Good morning, ladies and gentlemen, and welcome to the ACADIA Pharmaceuticals conference call to discuss the RADIANT phase II top-line results evaluating remlifanserin for the treatment of Alzheimer's disease psychosis. My name is Krista and I will be your coordinator for today. I would now like to turn the presentation over to Al Kildani, Senior Vice President of Investor Relations and Corporate Communications. Please go ahead.
Thank you, Krista. Good morning and thank you for joining us on today's call to discuss the top-line results from the phase II portion of our ongoing RADIANT clinical trial program evaluating remlifanserin for the treatment of hallucinations and delusions associated with Alzheimer's disease psychosis or ADP. On today's call, Catherine Owen Adams, our Chief Executive Officer, will provide opening remarks. Following Catherine, Liz Thompson, PhD, Executive Vice President and the Head of Research and Development, will review the study design and discuss the phase II top-line efficacy, safety, and tolerability results from RADIANT. Catherine will then provide closing remarks before we open the call for your questions. I would also like to point out that we are using supplementary slides, which are available in the events and presentations section of our website.
Before we proceed, I would like to remind you that during today's call, we will be making a number of forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements, including goals, expectations, plans, prospects, growth potential, development timelines, regulatory activities, future study outcomes, commercialization opportunities, and future results are based on current information, assumptions and expectations that are inherently subject to change and involve a number of risks and uncertainties that may cause actual results to differ materially. These factors and other risks associated with our business can be found in our filings with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which are made only as of today's date. I'll now turn the call over to Catherine Owen Adams.
Thank you, Al, and good morning, everybody. Thank you very much for joining us today. We're very pleased to share the top-line results from our phase II portion of the RADIANT clinical trial program evaluating remlifanserin for the treatment of Alzheimer's disease psychosis are phase III enabling. Importantly, these phase II results demonstrated meaningful and consistent efficacy trends across endpoints. The 60 mg dose narrowly missed statistical significance on the primary endpoint of change from baseline in SAPS-H+D total score at week six and demonstrated nominal statistical significance on the key secondary endpoint of change from baseline in CGI-S-ADP. Remlifanserin across both doses also demonstrated a favorable safety and tolerability profile with no new safety signals identified. Taken together, we are excited that the efficacy and safety results support the further development of remlifanserin in the two phase III ADP trials currently underway.
I'll now turn the call over to Liz to review the phase II study design and results in greater detail, after which I will return with some closing remarks. Liz.
Thank you, Catherine . I'd like to begin by thanking the patients, caregivers, investigators, study coordinators, and of course, the dedicated internal ACADIA team whose dedication made this study possible. RADIANT is a global randomized, double-blind, placebo-controlled, operationally seamless phase II and phase III program evaluating remlifanserin in Alzheimer's disease psychosis. The phase II portion of the study was designed to evaluate the efficacy and safety of two doses, 30 mg and 60 mg given once daily, and to inform the dose and patient population for the phase III program. The results provide clear and important information to support the continued development of remlifanserin, including the selection of dose and considerations on how we could refine the patient population for phase III. In RADIANT, patients were randomized in a 1:1:1 ratio to receive 60 mg of remlifanserin, 30 mg of remlifanserin or placebo once daily for six weeks.
The primary endpoint was change from baseline in the SAPS-H+D total score at week six, and the key secondary endpoint was the change from baseline in a clinician global assessment of severity, called the CGI-S-ADP at week six. Our pre-specified population for our efficacy analyses was the modified full analysis set, which is referred to in these slides as the mFAS. This comprised 326 patients who received at least one dose of study drug, had a baseline SAPS-H+D total score of at least 10, and had at least one post-baseline SAPS-H+D assessment. In the mFAS population, 109 patients were assigned to the 60 mg dose, 110 to the 30 mg dose and 107 to placebo. Demographic and baseline characteristics were generally well-balanced across treatment groups. The mean age was about 75 years old and approximately two-thirds of patients were female.
Baseline SAPS-H+D and CGI-S-ADP scores were also generally similar across the treatment groups, supporting the interpretability of the results. Going to the next slide. Turning to the efficacy results, the 60 mg dose of remlifanserin narrowly exceeded the pre-specified thresholds for statistical significance on the primary endpoint. At week six, the 60 mg dose demonstrated an effect size of 0.26 on the SAPS-H+D total score with a p-value of 0.0603. For the key secondary endpoint, the effect size was 0.37 with a nominal p-value of 0.0077. This corresponded to reductions from baseline of 12.4 versus 10.4 for SAPS-H+D and 1.3 versus 0.9 for CGI-S. A dose effect was observed as the 30 mg dose showed minimal improvement relative to placebo with effect sizes of 0.05 and 0.11 across the primary and key secondary endpoints.
