Good morning, and welcome to the Minerva Neurosciences virtual KOL event. At this time, all attendees are in listen only mode. A question and answer session will follow the formal presentations. As a reminder, this call is being recorded, and a replay will be made available on the Minerva website following the conclusion of the event. I'd now like to turn the call over to your host, Rémy Luthringer, Executive Chairman and Chief Executive Officer at Minerva Neurosciences. Please go ahead, Rémy. Thank you so much. Good morning, everybody. It's a real great pleasure to give you an update on the Minerva progress in bringing roluperidone to patients afflicted by schizophrenia and suffering from negative symptoms. We all know that negative symptoms is the type of symptoms which is keeping these patients out of any decent life. It is true that over several decades of research and failed clinical trials, you know, we have not obtained a drug which is helping these patients. I think today, this unmet medical need becomes a reality, and I think we are at the stage where roluperidone is probably the first treatment for negative symptoms in patients suffering from schizophrenia. Next slide. This is just disclosure, I will not insist on this one. So I'm very, very honored and very pleased to have with me today, Professor Gregory Strauss and Professor Brian Kirkpatrick. It would be difficult to give their complete CV, but what I can say, just simply, is that I think Greg and Brian have contributed enormously to advance the understanding of negative symptoms of patients suffering from negative symptoms. And they really are contributing immensely to advance the field, and hopefully help us to bring the first drug for negative symptoms to patients. So, maybe when Greg will speak or Brian will speak, they can give a little bit more details about the CV. But, again, thank you, Greg and Brian, to be with us today. So what we will try to address today are few points, and Greg will start first, and he will really define what are negative symptoms, because I think it is important that we have really a redefinition of negative symptoms, and Greg will do this, I know very well. But I think what is also very important, what Greg will address, is the impact of negative symptoms for patients and for their families. Because again, negative symptoms are the type of symptoms which keep these patients out of any decent life, any job. Afterwards, Brian will address the challenges, but I think also the solutions of assessing negative symptoms in clinical trials in patients with negative symptoms and suffering from schizophrenia. And last but not least, I will give you an update of the confirmatory phase III trial we have discussed a lot over the last few months and years with the FDA. Afterwards, we will open to Q&A. But before you know giving over to Greg, yes, I think that you know to develop a new drug, to develop an innovative drug, and to really have a paradigm shift in the way you're treating patients, you need to have several items, several aspects, which have to come together. Yes, and this is what I call the Minerva Confluences, and I think we have it as we speak. Yes. Why? Because when you're looking to, you know, the interaction we had with the FDA, and the very constructive and productive meetings we had with the FDA, in order to come up with the potential design of the phase III, I think this is extremely important. You know, the FDA even organized a public meeting, where they invited KOLs, they invited representatives, also the patients, in order to discuss what is the best way to move forward and to develop a drug for negative symptoms. And I can only thank them for all these efforts in order to help us designing the next phase III trial, the confirmatory trial. The other aspect, which is important, and we already spoke about it, a little bit, is to have the scientific medical, research community aligned. Yes, and, I think over the last, two decades, definitely, we made a lot of progress in the understanding of, psychotic disorders, of schizophrenia, and particularly negative symptoms. So, I think this was also important to come to a stage of understanding of the, negative symptoms, which contributes to this confluence I am speaking about. And you know, I have been very long in, drug development, and each time I have seen an advance in a, space, in an indication, a therapeutic indication, you always need a pharmacological tool. You need a drug in order to test hypothesis, in order to validate some scales, and I think roluperidone is really filling this gap, because you know, we have already clinical data, and definitely roluperidone is probably the best drug currently in development in order to improve negative symptoms. And last but not least, because all this needs to be financed, I'm extremely honored and proud that we have the chance to have top-tier investors who have you know, put a significant amount of money in order to help us to go to the next stage of development of roluperidone, and hopefully to bring roluperidone to patients. So this is really, I think, a key moment we have here, and this does not happen very often, but here we have all the alignments necessary in order to move forward. Let me just give you some color about, you know, the general alignment we obtained with the FDA, or we discussed with the FDA, for the phase III trial we are planning to start very soon, and obviously, we'll give you details about timelines at the end of this presentation. But so the first thing I think where we were able to get alignment with the FDA is that you know schizophrenia is a heterogeneous disease, and each patient is quite different, but nevertheless, when you go to groups of patients, I think we aligned with the FDA about the fact that there are patients out there who have really high negative symptoms and have a low risk of relapse of positive symptoms. So this was obviously a very important step in order to continue with the discussion about the study design. The second aspect, which is a very, very important aspect, is that we also got alignment with the FDA about how to design the study, and here, as you can see, we are aligned about using the monotherapy approach. So we are not putting this on top of antipsychotics, like most of the studies have been done in the past, but we are going with monotherapy, and we are comparing, in monotherapy, roluperidone versus placebo, because, as you know, there is no approved drug for negative symptoms. So this is also very important because this allows to really tell based on the data, if we have a direct effect on the primary, on the disease-related