Nxera Pharma Co., Ltd. (4565) Earnings Call Transcript & Summary

Good day, everyone, and welcome to today's Neurocrine Q3 update. [Operator Instructions] Please note, today's call will be recorded.[Operator Instructions] It is now my pleasure to turn the conference over to Todd Tushla. Please go ahead.

Thanks. Good morning, and welcome to Neurocrine Biosciences' conference call to discuss the positive Phase II study results for NBI-'568, a highly selective M4 agonist for the treatment of schizophrenia. I'm joined on today's call by Kevin Gorman, Chief Executive Officer; Eiry Roberts, Chief Medical Officer; Kyle Gano, Chief Business Development and Strategy Officer; Jude Onyia, Chief Scientific Officer; Samir Siddhanti, Vice President of Business Development and muscarinic agonist Team Lead; and Jaz Singh, Vice President of Psychiatry, Clinical Development. Kevin will kick off the call, then hand things over to Eiry, who will walk through the presentation that was posted earlier on the Investors section of the Neurocrine website. Following prepared remarks, we'll jump into Q&A. Before we begin, we will be making forward-looking statements. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to review the risk factors discussed in our latest SEC filings. So now, Kevin, take it away.

Thank you, Todd. Good morning, and I promise this is the last time you have to deal with me. It's an understatement to say how pleased we are with the results of our Phase II study with NBI-'568 to remind you, our selective M4 agonist for the treatment of schizophrenia. This was a dose finding and safety study in our target patient population, and we clearly identified the 20-milligram dose is very effective and well tolerated. Additionally, and importantly, we demonstrated that higher doses were also safe and well tolerated. Now a few things that I'd like to say before turning it over to Eiry and the team for the real details. First, this promise. We're providing you with quite a bit more data than we typically provide for Phase II results. Why? Because we are well aware that in this patient population, different audiences place different importance on the description of the PANSS primary M4 endpoint. What I mean by that is physicians tend to focus on absolute reduction in PANSS from baseline. Other stakeholders focus on placebo adjusted and most looked at effect size is the unifying analysis. Therefore, today, we are going to speak to all of them. The second, these results nicely confirmed our hypothesis that we had going into the study that the 20-milligram dose was likely to be an efficacious and well-tolerated dose. Now we note that the higher doses did not display a dose response. And this is a finding that is not uncommon in approved psychiatric drugs. Why do we see flat or inverted new dose responses in psychiatric trials? There's no definitive answer. We in the psych and the psychiatric community are not without a number of possible explanations such as it may or may not be due to the receptor system being studied, may or may not be due to the effector molecule being an agonist and may or may not be due to a trial design. Ultimately, it could be one or more or none of these explanations. But regardless, this off observed finding does not complicate it or detract from our robust efficacy and safety data set for the 20 milligrams, which we will now rapidly move into pivotal clinical trials. Additionally, and as you can imagine, these results further strengthen our conviction and enthusiasm around the possibilities for our entire muscarinic portfolio across multiple disease states. Finally, I just want to congratulate Eiry and her team. I want to congratulate Samir and Jaz working hand in glove with one another throughout this entire clinical program. And I want to congratulate Kyle, and again, Samir as the BD team as well as our partners at Nxera for this very successful outcome. Now with that, I'll turn it over to Eiry.