Now, as we have discussed this topic previously, I want to make a quick note about the NPI-C. As you will recall, we added this as an exploratory endpoint and collected it only in patients who were enrolled later in the study. We are early in our analyses of this endpoint, but to date it appears that a small numerical improvement in NPI-C was also seen in the 60 mg arm. Now returning to SAPS-H+D in this study. On this slide, we show the performance over time where the data suggests increasing separation through week six. In totality, the efficacy data combined with safety data that support either dose, which I will review later in the presentation, gave us confidence in selecting the 60 mg once daily dose of remlifanserin for further development.
The next question we turned our minds to was whether there were any modifications to the inclusion criteria that hold the potential to improve phase III outcomes. We used pre-specified subgroups to guide us regarding the potential impact on both efficacy and patient eligibility of several criteria modifications. One promising area with the potential to further improve efficacy in phase III while maintaining the significant majority of the trial population is further refining the enrollment criteria for modestly higher baseline psychosis. On this slide, you can see the impact of one potential version of this refinement when applied to the phase II trial. First, 80% of patients in the trial would still have qualified for participation. Second, the effect sizes in the resulting population increase for both the primary and key secondary endpoint.
For the primary endpoint, the resulting effect size was 0.33, and for the key secondary it was 0.43. Interestingly, on the later enrolled patients where we collected NPI-C D+H data, there was a similar suggestion of improved effect in this population, though again, I must emphasize that the data are limited based on the timing of adding the endpoint to the study. We are considering whether this refinement to modestly higher baseline psychosis or similar refinements would be beneficial to the overall profile of remlifanserin. Turning now to safety and tolerability. The overall safety profile observed in this study was favorable and supported continued development of remlifanserin. Now recall that one of our main goals with remlifanserin was to avoid the QT prolongation signal that had prevented our evaluating higher doses of pimavanserin.
Preclinical and phase I data had supported our desired profile for remlifanserin, and we were pleased to see that in this data set there was no signal of QT prolongation compared with the placebo group. Expanding to the safety profile more broadly, rates of adverse events, serious adverse events, and discontinuations due to adverse events were all seen at similar rates to placebo. There were no deaths in either remlifanserin treatment group compared with two deaths in the placebo arm. Rates of individual adverse events were also low. In fact, no individual adverse event was reported in more than 5% of patients receiving 60 mg once daily remlifanserin. Somnolence at 3.2% and nausea at 2.4% were the only adverse events reported in more than 2% of patients receiving 60 mg that occurred at a numerically higher rate than placebo.
Finally, I've talked previously about our target profile for remlifanserin and what aspects could yield an important treatment option for patients. I was pleased to see that this data set suggested no negative impact on motor symptoms or cognition. Taken together, the safety and tolerability findings were consistent with our hopes for the molecule and support continued evaluation of remlifanserin in the ongoing phase III studies. Looking ahead, we plan to present additional efficacy and safety results from the phase II study at the Clinical Trials on Alzheimer's Disease, or CTAD conference, which takes place November 16th through 19th in Boston. The phase III program continues while we implement protocol amendments, including removing the 30 mg dosage arm. With that, I turn the call back to Catherine.
Thanks so much, Liz. With these results providing us valuable information needed to continue the development of remlifanserin, I'd like to put the opportunity ahead in context, beginning with the significant unmet need it may address if successfully developed and approved. Alzheimer's disease psychosis is characterized by hallucinations and delusions occurring in patients with Alzheimer's disease. According to the Alzheimer's Association, more than 7 million people in the U.S. are currently living with Alzheimer's disease, and approximately 30% of these patients are estimated to experience psychosis, commonly consisting of hallucinations and delusions. These symptoms can be frequent, severe, and highly distressing for both patients and caregivers. They're also associated with worse clinical outcomes, including increased likelihood of institutionalization, greater disease severity, and increased morbidity and mortality.
Despite the substantial burden of disease, there are no currently FDA-approved therapies specifically indicated for hallucinations and delusions associated with Alzheimer's disease psychosis. We believe there remains a significant and important need for new treatment options, and today's findings reinforce our confidence in remlifanserin's potential to address this underserved patient population. Additionally, and importantly, we also continue evaluating remlifanserin in an ongoing phase II study in Lewy body dementia psychosis. Lewy body dementia is a progressive brain disorder affecting thinking, movement, mood, and behavior. More than 1 million people in the U.S. may be living with LBD, and an estimated 50%-75% experience psychosis. There are no therapies approved for Lewy body dementia psychosis, underscoring the significant need for new treatment options.