negative symptoms. So this, again, sorry to insist, but this is a very big achievement. So we also agreed about the duration of the study, and we have agreed also about what is a primary endpoint, and the primary endpoint, as you can see here, will be measured at week 12, like in the two previous studies we have carried out. And you know what the FDA asked us to do, and I think this is completely important because in the two previous studies, we had extremely low relapse rates of positive symptoms. So what the FDA asked us to do is to do a comparison between roluperidone and a standard of care, which are antipsychotics, in order to monitor the number of relapses in the two conditions, roluperidone versus a standard of care. And I think it is really fair to say that all this represents a new treatment paradigm, and this is what we are working on and trying to execute. Now, Brian... Sorry, Greg, let me hand over to you. Yes, please. All right. Thank you very much, Rémy. I appreciate the introduction, and I'm very honored to be here to speak to you today about negative symptoms and how they impact people with schizophrenia and their families. So I am a professor of psychology and neuroscience at the University of Georgia, and my research primarily has focused on negative symptoms in the schizophrenia spectrum, not just on adults with schizophrenia, but also at youth who are at clinical high risk for developing psychosis, who have prodromal syndromes. And much of my work is really focused on identifying the mechanisms of negative symptoms, in particular. Now, we know that schizophrenia is experienced worldwide. It's a diagnosis that affects about 83 million people worldwide, including about 3.4 million in the United States alone, and it has an incredibly high financial burden. We know that estimates are about in the billions, about $34 billion alone for the effect of schizophrenia financially in the United States annually, and it is, in fact, a leading medical cause of functional disability. So even compared to other diagnoses like Alzheimer's, dementia, even things like spinal cord injury, what you would associate with very high rates of functional disability, schizophrenia annually is one of the leading causes, if not the leading cause, each year. It also, it of course has a severe impact on social, occupational functioning and independent living. Many people with schizophrenia experience difficulty forming relationships, whether that be friendships, romantic relationships, relationships with family members, et cetera. Also, maintaining gainful employment, finishing school and basic independent living activities. And we know that negative symptoms are the strongest predictor of poor functioning and a strong predictor of functional disability itself. And if you look at the figure here on the screen, one of the things that you can see is positive symptoms, highlighted here in the green line, emerge in this prodromal or pre-illness period. So they emerge in an attenuated form before the illness even onsets, and then once the person hits their initial episode, they typically experience a very rapid increase, and then the symptoms will fluctuate throughout the course of their illness... and indeed, in fact, get better much of the time, later in the course of illness. With treatment, this rate of change will typically improve for positive symptoms. Many people with schizophrenia, their positive symptoms will respond to antipsychotic treatment. Interestingly, negative symptoms emerge often years before the onset of these attenuated positive symptoms. So years before these subtle hallucinations and delusions develop, that later become full-blown, people will have early negative symptoms, reductions in emotion, motivation, social activity, emotional expression, and speech, that occur here, often, up to five years before these attenuated positive symptoms, reflecting perhaps the earliest window we have into risk for the later development of schizophrenia. Now, importantly, once they do develop, negative symptoms typically persist, so they, actually become severe, clinically severe before the onset of schizophrenia itself, and then typically plateau after illness onset and on their own, without treatment, experience little to no improvement. They remain stable over time, and when treated with antipsychotics, are minimally responsive. So we know that negative symptoms are a critical treatment target. They're associated with poor functioning, poor quality of life, et cetera, and markedly associated with disability, much more so than positive symptoms, which are the key focus of antipsychotic treatments. There's general consensus in the field that schizophrenia has a profound impact on patients' lives in these ways, but also the lives of their relatives, their caregivers, in terms of impacting their quality of life and impacting the quality of lives of the patients themselves. Unfortunately, despite this clinical importance, we're really experiencing severe challenges in treating negative symptoms of schizophrenia. We know that current pharmacological treatments have been minimally responsive. Current psychosocial treatments, meaning talk therapies like cognitive behavioral therapy, social skills training, they're also minimally responsive to those types of treatments. So there's a really big landscape for treating negative symptoms, and there's a huge treatment need that remains unmet in the field of schizophrenia. We know that antipsychotic treatments may even worsen negative symptoms in some of the patients. They can, for example, induce sedation. They can induce what we call anhedonia, or reductions in the experience of pleasure, and actually worsen these negative symptoms for some people. Clinical practice and drug development have really focused on treating the positive symptoms, leaving negative symptoms as a key unmet need in the treatment of schizophrenia. And since there is no FDA-approved therapy for the treatment of negative symptoms in schizophrenia, this is really an urgent need for the field and something that the patients themselves are critically interested in. Now, when we talk about negative symptoms, I want you to know that, currently in the Diagnostic and Statistical Manual for Mental Disorders, the DSM-5, there are two broad dimensions that are described, and these are really organized hierarchically, meaning that there are two higher-order dimensions that we call experiential and expressive. Beneath those two higher-order dimensions are five lower-level domains of avolition, asociality, anhedonia, blunted affect, and alogia. These are thought to represent independent constructs that