Thanks, Kevin, and good morning to everyone joining us today. I'm excited to be able to share with you the top line results for NBI-'568. As background, NBI-'568 is a highly selective M4 agonist that Neurocrine in-licensed from Nxera Pharma, formerly known as Sosei Heptares. Shortly after in-licensing, we began a Phase II dose-finding study with the goal of identifying a well-tolerated dosing regimen with a competitive efficacy profile to progress into Phase III testing in schizophrenia and other indications. I'm pleased to say that with the results now in hand, we have achieved our goal with a positive outcome for this study. On Slide 4, you can see that the 20-milligram once daily dose demonstrated statistically significant and clinically meaningful improvements across the primary endpoint and other key measures. This included a PANSS total score improvement of 18.2 points, a placebo-adjusted pan improvement of 7.5 points and an effect size of 0.61 at week 6. Treatment with NBI-'568 20 milligrams once daily dose also resulted in statistically significant improvements in additional endpoints, including Clinical Global Impression Severity Scale, and both the Marder Factor Positive and Marder Factor Negative subscales. NBI was also generally well tolerated across all doses tested. This was reflected in low treatment discontinuation rates due to adverse events, which was similar across all 568 doses and placebo. Adverse events with highest incidents, namely somnolence, dizziness and headache were generally mild and moderate and were consistent with those seen in Phase I studies. No new safety signals were identified in this patient population. Additionally, GI-related side effects, including nausea and constipation, were low in frequency and similar for all NBI-'568 doses versus placebo. Finally, NBI-'568 was not associated with a greater increase in weight versus placebo. In aggregate, the combination of the efficacy, safety and tolerability profile, combined with a convenient once-daily dosing regimen administered with or without food provides a compelling profile, supporting the advancement into Phase III development for NBI-'568 in schizophrenia beginning in early 2025. In addition, we plan to evaluate other potential indications for NBI-'568 as well as advancing follow-on compounds in our muscarinic agonist portfolio. I'll now dive into more detail on the clinical trial design and results starting on Slide 6, where you'll find a general overview of the NBI-'568 Phase II study. This exploratory dose-finding study was designed to achieve 3 main goals. Firstly, to identify one or more doses with compelling benefit/risk profile for advancement into Phase III clinical trials. Secondly, to evaluate the efficacy and tolerability of higher doses in patients with schizophrenia up to a maximum of 60 milligrams per day. As a reminder, previous Phase I studies with NBI-'568 had evaluated multiple doses in healthy subjects up to 20 milligrams daily. And thirdly, we sought to evaluate the tolerability and efficacy of BID versus QD dosing in patients with schizophrenia. I'm delighted to say that we successfully delivered on each of these goals. This inpatient study enrolled adults with schizophrenia of at least marked severity as determined by the PANSS total score of 80 or above across 15 sites in the United States. After a screening and eligibility review period, individuals were randomized in a 1:2 ratio of placebo to active treatment. The double-blind phase of this study was 6 weeks in duration with a primary endpoint of change in PANSS total score from baseline to week 6. As you can see from the overview, there were 3 phases to this study. In the initial phase, subjects were randomized to placebo, 20 milligrams once daily or 40 milligrams once daily of NBI-'568. Those subjects were randomized to the 20-milligram once daily dose arm began their treatment on 20 milligrams with no titration. Those subjects who were randomized to the 40-milligram once daily received 20 milligrams once daily for the first week of treatment. Barring any safety or tolerability concerns as predefined in the protocol subjects would then increase dose automatically to 40 milligrams once daily at the end of the first week. The first interim analysis in the study occurred after approximately 12 subjects in each of the dosing arms had completed 4 weeks of study participation. During this first interim analysis, an independent data review committee reviews the unblinded safety and tolerability data from each of the treatment arms. Based on their assessment using a predefined set of criteria for next dosing options, the committee determined there were no tolerability concerns and added the 60-milligram QD dosing arm. The addition of the new dosing regimen to the study was done in a blinded fashion such that the NBI-'568 study team, study site or anyone who was actively engaged in the conduct of the trial or review of data, were blinded to any change in treatment arms. After interim analysis 1, subjects were then randomized between placebo 20 milligrams once daily, 40 milligrams once daily and 60 milligrams once daily. Similar to the 40-milligram once daily arm, those subjects randomized to 60 milligrams once daily was started at an initial lower dose of 40 milligrams once daily. Barring any safety or tolerability concerns, these subjects are automatically titrated to 60 milligrams once daily at the end of week 1. The second interim analysis occurred after approximately 2/3 of study participants had completed the week 6 assessment. At this time, the same independent data review committee reviewed unblinded safety and tolerability data from all active treatment arms compared to placebo, and made the assessment that there were no safety or tolerability concerns. As a result, as prespecified in their charter, the 30-milligram twice daily dosing arm was added for the remainder of the study. To maintain the blinding of the dosing regimen, all subjects were dosed twice a day throughout the study, with those subjects randomized to once daily NBI-'568 receiving placebo capsules in the evening. On Slide 7, looking at the baseline demographics and characteristics of study participants, we can see that the study was well balanced with no major differences between the placebo or any of the active treatment arms. These subjects are quite representative of what we have seen in similar inpatient acute schizophrenia studies conducted recently with other