Approximately 200,000 patients with Lewy body dementia psychosis are currently treated with antipsychotics, further illustrating the need for an effective and well-tolerated therapy specifically developed for this population. Looking ahead, we expect our existing products to generate meaningful near-term growth, with projected global net sales of approximately $1.7 billion through 2028. Over the long term, we have several attractive pipeline assets with strong commercial potential in areas of significant unmet need. Collectively, we estimate these programs could represent approximately $11 billion in unadjusted global peak sales potential, including $4 billion for remlifanserin across both Alzheimer's disease psychosis and Lewy body dementia psychosis. While these estimates are not financial guidance and drug development carries inherent risk, they illustrate the substantial activity we see across both our existing portfolio and pipeline. More broadly, remlifanserin is part of a robust pipeline with multiple ongoing and planned programs across neurological and rare diseases.
We expect to announce a further three phase II or phase III study readouts through 2027, with additional development and regulatory milestones across the pipeline. Today's RADIANT phase II results reflect ACADIA's continued commitment to developing innovative therapies for patients with serious neurological conditions where effective treatment options remain limited. I would like, once again, to thank the patients, caregivers, investigators, and study personnel who participated in this study, as well as our employees and collaborators whose hard work and dedication has made today's milestone possible. We look forward to presenting additional phase II findings at our CTAD meeting in November and providing updates on our continued progress. With that, operator, we are now ready to open the call for questions.
Thank you. We will now begin the question and answer session. If you would like to ask a question, please press star one on your telephone keypad to raise your hand and join the queue. If you would like to withdraw your question, again, press star one. We kindly ask that you limit yourself to one question and one follow-up. For any additional questions, please re-queue. Your first question comes from Ritu Baral with TD Cowen. Please go ahead.
Good morning, guys. Thanks for taking the question. So many questions. We will start with the NPI. I think, Liz, you mentioned that you are seeing something. Are you seeing an effect size similar to the CGI and the SAPS-H+D, and have you done the correlation analysis that we have spoken about that would really validate the SAPS-H+D? I guess I am wondering, is the SAPS-H+D, in your mind, still the appropriate endpoint, and do you have to talk to FDA before making any changes to the phase III around powering? Thanks.
Excellent questions, Ritu. A couple of thoughts. First, I do want to say these are top-line results. We have had these data for a very short period of time, so we have done initial analyses. There is more that we have yet to do, but there are some comments that I can make for now. The first of these, as we have discussed before, one of the things with the NPI-C was we did it late. So there is a relatively limited proportion of the population that actually do have these data available. If you look in the overall population there, again, going back to my remarks earlier, it is a relatively small numerical improvement that you see with the 60 mg arm.
When you get into the enriched population that I showed an example of what it could look like, you do see an effect size that is more similar to the effect size that you see with the SAPS-H+D. But again, this is very preliminary at this point. We absolutely have not, at this point, done the kind of validation analysis that we would need to do to support primary endpoint dossier. That is stuff we will do now that we have the phase II data in our hot little hands. That is part of our intent. In terms of talking with FDA, we do not believe that we need to, for example, discuss with them to get their consent on dropping the 30 mg dose arm. I think that that is very clear and the data support it, and we are planning to go forward with that as quickly as possible.
Were we to make a change to the primary endpoint in the phase III eventually, I would want to discuss that with FDA. At this point, we are not proposing that.
Your next question comes from the line of Yigal Nochomovitz with Citigroup. Please go ahead.
Hi. Great. Thank you for taking the questions. I had a few on, basically related to slide 11. First of all, you mentioned, Liz, that this is one of the exploratory analysis you did. Is this the most likely course of action with regard to a change to the phase II population, or are there other slices that you might enumerate that would be of interest with regard to enriching for a higher responding group? Secondly, could you comment at all with respect to whether the efficacy was more enriched on the H, the hallucination, versus the D, delusion, with regard to the primary endpoint? Just wondering how that shook out.
My last question is regarding the 30 mg. I know it didn't hit, but I'm just curious if you did the analysis on slide 11 for the 30 to potentially show that there may have been a little bit of a separation there, if you enriched for the high baseline psychosis, even at the 30, which would give you more confidence, in that subgroup. Thanks.
Okay. Quite a few things there. Hopefully, I got them all jotted down. We are evaluating various possible options of what we might do in terms of minor modifications to the patient population. It's always a trade-off in terms of the proportion of your population that remains relevant and the potential bump in efficacy that you could see. I will say that I think that focusing in on a little bit more higher baseline psychosis severity, I think is a promising area. That is where I am most enthused. But we are thinking about what the appropriate way of doing that would be.
