where we are right today in terms of 15% on a VMAT2 inhibitor down the road. That's why this type of investment, where we are now, 14 years of more patent exclusivity leads us to want to try to accelerate that as quickly as we can.
The two primary dynamics that you're trying to solve here in terms of how do we evolve the market, the first one is these are patients primarily being seen by psychiatrists, and you're asking them to diagnose a movement disorder.
By and large, those clinicians are thinking about the schizophrenia, the bipolar, major depressive disorder. That's why call frequency matters so much is just to keep thinking about the secondary or third item that may be on a psych's list or an APP's list. Just make sure TD stays on the radar and that they're comfortable making the diagnosis. That's the impetus of why do you extend the sales force?
The second aspect then is on the patient side. A patient has these weird movements. They may have no idea where they came from, and the thought of asking your psychiatrist about a movement disorder is like asking your dentist to check out your ankle, and so I think the direct-to-consumer advertising campaign and a lot of the other communications, that's trying to get at that angle, so that's how we think, just generally speaking, when we make investments, if we're looking at returns on those investments, we're really thinking about cracking the code of confidence by the clinician to make the diagnosis and keeping it on the radar and then having patients actually be encouraged to talk to their doctor about it. Because many times, if they don't talk to the doctor, the doctor doesn't think it bothers them, and so they're not going to ultimately prescribe.
It's an interesting market. I mean, it's something that we've used this description as a learning launch since really 2017, but there's a lot of aspects of that that are still relevant today. COVID, from a telemedicine perspective, has made that really be entrenched in the psychiatric community. And that's really difficult to diagnose a movement disorder where you need a high-fidelity in-person interaction to see that. And working through that telemedicine piece is best addressed by keeping TD top of mind with physicians, and that's done by frequency of interaction. The other piece to that goes with an appreciation that a lot of psychiatrists, if they're at home doing telemedicine, they're relying a lot of their office work to be run by nurse practitioners, and there's significant turnover there.
So as you do your education with one nurse practitioner during one visit, and your next visit, there could be a new one. So you're starting your education all over again. You can cut that time down by increasing your frequency of interactions, and that's where the sales force comes into play there as well. And then lastly, it's amazing after APA guidance recommending VMAT2 inhibitors as the way to treat TD, physicians still lean on reducing their antipsychotic dose, replacing it with another one, or removing it before thinking about a VMAT2 inhibitor. So again, keeping TD top of mind with the sales force being out there, being more frequent in their visits all plays into increasing awareness and ultimately diagnosis.
Got it. All right. One more on Ingrezza's. Assuming Austedo is selected for price negotiation under the IRA, what do you think the impact might be on the Ingrezza business? And are there kind of levers that you could pull to avoid leakage into the commercial side?
Yeah. It's a question that we get a lot because it's an interesting dynamic that we have that we haven't fully seen work out with the first round of 10 medicines that were negotiated. That is, what happens in a two-product category where one product is negotiated, but there's another brand that's not negotiated? That's the situation that we're talking about here. And I guess where I'd start on that is that we have an analogy of that today on certain plans. But it all begins with the appreciation that Ingrezza is a very sticky medicine. There's a very high compliance and persistency among patients that are taking Ingrezza. Once they're on it, they tend to stay on it. And the reason why is once you go off the medicine, you can actually see your movement disorders come back. That's a very tangible way of knowing that the medicine works.
So, we're really talking about the incident patient population, the new patients that would be diagnosed with TD, what happens with those if we're talking about a plan where Ingrezza is disadvantaged. And in those situations, which we deal with today, and there are some other plans where we're advantaged and deuterated tetrabenazine is not, there is always an exemptions process that we can go through and get our medicine in the hands of patients. And I can lean on today we have over 80% of our medicines are fulfilled regardless of formulary status. For those patients that go on to get their medicine, their copay is less than $10 per month. So we have experience fighting through these points of disadvantage, and we expect that to continue to play out for us ultimately down the road when deuterated tetrabenazine is negotiated.
All that being said, there's still a lot to learn about IRA between now and when Teva goes through their price negotiation. When we go through our price negotiation, there's a new administration coming on board. How that's going to play out and all this is to be seen. So we're going to sit back and we're going to learn a lot over the next couple of years. We're going to be able to plan our best approach for writing through our own negotiation later this decade, and we're going to continue to strengthen the company across their investments within the portfolio as well.