muscarinic agents. Please note that the PANSS total score baseline ranged from 95 to 98 across all treatment groups, which reflects a markedly to severely ill population. Slide 8 provides more information regarding the efficacy analysis. As described earlier, the 20-milligram once daily dose met the primary endpoint of PANSS total score change from baseline at week 6. As you can see here, the PANSS total score changes across all dose levels tested, drawing your attention though to the 20-milligram once daily dose we see a least squares mean change from baseline of over 18 points. And of course, the separation between 20-milligram treatment and placebo was minus 7.5, which is both statistically significant and clinically meaningful. These results led to an effect size of 0.61, which is compelling and highly competitive with other effective antipsychotic medications. Notably, in the other treatment arms, we did not reach statistical significance, though we do see trends towards improvement across all treatment arms. On Slide 9, we take a closer look at the PANSS total score change over time for the 20-milligram once daily dose. There were improvements noted as early as week 1 in this dosing arm with the placebo-adjusted change from baseline becoming significant, starting at week 3. The effect size is sustained through week 4, 5 and to the primary endpoint at week 6. The table on the right includes the least-squares mean improvements in PANSS total score at each of weeks 4, 5 and 6 as well as the difference versus placebo and the effect sizes of 0.53, 0.72 and 0.61 at week 4, 5 and 6, respectively. Turning to Slide 10. Not only did the 20-milligram once-daily dosing schedule demonstrate clinically meaningful and statistically significant improvements on the PANSS total score, it also demonstrated statistically significant improvements in other endpoints at week 6. This included the Clinician's Global Improvement (sic) [ Impression ] Severity Scale, as well as the Marder Factor Positive and Marder Factor Negative subscales. Slide 11 outlines the safety and tolerability profile of NBI-'568. I'm happy to report that NBI-'568 was generally safe and well tolerated at all doses studied. Treatment emergent adverse events occurring in 5% or more of the NBI-'568 all treated group are depicted on this slide. The most common adverse events included somnolence, dizziness, headache, nausea and constipation. I will point out that while we did include headache, given that it occurred in over 8% of patients -- subjects treated with NBI-'568, the incidence of headache was higher in the placebo group. Of note, the discontinuation rate due to adverse events was low at 5% across all NBI-'568 treatment arm versus 4.3 for placebo-treated subjects. Moving to Slide 12, let's discuss the differentiation of '568 versus other molecules in development or currently on the market. There are currently 3 different approaches in the clinic to target the M4 receptor. The first is pan-muscarinic activation (sic) [ pan agonism ], which non selectively targets the M1 through M5 receptors. This approach activates muscarinic receptors other than M4, providing the potential for off-target side effects. A second approach uses a positive allosteric modulator, or PAM, this approach requires the endogenous neurotransmitter, acetylcholine, to be present, which could pose a challenge given that we know acetylcholine levels can vary within patient populations and disease states. The final approach is the selective M4 agonism that we have with NBI-'568. NBI-'568 has 500-fold cell activity for agonist activity at the M4 receptor over other muscarinic receptors. It does not target the muscarinic receptors and therefore, could avoid off-target effects. Also, because '568 is an orthosteric agonist, there is no requirement for an intact cholinergic system as is required for a PAM. We believe that NBI-'568 new mechanism, combined with the strength of the efficacy and safety data from our Phase II study, could represent a significant advancement in the treatment of schizophrenia and other diseases where M4 activation may be beneficial. Slide 13 compares the effect sizes between the NBI-'568 Phase II study, other muscarinic targeting compounds in development and currently approved antipsychotics. As Kevin mentioned in the prepared remarks, many psychiatrists deal with effect size as a great equalizer as it factors both placebo-adjusted difference and standard deviation of the sample into consideration. On the left-hand side of the slide, we see the NBI-'568 effect of 0.61. This is compared with the effect sizes from the KarXT Phase II and Phase III studies as well as Emraclidine Phase Ib study. On the right side of the slide, we see effect sizes from currently available antipsychotics. What's exciting is that the effect size of '568 is similar, if not greater, than what we have seen with currently available medicines. Looking at this efficacy in combination with the safety and tolerability profile of '568 leads us to believe that there could be a large opportunity for NBI-'568 as a novel and differentiated asset in schizophrenia. Moving now to Slide 14 and looking at the broader portfolio. NBI-'568 represents the leading compound out of Neurocrine's 5 muscarinic agents in development, which includes 3 additional agonists and 1 antagonist. With these proof-of-concept data in hand, Neurocrine now plans to expand development of our muscarinic franchise in additional indications. We will also share more details of these programs in the future. In summary, I'm very pleased with the results of our NBI-'568 Phase II study. I believe we have demonstrated that we have a compound with a novel mechanism of action that is highly efficacious and well tolerated. The convenience of medicine that is administered once daily with no GI effects or weight gain relative to placebo is something that we believe could be attractive to both the schizophrenia patient population and to their supporting caregivers. We look forward to advancing NBI-'568 and our other muscarinic programs in development. Before shifting to Q&A, I want to thank all the participants in this study, their family and caregivers together with the sites that were instrumental in generating these data. I also want to thank our colleagues at Nxera and our internal cross functional clinical development team for their hard work and diligence which led to the success of this study. With that, let's open it up for Q&A.