I do think, slide 11, we gave that as an example because we think that this is a strong contender that really does balance the keeping the broadest possible eligible patient population for the trials, while also somewhat increasing potentially the efficacy that we might expect or at least would have seen in phase II with that application. We are keeping high level at this point in terms of data, so I'm not really going to comment on the breakdown between hallucinations and delusions. But I will say that across endpoints, we did see impact on both. We did also look at the 30 mg dose slide 11 type analysis as well as other versions of that. We did see some increase, though it is consistently not in the realm of the 60 mg arm.
We feel very confident that 60 mg is the right dosage arm to take forward.
Your next question comes from the line of Tessa Romero with JP Morgan. Please go ahead.
Hi, guys. Thanks very much for taking our questions. Catherine, Liz, as you saw these results and thought about the pushes and pulls of moving remlifanserin forward, what ultimately made you decide that moving this program forward was worth the investment for ACADIA relative to all of the other initiatives at the company? As a follow-up, what additional analyses are you working through that we can expect to see at CTAD here in a couple of months that may be supporting your view? Thank you.
Thanks, Tessa. I'll start and give Liz a quick break. In terms of balancing investment choices at ACADIA right now, we're in a fortunate position that we don't have to make those trade-offs specifically for any of our programs. We have, as you know, a strong balance sheet and a strong investment focus on our R&D portfolio. We were very encouraged by the results we've seen. We are continuing to look at how to enrich the population for further enhancement through phase III.
We believe with the high unmet medical need in this population, the efficacy that we've seen so far that Liz has described, and we will continue to describe as we move forward in the next few months, as well as the safety and tolerability profile, that this molecule offers the potential for patients with Alzheimer's disease psychosis, and it is absolutely worth our investment to move this forward into the phase III trial.
Absolutely. Echo all of that. It is good to be in a position where the choices we are making is this worth taking forward versus which thing can't we take forward? So we're pleased to be in that position, and we feel good about the fact that this is a program that has the potential to meet a real meaningful unmet need for patients. In terms of CTAD, having only gotten this data very recently, we're very early in putting together what our actual presentation for CTAD would look like. Obviously, we're going to have to work with investigators on what the most appropriate things to put forward are. Certainly, you should anticipate that you're going to see some additional endpoints beyond this, some additional description of safety.
If there are things that we think are especially meaningful in terms of ways that we could refine the patient population, we likely would address that as well.
Thanks, Tessa.
Thank you.
Your next question comes from the line of Sumant Kulkarni with Canaccord Genuity. Please go ahead.
Good morning. Thanks for taking our questions. Given the safety you've seen so far, could a dose higher than 60 mg be added? Is there any merit in considering later time points beyond week six? If you look at dementia with Lewy bodies, that tends to have higher rates of psychosis versus Alzheimer's disease psychosis. Do you expect any different types of behavior of this product in that patient population as you consider the phase II trial there?
I am not sure that I grabbed all of those. I'll comment on the ones that definitely stuck with me, then somebody around the table will prompt me for what I forgot. I'll say, certainly an interesting question. We really did feel like we were targeting an exposure that was going to be associated with near maximal efficacy. I will say that one of the things that we'll be continuing to think about is exposure response analysis to see whether there's a reason to believe that going even higher might be helpful.
All that said, we think 60 mg, based on the profile seen to date, recognizing we have to do the phase III trials and are, we think that 60 mg represents a profile that is potentially an approvable medication if the phase III were to look like we are thinking that it could based on this information that we have about how to refine the phase III program. I think we don't believe we have to go to a higher dose, and we're looking for the exposure response to see if there could be any benefit to this. But for now, we really do think 60 mg is an important treatment option. As far as a longer time point, patients do roll into open label here. Obviously, there are always things you need to think about in terms of comparing open label to double-blinded data.
We think that week six gives us a good demonstration of the efficacy. The shape of the curve, particularly if you look at SAPS-H+D, does suggest that maybe you could get a little bit more if you look a little bit further out. But we want to focus in on week six as a place that can demonstrate the efficacy and where we have an understanding of both how our drug works as well as the placebo arm. We do anticipate maintaining the week six time point as our primary endpoint for the phase III program. As far as DLB, Lewy body, we continue to be very enthused about the potential profile there. I have always thought that the efficacy, while in limited numbers of patients with pimavanserin, was striking. Suffice it to say, nothing about these data have decreased our enthusiasm about that.
We really are looking forward to those results. We do have to run the study in Lewy body because exactly as you note, it is a distinct patient population that can have distinct reactions to medication and sort of a distinct profile in terms of how sensitive they are to safety. We look forward to understanding the application of remlifanserin in Lewy body. But we think this is certainly supportive of that and feels good. I think that was all the questions.
It was. Well done.
Your next question comes from the line of Ash Verma with UBS. Please go ahead.