Okay. All right. So let's transition over to the pipeline. I definitely have some questions on both your MDD program and schizophrenia. We'll start with MDD and the AMPA program. And I guess first things first, when do you expect to present the phase II results beyond the top line that we saw last spring? And you had some detail in there. How much more do you think investors will be able to learn about that program and its potential when you do have the full phase II results out there?
Yeah, I think maybe I can tackle two questions there rolling up into one because I think we get the same question for NBI-568 as well.
Yeah, it's on the list.
[crosstalk] So I think in terms of both data sets, we're looking at the right way to provide additional data for both of the studies, phase II trials, sometime next year. We'll solidify a plan on that here shortly and share that with you all, but we'll be getting more data out there in the not too distant future. In terms of the 845 program, just a reminder, the phase II study results that we saw that came out in Q2 of this year, it was a phase II trial that had about 180 subjects, two doses of actives versus placebo, and the primary endpoint was the MADRS measure at one month, the secondary being the MADRS measure at month two, and then we had some additional secondaries that are standard within this category.
With the dose that outperformed, performed better than the second, we saw a placebo-corrected MDRS improvement that ranged from 4.5 to about 7.5 points, which is pretty remarkable going from one month to two months, and that corresponded to an effect size of 0.55-0.75. The other dose also active. We saw a placebo-corrected MDRS improvement of about 3-3.5 points from month one to month two with an effect size of 0.35-about 0.4. So both doses are very robust. We've seen many companies make investments on those types of benefits versus placebo the past couple of years. We think this is an approach that's been validated through the ketamine NMDA pathway where the AMPA receptor operates downstream of NMDA. It's just been a really difficult target for many companies to tackle over the past 20 years.
A kudos really to Takeda for sticking with this target. This is the second molecule that they brought forth to the clinic and literally learned a lot from the molecules that they discovered and developed over the past couple of years to get this one with hopefully has all the right characteristics for us to win in phase III and for patients. Overall, the data set looked really good from an efficacy standpoint. On the side of safety and tolerability, the only thing that stood out relative to placebo was headache, and it was pretty nominal in this patient population. The next steps here with 845. Then next couple of months we're all set up into phase II meeting with the agency. If that goes favorably, we'll be starting the phase III program next year. Being in the largest disease state, MDD, within psychiatry and outpatient study, this is something that with a phase III start in the first half of next year, we could have data in a two-year time point.
Okay. So another question that probably overlaps both of these neuropsych programs is I think one of the strengths of the phase II is that it did demonstrate that really nice effect size, but it also had data coming from 40-plus sites and some international ones in there, I believe, as well. And it's kind of similar to the muscarinic phase II in terms of being a robust study. Does this in any way help kind of counter the unpredictability that's often seen in CNS drug development? And maybe what other things could you do to help kind of better understand the behavior of these products as you move them into phase III?
Yeah, it's an interesting dilemma that we have in psychiatry and how to limit some of the variability that you see going from phase II to phase III trials. And just as a reminder for the depression trial, this is a traditional outpatient study where medicines are delivered to patients and they take them through the course of their everyday life. The muscarinic program was an inpatient study, so the patients were actually in a hospital-like setting for six weeks. So they have their own differences in terms of the variability that you introduced to the study. But the things that we see that triangulate to the best outcomes ultimately is managing the clinical sites conducting the studies very carefully. And for muscarinic, for example, and I'm going to kind of blend both of these programs together, we actually oversaw those studies, that study ourselves.
We didn't use a CRO. And that high-touch white glove interaction, we understand speaking from the sites, was something that they valued. They always knew who to call and who would reach out to them when there was a question, and that was done very quickly. So management of the oversight, management and oversight of clinical sites is very important in these psychiatry trials, and that's where we'll certainly over-index in both the MDD and schizophrenia trials. The other one is managing placebo effect and expectation bias. And it's also intertwined with these different things that we've learned. But for the muscarinic program, I can't think of a phase II trial that had more expectation bias built into this category overall as we saw during the course of our phase II trial. You had two companies being acquired for $10 billion-$15 billion.
You saw positive data come out of their own programs, and we're all using the same sites because these hospital-based acute studies are really limited in the number of sites that you can utilize in the U.S. So all of this was going on, and yet we were able to maintain a pretty good placebo effect in our phase II trial for the muscarinics, which leads me to the last interconnected piece, is trial design. So whether you're talking about 845 or the muscarinics, you really want to have a very simple trial design, one-to-one active to placebo, a parallel design, meaning all the doses are being started at the same time. There's no sequence effect that you see, and really not talking up about the data a lot out there. And that is something that we believe was very helpful for us in 845.