[Operator Instructions] And we'll move first to Paul Matteis with Stifel.

As it relates to the nonlinear dose response, can you share any information you have on exposure across doses in both the periphery and the CNS? And is there any plateau exposure or anything that might explain why some of these higher doses are not separating or at the very least you know hypothesis might be that they're not any better than 20 milligram? And then I guess just like taking a step back, certainly, nonlinear dose responses have been seen in sight, but we haven't seen this for the muscarinic class specifically. What gives you the conviction here that the truth in the effect size for this compound isn't somewhere in between what you're seeing with 20 milligram and the other doses as you go into a bigger study?

Paul, thanks for the question. Look, we're aware of the nonlinear dose response curve is something that is off seen, as I've said in my opening remarks. And there are -- there can be a number of reasons why that is the case. And you're right, it hasn't been seen in the muscarinic class before. The other 2 that came before us particularly KarXT has been in development for 30 years. Many doses have been studied over that 30 years, they had a real good idea of where they were going to see efficacy after 30 years of trials. So I don't think that this was anything that couldn't have been, if not anticipated, but may be predicted in advance. This was a study that had several goals, one of which was to find an efficacious dose and elucidated safety profile -- and elucidated safety profile by going multiple doses higher. And in that regard, it was very effective. We may never know why in this particular molecule, this particular mechanism that we're using here why we saw this. But what is absolutely clear, and it is not -- is that the 20-milligram dose is a real dose. The effects we see with this because of the way we pounded the data, we've looked at it every which way. You see that it holds up all the way through, through every analysis we can put it through, meaning that you are seeing a reproducible response here that's on the primary endpoint. You're seeing it start to separate from placebo even as early as week 1. You see statistical significance between week 3, week 4, week 5 and week 6. You also see that on the other endpoints that we studied it's positive throughout now. It all hangs together and with a very nice effect size, which I think is really the great equalizer. So in that stepping back and taking a look at this, will we or any others ever have satisfying answers to these kinds of dose response curves and psychiatry? Maybe, maybe not. It's going to be from drug to drug, but it's certainly been seen. What really matters is do you have a dose that we have high conviction up in going forward, and we do. I'll let Eiry take the first part of your question.

Yes. I think it's pretty straight, Paul. We do not see a plateauing in exposure in terms of the pharmacokinetics. And what I will say is both in terms of peripheral exposure and central exposure from both our preclinical and Phase I data, we had confidence that the 20-milligram dose that we started the study with was going to be a potentially efficacious exposure in patients. As Kevin said, with respect to the dose response, it's really not uncommon to see a lack of traditional dose response in these types of trials. What was very encouraging to us, though, was the tolerability and safety at the higher doses that we saw, which we believe gives us a really clear path for the 20 milligrams into Phase III.

We'll move next to Akash Tewari with Jefferies.

So is there something about '568 being a direct agonist that could fully degrade the M4 receptor versus a PAM like Cerevel's drug that could explain that dose response or at least lack for up here? And if that is the case, what do you think we didn't see the same effect with KarXT? And now that you have the data in hand, are there plans to explore '568 in Alzheimer's psychosis? Are there other molecules that you're more excited about in that indication?