Hey. Yeah, thanks for taking our question. I wanted to understand the enrichment for more severe patients that you've talked about. I know you mentioned that this phase II RADIANT is enriched already with 80% of these patients have modestly higher baseline psychosis, but you're also saying that you will try for modestly higher baseline in the phase III. What would that look like? Then just on this same topic, maybe when you compare the psychosis level in this phase II RADIANT, how did that compare to the prior Study 019? Thanks.
Thank you so much for giving me an opportunity to clarify something that I may not have said very clearly. That example that we gave of an enriched population, when I was saying 80%, that was actually indicating that 80% of our currently existent population would fit under this new definition. That's just to be clear on what that meant. We do think that obviously that does mean that there is a potential to nudge our population such that everybody fits within this in the future study. We are considering it. We have not landed on this as the absolute way that we're going to go forward, but that is what we were thinking of because it does appear that there's a possibility of increasing the efficacy that we could see out of it.
In terms of comparisons with the prior study, what I will say, and again, you'll see more granular data on this, I think at CTAD. What I will say, generally speaking, is that we had indeed enriched our phase II program compared with the 019, the phase II study with pimavanserin, to try to move the general population to a somewhat more severe psychosis phenotype. We were successful there. We had increased the severity here compared with the 019 study. That said, we do think that there could be some benefit potentially to increasing that just a little more, a modest increase there, and that is what we're focused on as one very promising potential area for refinement of the population.
Fantastic.
Your next question comes from the line of Brian Abrahams with RBC Capital Markets. Please go ahead.
Hi, team. Thanks for taking our questions. This is Nevin on for Brian. Just wondering if you could talk a little bit more about what you think might be clinically meaningful delta for the SAPS-H+D. Just given that the 60 mg arm showed around a 2.2 point delta. How do you interpret this in the context of the current regulatory landscape, particularly given the high unmet need that we've seen? Yeah.
Okay. Fantastic question. I think a lot of this we do need to ground in the significant amount of unmet need that I think Catherine eloquently covered in the presentation. Given that, I think that we do believe that these results, colloquially, we believe that these results are clinically meaningful and could represent a clinically meaningful treatment option for patients. From a technical perspective, some of the analyses that we are going to be doing is demonstrating that for purposes of regulatory consideration in terms of what degree of change is clinically meaningful to meet a regulatory bar.
Certainly, based on conversations running into this readout and very limited conversation since, we think that this represents a potentially clinically meaningful profile, especially, one, in the context of what thus far is a very supportive safety profile, and two, in a patient population with truly significant unmet need, and at least at this moment, no approved treatment options.
Your next question comes from the line of Malcolm Hoffman with BMO Capital Markets. Please go ahead.
Hi, everyone. Thanks for taking my question. I wanted to ask why you guys think that there wasn't as much activity in the 30 mg arm. Do you think this is a receptor occupancy issue, or what else could be potentially driving this? Thinking about the phase III, are you thinking about increasing the actual enrollment size for the 60 mg arm, given that you're going to be dropping out the 30 mg arm? Appreciate your thoughts here. Thanks.
Hey, Malcolm. Thank you. About the 30 mg dose, I guess I'm going to take a step back and say a couple of things. We designed our phase II program based on learnings from pimavanserin. The good part is now we have the opportunity to design our phase III based on learnings from remlifanserin. That said, we did always anticipate that increasing exposure was going to be helpful in this. I think that the relative behaviors of the 30 and 60 mg really just bear that out, of the increasing exposure here does seem to be important. I think we've talked before about it is hard to draw a direct line to what we know about receptor occupancy, because our studies by and large have been in healthy young male volunteers, and so that receptor occupancy information is maybe not as directly translatable.
Certainly, data with PIM suggested that getting to higher exposures would be helpful, and while we have not yet been able to do the exposure-response analysis on remlifanserin, certainly looking at the behavior of the two dosage arms does seem to suggest that exposure is important here as well. In terms of enrollment size, what I can say is that originally we were anticipating we were going to need three arms. Now we think we're only going to need two arms, so that should be helpful from that perspective. We do need to consider what other modifications we might be making, including around the target population, and that could have impacts, but at this point, I'm not in a position to really say that.
Your next question comes from the line of Paul Matteis with Stifel. Please go ahead.
Hi, Liz, Catherine, team. Thanks very much for taking our questions. This is Julian on for Paul. Would you guys mind stating what is the actual threshold for this modestly higher baseline psychosis population that you are citing on slide 11? Is that a specific SAPS-H+D score? If you could share it, that would be really helpful. Can you also confirm that this was pre-specified, and were there any other pre-specified analyses that you were planning on sharing today? Just one other question is, just given effect sizes tend to regress in phase II to phase III in neuropsych, as you guys know, how do you balance in the phase III powering this for success while still trying to achieve a result that is clinically meaningful? Thank you.