I think there was no expectation that an AMPA potentiator or an AMPA PAM would work in MDD. And I think we did a good job of keeping that chatter, if you will, to a minimum, and we saw some very spectacular results. So when you talk about when we all talk about when are we going to disclose data, we do have that in the back of our mind. How much do we want to disclose and what type of venue? Because we don't want to add to that noise ultimately as a variable in phase III.
Yeah, it makes a lot of sense. Specifically on the muscarinic pipeline, I mean, I'd say the industry was pretty shocked with the outcome of the emraclidine data, the trials. What were your biggest takeaways from that, and how did those results impact the outlook for your own M4 program, if at all?
Yeah, maybe I'll start by saying sometimes maybe change isn't a good thing. We saw a lot of changes from the emraclidine phase I- B trial to their phase II, III trial. Whether these played a role, we have no idea. We're not knowledgeable about the data sets. I'm sure AbbVie's poring over all the data, but you start with the trial went from a very pristine five clinical sites, 80 subjects to one that had 25 clinical sites, 375 subjects. You went from a study that was only in the U.S. to a study that incorporated sites in the U.S. and Europe. The company was acquired during the conduct of the study. So when you talk about management oversight of clinical sites, you wonder how that played out during the course of an acquisition. We also know that Cerevel and AbbVie used multiple CROs.
So again, that management oversight is an issue. All those things can still be there, and you can still get a positive outcome. But normally you wouldn't like to have all those things changed during the course of a small phase I-B trial to a larger study. So that could be a factor in something that they're considering as rationale for the outcome of the study beyond a biological one. But at the end of the day, we really like the data that we have for our own program, and we view this situation more as a gift. We have the opportunity to leapfrog a program that was ahead of us and become second to market with a molecule that's both selective and directly activating M4, which we think is important. That is an orthosteric agonist. And the data that we saw in phase II was impressive.
Just to tick the boxes here, on a 20-mg dose, we saw a total PANSS improvement of over 18 points, a placebo-corrected PANSS improvement of 7.5 points with an effect size of 0.61. Those three measures in and of itself puts it in really rare air relative to all the antipsychotics that have been approved the past 20 years. And then you layer on things that differentiate over COBENFY today, once-a-day dosing, no titration, no food effect, good safety, good tolerability. And we think we've got a really nice medicine that can fulfill the needs of a lot of patients with schizophrenia, not too far behind, but we need to get the phase III started early next year as quickly as we can.
Okay. And I realize this is all speculation on what drove the disappointing outcome for emraclidine. But one of the things that's been hypothesized in addition to the change in control and the trial conduct is this idea of also targeting M1 or needing to also target M1 on top of M4. What's your take on that? And on that front, when could we see phase initial data on your own M1, M4 asset?
We really are in an enviable position in the sense that not only do we have a selective M4 agonist, we actually have an M1, M4 dual agonist that's not too far behind 568 in phase I development, so I think the message is that, and I think we all appreciate this, is that no one's really studied the pharmacology of selective molecules versus dual, and we're going to be the first company that does that. In terms of where M1, M4 ranks relative to 568 in efficacy and schizophrenia, time will tell. I mean, I like the data that we have coming out of the phase I study, but ultimately we're going to have to take that into a patient population and we'll be able to answer that question.
And that's something that we'll look to start next year with all the phase I data coming through on our dual agonist, which is NBI-570. The other piece of that, just to give everyone some context, if you put xanomeline in, albeit in animal models of schizophrenia, we have to take it all with a grain of salt. And we compare that with efficacy data with our selective M4 agonist or even our dual. They all get to similar levels of efficacy. Now that's in an animal model of psychosis. It's not the human condition. And there may be incremental benefit of having M1. We'll see. Fortunately, we're in a situation, as I mentioned, that we can test that hypothesis. If there is an advantage, we're more than happy if we're lucky enough to move 568 to commercial and 570 to commercial to eat our own lunch.
Got it. Well, unfortunately, we are out of time. All 45 minutes are gone. I didn't even get a chance to ask Todd about his favorite concert and his best round of golf in 2024. So they're out of the way.
Next time. [crosstalk]
Thank you guys. Appreciate the time.