So what I would say is do we have any evidence that there's -- there could be an accommodation that takes place here desensitization that takes place there? No, we don't have any preclinical or clinical evidence that would suggest any of that is taking place. So whereas can't close the book completely on any explanation, there's really no evidence that we have in hand that would suggest that would be an explanation for this. As far as other indications that we're going -- that we're going to be going forward with, we have several others M1 preferring agonist that M1, M4 balance -- the highest conviction we have, however, is our -- is '568 in M4. And we're going to be moving that not only forward in schizophrenia, but we're going to be looking at other indications to move forward into as we move the other compounds through Phase I and into Phase II studies. So stay tuned for where we go with '568.

We move next to Anupam Rama with JPMorgan.

Just looking at Slide 9, it seems like you had an increasing treatment effect at 20 mg dose over time out to week 5, but then the 20 mg arm kind of maybe regressed a little bit lost 2 points on PANSS. Can you explain what happened between week 5 and 6? Or is that kind of just law of kind of sample size? How do we think about that?

Yes. It's kind of in-noise is our view right here that this is something you see. What I would say is that, what is most important here is the overall shape of the curve, again, repeating that weeks 3 through 6 are all statistically significant. You're not seeing that -- we don't have an effect through week 5, and then you get finally a downtick in week 6 that we show you a statistically significant. That's not what we saw. So honestly, I believe it's just the noise of the system -- the noise of these kind of trials. Eiry or Jaz, do you have anything else to add?

Anupam, I would just add, I totally agree with that. I mean, this is an interview scale that has a lot of variability in it from patient to patient and week to week. And so I think we believe that's within normal variability, and that's one of the reasons we were very confident in this 20-milligram dose and its performance over time through the trial.

I'll move next to Cory Kasimov with Evercore.

Wanted to ask you about difficulty in comparing across trials, especially with more and more known about muscarinic program. So on a placebo-adjusted basis, the PANSS score clearly doesn't look as impressive as the earlier studies run by Karuna and Cerevel. But then when looking at absolute PANSS reductions and effect size, it's more in line. So I'm just curious how you interpret the read across from your study to others that are out there?

It's always difficult to make cross-trial comparisons, but you make a very good point. And again, this is why we have a high level of confidence in what we're seeing at the 20-milligram dose here. If you look at the absolute PANSS reduction here of 18.2 at the primary endpoint, we believe that's highly compelling from an efficacy point of view. And we were also really pleased with the degree of placebo response that we saw because we think it's much more indicative of what we might actually end up seeing in Phase III. And there are several reasons why that might be. This was a somewhat different trial design being adaptive, it also had more centers than some of the previous studies that had been done and obviously, being the third in a class, we believe that the expectation bias out there was likely that this is going to be a positive trial. And so I think we were very pleased to see that placebo response. And as a result, we do get a 7.5 versus anything that might have been seen previously that might be somewhat higher. But looking at the absolute PANSS reduction and particularly looking at the effect size, we're really very confident in what we're seeing at that 20-milligram dose.

We will move next to Phil Nadeau with TD Cowen.

Your press release and the prior Sosei data on the compound referenced CV effects, but they weren't in your adverse event table and there's not a lot of detail on those. Could you go into a bit more detail what are the CV effects of '568? How severe are they and how long lasting?

Yes, I can take that. I mean they're not in the adverse event table because we really didn't see anything. And I think that was very encouraging for us that across all the doses tested in this trial, in particular, we didn't see a signal of hypertension that was clinically relevant or meaningful and neither did we see an issue regarding orthostatic hypotension, which we know has been seen before. So overall, from a CV safety profile, we were very encouraged by all doses within the study. And if you think about the fact that we're actually moving forward with the lowest dose that we tested, that gives us a high level of confidence.

We will move next to Brian Abrahams with RBC Capital Markets.

I appreciate all the detail in the presentation and the press release. In looking at the 20 mg QD dose, it does look like there were a few more dropouts in that dose relative to the others. I was wondering if you could maybe tell us a little bit more about the reasons for the dropout and describe how the PANSS data were imputed for those patients? And then secondarily, I'm curious if you had any patients allocated to the 40-milligram QD arm who weren't able to titrate up and stayed at 20 milligrams and how did those patients do on PANSS improvement?