Sorry, I was madly writing, and I am 100% sure I missed one. Somebody will prompt me.
Follow-up please.
We are not going to share right now what the specific threshold is that this example on slide 11 is. There are two reasons for that. Reason number one is this is an example. We did look at a number, not an infinite number. We are not trying to data dredge here, but we did look at a number of different potential subgroups to inform this. That is reason number one. But reason number two is that we also do want to be careful about certain specifics that we put out publicly, because it does have the potential to impact placebo response rates in future studies based on if people are trying to target a certain level that they are trying to achieve to get into a study.
We likely will continue to take the approach we've taken historically, which is that we are not overly specific around what our inclusion criteria is from point of view of those measures that could impact our overall placebo response rate. We did have a relatively limited number of pre-specified subgroups that we've looked at. We're not planning to share any additional subgroups today other than the one that we have already shared.
There often is a change in effect size going from phase II to phase III, and that is one of the considerations that we are looking at here as we think about ways to potentially increase the effect size we might be able to see in phase III, so as to balance exactly what you say, the practicalities of making sure that we have something clinically meaningful and enrollable, while also reflecting what we think the likely profile of the drug could be.
Your next question comes from the line of Jack Allen with Baird. Please go ahead. Jack, your line is open.
Yep. Sorry, apologies. Was just looking for the mute button. Thanks so much for taking the questions, and thanks for the data presentation here. Just a few from our end. On the receptor response analysis, I'm just curious, it sounds like that work is still ongoing. Could we get that data at CTAD, or do you have any timeline as it relates to when we could get that receptor response analysis? The other one we had briefly was on the phase III and this modestly higher baseline psychosis potential modification. I know you're still considering whether to implement that, but any high-level thoughts as it relates to how that would impact trial timelines would be helpful as well. Thanks so much.
Thanks, Jack. I am not going to give specifics on when we expect the dose response analysis at this point. If we have something meaningful out of it, that is by the time of CTAD, we will include it, but we may or may not have that by that time. In terms of the phase III potential modification and whether that could have an impact on overall trial timelines, there is obviously a complicated interplay here of what that does to your potential effect size and what it does to the size of your potentially enrollable patient population. So right now, I am not prepared to say what that could be. Again, I would say if nothing else, it is probably useful to keep in mind the fact that certainly compared with a three-arm study, we would be looking at a smaller study here, comparatively speaking.
But the exact impact is going to depend on the specifics of which flavor of refinement we pursue.
Your next question comes from the line of Sean Laaman with Morgan Stanley. Please go ahead.
Good morning, Catherine. Team, hope all is well. Couple of questions. What specific factors do you believe prevented the study from reaching stat sig? How much of the shortfall was attributable to placebo response versus treatment effect size? Are you able to share the overall average baseline SAPS-H+D score in the study?
Working backwards, I believe the SAPS-H+D baseline score is in one of the slides.
It's on slide eight.
Slide eight. Thank you.
We were fairly not sure whether it's the mean.
Thank you.
The median, the min, and the max. Yeah.
Thank you.
In terms of specific factors that prevented us from meeting statistical significance, it is always hard to pull out exactly what it was. A very small number of additional patients hypothetically could have gotten us there.
A minutely smaller placebo response could have gotten there, slightly decreased variability. I think it's the normal sort of contributors here. I do take it, again, as our goal with this phase II was to get the information that would help us design our phase III program, and I think that from that perspective, this has done what we needed it to do. It has clearly helped us identify the dose, and it has given us the information that we need to consider what refinements we might make to the patient population.
Yeah, I just want to underscore that this is a highly phase III-enabling set of data. Again, to Liz's point, we've been joining the dots between pimavanserin and remlifanserin for a while now, and now we're able to really look at remlifanserin as its own molecule and really understand that from a different perspective and in patients who we'll potentially be treating in the future. That ability now to allow us to do that is going to give us the confidence to design a phase III trial that we believe has the ability to hit technical and regulatory success, and that's what we're doing right now. We look forward to continuing to share that as we move forward in the next few weeks and months.
Your next question comes from the line of David Hoang with Deutsche Bank. Please go ahead.
Hey, this is Sam on for David. Thanks for taking our question. Just on the topic of population refinement in terms of potential enrichment for modestly higher baseline psychosis, I wanted to ask how you think about the balance between increasing treatment effect versus any potential commercial impact in terms of broad applicability or any potential labeling considerations, if there are any, when you weigh these phase III enrollment refinements?
That is an excellent question, and as you can imagine, it is one that we have discussed internally as we've been thinking about this. I think a couple of general comments there, which is I think that thus far, there do not seem to be a lot of precedents within the neuropsychiatric space of populations being restricted, for example, to moderate or severe versions of disease, like you may see in other more common diseases. There don't seem to be a lot of regulatory precedent that suggests likelihood of significant restriction. I think that it is important to say that as we look through the data that we have, there is indication of impact even in the patients that are somewhat lower than the thresholds that we are looking at here. There's just greater impact in the higher thresholds.
While it would be subject to eventual label negotiation with the agency, and I suppose for that matter, also subject to seeing data in phase III that looks similar to what we saw in phase II, we think that it is reasonably likely that we would not be looking at restrictions based on this kind of relatively modest refinement that we're talking about.
Just to sort of underscore that commercially, it is a modest refinement. Liz has already said that within the phase II trial, it would've included 80% of the patients. You can see the mean, the medians, the min, the maxes of SAPS-H+D and CGI-S on the demographic slides. You can kind of work out from there what sort of patient population we would be looking at. From a commercial point of view, we still believe this includes a lot of patients with hallucinations and delusions and represents, beyond a commercial opportunity, a huge opportunity with patients in terms of the unmet need for a treatment that balances efficacy and safety.
We haven't had that many questions about the safety profile, but I do encourage you to look at that because it is very positive data, and we look forward to continuing to monitor that as we move through the phase III.
Your next question comes from the line of Marc Goodman with Leerink. Please go ahead.
Hi. Good morning, everyone. This is Alyssa on for Marc. Just a few from us. I was wondering if you could comment on the placebo response, the magnitude of the effect. Just looking at the previous trials using the same endpoint, it seems like there is a stronger effect here in the placebo arm. Just wondering if you have any thoughts around that. Secondly, if you could comment on the baseline SAPS-H+D threshold that you're targeting for the Lewy body dementia study. Thank you so much.
All right. In terms of placebo response, I guess I'd say a couple of things. First is there aren't a whole heck of a lot of datasets out there in the ADP population with this endpoint. That was one of the things that we did. When we were originally designing the phase II trial, we were doing a certain degree of extrapolation from different studies, different endpoints, and in some cases, a little bit different populations. What I'll say is the placebo response that we saw here in terms of its magnitude and its variability was within the range of things that we considered as a possible outcome. Obviously, we are always focused on, and will continue to focus in phase III on whether there are things we can do to try to minimize that placebo response. That is always a beneficial thing.
But this wasn't outside of our range of expectations of what we could see in the trial. I'm not going to comment too specifically on the inclusion criteria around disease severity that we apply in our trials for the same reason I talked about earlier, about we don't want to potentially inflate our placebo response by very publicly giving people a target that they should be working to of what you need to get into our studies. But I will comment that we are looking similarly in the Lewy body population to how we had approached the original phase II of ADP with ensuring that we have adequate disease severity to be able to distinguish a signal if there is one to distinguish, and then we'll take those phase II data and use that to inform our phase III program there should it be enabling similarly.
Your next question comes from the line of Rudy Li with Wolfe Research. Please go ahead.
Hey, thanks for taking my question. So given that RADIANT is 80% power for 0.4 effect size, I know it's still early, can you maybe provide additional color how you think about the powering assumption for phase III based on current data and potential change of the protocol? And just to confirm, do you need positive data from both phase III studies to support approval? Thanks.
In terms of phase III powering, I guess I'll kind of reiterate, it's going to depend on a few factors. It's going to depend on the powering level that we look at as well as the approach that we take in terms of what further refinement we might make. We are going to be basing our phase III powering based on the information we have from remlifanserin rather than what we went in starting with. So I think that that's going to be a more informed view of powering, and we look forward to sharing that with you as we land on what we're looking at from a population perspective.
Well, we need both studies.
Well, we need both studies. Thank you. My notes are terrible, and I couldn't even read it. I will say that particularly in the world of neuropsych, there's ample precedent for approvals that do not have two positive phase III trials. Certainly, we are designed for success across our program. What will eventually be acceptable to regulatory agencies does remain to be seen and is going to be data-dependent. But if you look across the neuropsychiatric field, there are a number of examples of assets with one or more failed phase III that nevertheless get approved.
Your next question comes from the line of Ami Fadia with Needham. Please go ahead.
Hi. Good morning. Thanks for taking my question. Based on some of your comments before, would it be fair to assume that you're unlikely to narrow the inclusion criteria beyond that 80% subgroup that you showed on slide 11? If you could lay out what might be some of the next steps in terms of really figuring out what might be the various changes you make. Are there other changes beyond the inclusion criteria that are being considered, and leading up to sort of finalizing the protocol for phase III?