Yes. Let me address the second question first. No, actually, all patients were able to titrate to the dose that was the assigned dose level. With respect to the dropouts, I mean, obviously, this is a small study. And if you look across the groups, we would expect a little bit of difference in the dropout rate across the groups. The definition of -- when people drop that is they have to actually have at least one post-baseline assessment in the study. And so when we actually look though at the impact of both dropouts in that sense, plus, any dropouts from the study related to adverse events or other findings, we do not believe that any of the dropouts drove or had an impact on the efficacy or tolerability outcome in the study.

We will move next to Joshua Schimmer with Cantor.

So I guess the 40-milligram dose arm had the initial 20-milligram lead-in for a week, and you did see a separation in the 20-milligram dose arm at a week. So for that -- for the 40-milligram patients who started at 20 milligrams, did you see any clinical benefit over that 1-week period? And then second, Kyle, the incoming CEO, love to get your impressions on the data?

Yes, I can answer the first one and then I'll will hand it over to my upcoming new boss. The reality is these are relatively small sample size. As we said, in terms of the number of patients that were looked at in the first interim analysis and looking at week 1. The -- they're comparable in terms of the effect that we saw. And as I said, then all of that group went to the 40-milligram dose level because of the good tolerability.

Yes. And Josh, just for me. I think for Neurocrine, we think about muscarinic alone or either with Nxera, we've been working in this space for over a dozen years. And there are a couple of reasons for this that today is so rewarding. One is if you think about INGREZZA and tardive dyskinesia. Here's a medicine that treats a disease that's caused by the long-term use of antipsychotics. And we've always had a long-term vision here in Neurocrine to offer patients that we serve today on alternative medicine that may be void of tardive dyskinesia in the same patient population. And we think we have the opportunity with the muscarinic and starting here with '568. The other piece that's exciting is that the efficacy that we have here is the table stakes, but with the safety, tolerability and the dosing convenience that we have here once a day, no food effect. These are all things that are going to allow us to pivot into other indications in different patient populations that require the safety and convenience of that once-a-day dosing. So we're very excited to be a part of this new class of muscarinic, antipsychotics, if you will, that will start with schizophrenia, but move into other disease states and other molecules that we'll be able to leverage M1 to M4 agonism. So I think this is the start of something really exciting here in Neurocrine and we'll be looking at a lot more development we're going to be starting with '568 in 2025 as well as the other compounds that we have in the portfolio.

We will move next to Mohit Bansal with Wells Fargo.

Maybe if I could ask one more question on placebo response. Was there any washout for the patient on the [indiscernible] could that have affected the placebo response? And then I completely understand your point about -- in real world now with the 2 muscarinic working, patients' placebo response could improve from here on. But how would you think about differentiating this asset compared to 2 front runners a few years down the line?

Well, let me start. So in terms of the washout yes, subjects were off their treatment prior to entering into the study. And so that is not uncommon in these programs. And I think it's consistent with other acute schizophrenia studies that have been performed recently. I want to reiterate, though, we were very pleased with the placebo response that we saw in this study because it is much more reflective of what we believe happens in the broader environment regarding these types of studies. And then with regard to the second question, can you just repeat the second question for me?

I'm just trying to...

Yes, I'm sorry. So from a differentiation point of view, I think we believe we have a very compelling benefit/risk profile here. And really, that includes both the strength of the efficacy data in terms of the PANSS reduction at both absolute and the effect size and also the tolerability and safety profile, as Kyle alluded to.

Yes. Maybe I'll just add to that. I think what we see out there in the muscarinic class is that there are 3 different approaches for activating this muscarinic system. For me being in the space for 20-plus years, I've never seen 3 entirely different approaches try to activate a particular pharmacology as we see here with muscarinic today. If you start with one approach, you've got KarXT out there that has a pan agonism approach that has off-target effects in some of the muscarinic subtypes. The solution here is to add back a pan-muscarinic antagonist that blocks some of the side effects associated with this off-target pharmacology. It's not a perfect fit. So you get some of the safety and tolerability concerns of the agonist in some of the safety and tolerability concerns of the pan antagonist. It's also twice a day. And the elderly we've seen in different patient population its 3 times per day. So I think that the differentiation here with '568 is quite clear in terms of the efficacy, the safety tolerability, the convenience of once-a-day dosing, no food effect, the list goes on and on. I think that's a very clear approach that we look at and will lean on for differentiation moving forward. In terms of the other way of activating the system, we see the alternative being an M4 positive allosteric modulator. And unlike an agonist the PAM requires acetylcholine levels to be present in the concentration sufficient to drive efficacy. And we know in some populations, in particular, elderly acetylcholine levels are compromised. So I think that there is ample room here to see an approach with our molecule to differentiate over time either in schizophrenia and/or in other disease states, it's something that we'll look forward to as we move forward in the development program. I think at the end of the day, we're very happy with the profile that we have here. And as I mentioned previously, to be able to offer a profile to the patients that we know to take advantage of the simplicity of our dosing schedule with '568 and the safety and tolerability is really going to be what matters ultimately as we think about differentiation moving forward.

We will move next to Carter Gould with Barclays.

I believe it was on the 1Q call, I asked Kevin around the sort of the capacity across the R&D franchise to fund everything. And I think at the time, there was an acknowledgment that you can't do everything. But since that time, you both moved AMPA into Phase III and now this. So you sort of are doing everything. Is there implied in there some sort of assumption around the prioritization of the rest of sort of the mid-stage portfolio? And any sort of thoughts on how we should be thinking about that R&D line in the years going forward?

Yes. So I'm going to take a first crack, but then we'll let the guys who have to live with us going forward, take the next crack. But what I would say is that, boy, we're beating the odds, right? We've just read out here in a few weeks 2 very important mechanisms in order to treat psychiatric diseases, and they've both been very positive. So they absolutely deserve our investment to carry them forward. We're constantly doing a review of prioritization. I'm not going to fall back on the trade saying that this is a good problem to have. We're going to have our failures as we go forward just as we're going to have other successes as we go forward. So nature is going to take care of some of the prioritization, but it's up to management to be diligent in our prioritization.

Yes. So this is Matt. We're really fortunate with this data between this and the AMPA program to be able to have all the data like this. We're going to fully fund these programs through Phase III. And as we said, look at other indications that we had run in parallel. So we find ourselves in a really fortunate position and quite excited with everything that we have going forward.

We'll move next to Marc Goodman with Leerink Partners.

This is Rudy on the line for Marc. So given the dose response of '568 in schizophrenia, how should we think about the doses for other indications like Alzheimer's psychosis? And second, can you provide more color on the PANSS positive subscale and the negative subscale score? And do you remember any cognition-related complaints?

Okay. Let me take the -- I'll take the first part of that and say that, obviously, we were very confident and very pleased with the data that we saw with the 20-milligram dose level here and being able to take that forward in schizophrenia. And given that dose, that also positions us well for other indications. Clearly, as we think about other indications, we'll be giving more thought to that from a dosing point of view, and we'll certainly update you on that as we go forward. With respect to the subscale, we reported in our press release and in our presentation, the Marder subscales positive and negative, both of which statistically significant as a primary endpoint. The reason for doing that is that the field really generally believes that these are more clinically representative and important to understand. But that's not -- we didn't present just that because of a lack of effect or lack of finding on the PANSS subscale. In fact, what we saw on the PANSS subscales was a statistically significant change in the PANSS negative scale at the primary endpoint, and a trend towards statistical significance on the PANSS positive. Obviously, in small sample sizes, that's not unusual, but the data are really very consistent across all the scales that we looked at.

We will move next to Myles Minter with William Blair.

Just maybe looking forward into the Phase III trial. Would you consider looking at any additional doses beyond that 20 mg once daily? Or are you definitely set on doing a 1:1 randomized trial against placebo there? Just curious as we know your peers in Cerevel and now AbbVie are obviously still doing some dose finding work in what may be a series of pivotal studies there.

We haven't made a final decision on that. Obviously, the data is pretty fresh to us still. I think we have confidence going in around the 20-milligram dose from our preclinical and Phase I data that, that was likely to be an efficacious dose. Is there a possibility of considering a lower dose? I think that's going to be part of the discussions moving forward. And then -- so I think we haven't made a final call around that. And then, oh, yes, the one thing I would say, though, is obviously in the context of a Phase III study, we'll be looking for as simple as straightforward design as possible. In this -- as you noted in this study, we had a 2:1 randomization of active to placebo. I think in most circumstances, we will be likely trying to get to a 1:1 randomization to -- as we move forward to keep things as simple as possible.