Thank you. Starting with the latter, the easy one that we know for sure we're doing and we're going to do as quickly as we possibly can is the removal of the 30-mg arm. We're not anticipating broad changes beyond that at this point. I think that was what I wanted to say on the protocol amendment front. Are we likely to narrow the population further than the 80% that we talked about? I think it's relatively unlikely that we're going to do something that cuts into our trial-eligible patient population too much more than that. We really are trying to get that balance between something that doesn't have a meaningful impact on enrollment but does have an opportunity to increase our overall potential phase III efficacy. Something in that vicinity is probably about as significant of a refinement as we would anticipate making.
I think with Ami's question, she was also asking about the FDA interaction that might come with some of those discussions. So maybe you could talk about the phase II, phase III situation.
Oh, okay.
And kind of what that would entail.
Yeah, absolutely. This is an operationally seamless phase II, phase III program. I think probably everybody's heard me say about a million times at this point. Our phase III is currently going. In terms of being able to remove that 30-mg dose, again, we're going to be doing that as quickly as possible, and we do not believe that we need any FDA discussion around that. We think it's a fairly clear story, a fairly clear and justifiable decision. In terms of FDA engagements, one of the questions earlier on was whether there was any potential to consider other endpoint hierarchies. If we were to do that, we would anticipate having an FDA engagement.
But in terms of being able to solidify our dosing and potentially even one of these more modest refinements of the population, we do not believe those are things that are going to require FDA discussion.
Your next question comes from the line of Yatin Suneja with Guggenheim Securities. Please go ahead.
Hey, guys, this is Eddie on for Yatin. Thank you for taking our question. Just to follow up on what you just said, with that phase III currently enrolling, will you have two separate populations to analyze, and sort of how will those be handled in the primary analysis, pre and post amendments?
It's a great question. I will say that, primarily, there will be a limited number of patients who were randomized to the 30-mg arm before this amendment went in place. I would anticipate that those patients will be, if they choose to and are eligible for other reasons, they would be eligible to go into the open-label extension, where they would receive 60 mg and could contribute to our overall safety database. I don't think that we would need to handle it analytically any differently from that perspective. Depending on the nature of the refinement we applied, we would think about what the appropriate statistical handling of that would be. But I anticipate that it would likely be of the vicinity of having our future modificable analysis, that population be specific to those patients that met that criteria, would be the most likely outcome.
Your next question comes from the line of Salveen Richter with Goldman Sachs. Please go ahead.
Hi, Catherine, Liz, and team. This is [inaudible] on for Salveen . Thank you for taking my question. A couple of quick ones. One, based on the phase II data that you've seen, the top line, any updated thoughts on the commercial outlook versus the emerging muscarinics, given Bristol will also be having data sometime early next year? The second is acknowledging that this is very early data. Did you also assess impact on any of the related symptoms, like agitation? Can we expect any commentary on that in the near term?
Let me just address the commercial outlook versus the muscarinic. I think we remain confident that, first of all, this is a very large population. There are no currently FDA-approved drugs. In most neuropsych spaces, there's more than one option for patients, which is highly appropriate and positive for those patients. So regardless of however Bristol turns out with their outcomes for their trials, there are a lot of patients with high unmet medical need in this Alzheimer's disease psychosis population. Within our own trial data, as we've already said, I hope, and reiterated, we now feel very positive about the possibilities for remlifanserin in this patient population, not only for the efficacy and the refinements that we are looking to put into place, but also the safety profile. This is a once-daily dose.
As we've said in the press release, and you've now seen, the safety and tolerability profile is very similar to placebo. We haven't seen any QT prolongation issues. That was something that the team had designed into remlifanserin, and we're now very pleased to see that has not come to fruition to date. And obviously, we continue to monitor that. So overall, the package we believe we're putting together for remlifanserin is very compelling for both patients and clinicians, and we look forward to ensuring that our phase III trial has technical and regulatory success, that we can actually get this product launched to patients who need it. Beyond that, I'll let Liz take it.
Yeah. We did as exploratory, collect a number of different associated symptoms. You'll see those data in due course. But what I will emphasize is that, of course, this is in the patient population with psychosis, and that really is what remlifanserin, we think, is most suited to impact. And so you would be looking at agitation or whatever else within the context of patients whose psychosis was a significant portion of their presentation.
That concludes our question and answer session. I would now like to turn it back over to management for closing comments.
We'd just like to say thank you all for joining us today for our presentation of the RADIANT results. We appreciate your participation, and we look forward to continuing the development of remlifanserin for both Alzheimer's disease psychosis and Lewy body dementia psychosis. And we'll speak to you all soon. Have a great day.
Ladies and gentlemen, this does conclude today's conference call. Thank you for your participation, and you may now disconnect.