We will move next to Jeffrey Hung at Morgan Stanley.

This is Michael Riad on for Jeff Hung. For '568, why do you think the results on efficacy fall below that [indiscernible] M4 Emraclidine Phase Ib? Does it suggest that maybe allosteric are potentially more effective than orthosteric, especially in patients where acetylcholine levels are compromised?

Yes. We don't think this is a different result in any meaningful way from what we're seeing for Emraclidine. I think we're very confident in the total PANSS score reduction that we saw. The difference in the change from placebo is essentially driven by a different placebo response in this study in our mind, which was a higher placebo response, more reflective likely of what's going to be seen in other trials. And if you look at the effect size, they're pretty much on top of one another.

That's very helpful. And then just as a quick follow-up. I was hoping you could provide some added color on what was driving the hypothesis that the 20 mg would be the optimal dose going into study?

It was based on a series of preclinical assessments that we've done in animal models, reflective of schizophrenia and also EEG measures and biomarkers in the Phase I study.

We will move next to Laura Chico with Wedbush Securities.

Just wanted to follow up on the cardiovascular effects or lack thereof that you've seen so far. Is the expectation then that there would not be a need for additional studies to more fully describe the cardiovascular impacts on hypertension and blood pressure? And then separately, just I guess what steps are you taking in the Phase III study to minimize or reduce variability? Any comments there that you can add in.

Yes. Regarding the cardiovascular study, I mean, we're fully expecting given the class that we'll be required to do that. And at least we have the confidence going into that now based on the Phase II data that that's not something that we're concerned about. But I think you would expect that we would do that given that this class of drugs has been required. And then in terms of the kind of management of variability, I do want to give a shout out, first of all, to Samir, Jaz and the whole clinical development team because we run a very tight ship on this clinical studies, Phase II to manage variability to understand that engaging with the sites and having a really ongoing set of work there. And we're going to continue that into Phase III because I really believe that for these types of programs, that high contact, high impact and involvement with the investigative sites. It is critical to understanding the quality of the data. And what we got here was very high-quality data.

And this does conclude our Q&A session. I would now like to turn the call back to Kevin for any closing remarks.

Thank you very much. Really appreciate all the questions that you've had. I realize -- we all realize it can be unsatisfied to not see a traditional dose response going on here. But your questions go to the heart of the matter and you've challenged us. And what you've seen is, in our answers, a high degree of confidence and the high degree of confidence is data-driven in the 20-milligram dose. We identify a very good dose here. And we identified a dose that's not, if you will, hanging on by a skin of its teeth to go forward. Every way you can pick at this dose, every way that you can pick at the trial and the data that goes into that 20-milligram dose, it not only holds together, it's robust. Eiry said something that you probably haven't heard very often in a psychiatric trial. Well, we're glad to see a higher placebo effect. Yes, that can bring a chuckle to people's face, but it is actually -- that is very gratifying when you look at this because we have a Phase II trial here, which we think is going to be indicative of what we're going to see in Phase III. There's soon to be puts and calls in what will ameliorate a placebo effect in the Phase III from what we found in Phase II and then you're going to see things that are going to add to the placebo response in Phase III over Phase II. All in all, the belief here is that -- and the belief comes from members of this team who are in the study, have 30 years of experience of running these types of trials. Now they're going to lead to a placebo response, it's going to look much like this. And therefore, we think we're going to see effect sizes much like this in Phase III, highly competitive what is on the market and what we see from our competitors. There is every endpoint hangs to get there at every time point it hangs to get there. And I don't think you see defensiveness here on our part. I think that what we are trying to bring across with your questions really drew out of us is, the consistency, the robustness of the efficacy and equally important in this patient population and future patient populations that we're going to study with this drug, is the safety that we have here, which is always key to that. And then I'll go into the convenience that this drug brings with no food effect, single dose. So we're going to be out talking to you a lot over the coming weeks. We're looking forward to talking to you more about the study. We're going to be working hard at meeting with FDA as rapidly as possible and moving into pivotal studies. So I really want to thank you for this. And in my short time, I am really looking forward to talking more about this data. Thank you very much.

This does conclude today's program. Thank you for your participation. You may disconnect at any time, and have a wonderful morning.