can reflect different treatment targets. Now, I want to tell you a little bit about each of these so you have a sense of what the five negative symptom domains are. The first is avolition, which you can think of as a two-pronged abnormality. One is in an experiential component of having a subjective lack of motivation, so a lack of desire for engaging in goal-directed activities, for example, but also that manifests in a behavioral component, as indicated by a reduction in engaging in goal-directed activities, reductions in engaging in work or school activities, and also poor self-care. So these are often folks who do not desire to engage in goal-directed behavior, and they don't do so. Asociality, the second domain, of course, revolves around social interest and activity. This is a reduction in the interest in and engagement in social relationships of all kinds. These can be friendships, romantic relationships, family relationships, across all of the different types of social interactions we might have. These folks will have reductions in how often they interact with others and the size of their social networks, and critically, they're not interested in developing those relationships. They're not important to them. They don't think about them often. Now, anhedonia, the third domain, is classically referred to as a reduction in the ability to experience pleasure. So things that would have typically been experienced as pleasurable by most people would not necessarily bring these people fully intensely pleasurable experiences. We now know that it's not just restricted to that ability to experience pleasure in the moment, however, but also to anticipate future pleasure. And that's really critical for finding the motivation to engage in futural pleasurable activities, right? For getting people off, up off the couch, to actually engage in a recreational activity that can bring them pleasure. They need to anticipate future pleasure by generating simulations of pleasure mentally, that can produce enough pop in that moment to get them to then act on it. And of course, anhedonia also is associated with a behavioral component of a reduction in the frequency of pleasurable or recreational activities. So each of these three domains within the experiential dimension, they all have in common that they have this subjective internal experience component, but also this diminished behavioral component, where they don't engage in goal-directed, social, or recreational activities. Now, the second dimension, the expressive dimension, includes the two domains of blunted affect and alogia. And blunted affect refers to reductions in emotional expression in the face, and the voice, and in body gestures. So these are people who we refer to, for example, as having flat affect. They have a monotone voice. They have a wooden, emotionless expression, for example. Alogia is basically going to consist of a reduction in the quantity of speech. So these people, when you ask them a question, will respond with bare minimum response. It may be a one- or two-word answer, and the person who might be speaking to them may feel that they really have to pull to get more detail, to get more information out of the person because they don't spontaneously elaborate. They're providing just enough information to answer the question, and sometimes not even that. So importantly, these five domains are minimally responsive to antipsychotic treatment, and they reflect a critical treatment need. And even though we talk about them as being five independent constructs, we think that they may not, in fact, all be created equal, if you will. We know that the domain of avolition, which again, is a reduction in motivation in goal-directed activity, is more central than the others. We've learned this through a number of different types of mathematical approaches, such as network analysis, for example, where we've mathematically tried to deconstruct which of the domains carries the effect on the other. Meaning that even though they're independent, these domains can interact with each other. They can have causal influences on each other. A good analogy for this is imagine that the symptoms, the five domains, are airports, and one of them could be the major hub. I'm in Georgia, so I'm going to say Atlanta. Imagine Atlanta is a major hub, and to get to all of the other locations, one would have to go through that major hub, go through Atlanta, to get to these other cities. We think that avolition has this role in negative symptoms. In other words, why does someone not engage in social activity, recreational activity? Why don't they show emotion on the face or in the voice or talk much? It's because of deficits and motivation. The deficits and motivation are so central that they underlie and even have causal effects on the other domains. So when someone has deficits and motivation, these other domains are more likely to emerge. And we think that avolition is driven by specific neurobiological mechanisms, and these are true across psychiatric diagnoses, not just within schizophrenia or the schizophrenia spectrum, but other diagnoses such as neurocognitive or neurological disorders such as Alzheimer's, dementia, Parkinson's, traumatic brain injury. All of these are conditions that also display negative symptoms that manifest, behaviorally and experientially similar to what you see in schizophrenia, with similar severity in general. We know now through, different modes of research that use different neuroimaging techniques, that corticostriatal circuitry in the brain is really critical for this symptom of avolition, and this cuts across diagnostic boundaries. Here in this, diagram, you can see that avolition is, thought to, in fact, have this causal effect. When it's present, it drives the existence of the other domains, but also poor functioning. So it's driving poor social functioning, poor occupational and school functioning, and activities of daily living. It also drives another critical treatment target in schizophrenia, which we refer to as cognitive impairment. Deficits in things like attention, working memory, executive functioning, that are also related to poor functional outcomes. Avolition is a key driver of cognitive impairment as well. Now, roluperidone has shown very interesting effects that were replicated in the phase II and III trials. What we did that you can see illustrated on the screen here is we took a network analytic approach to understanding why the drug achieved its effect. So we know that the drug was achieving an effect on the broad, constructs of negative symptoms, the broad construct, the two dimensions, but we, we didn't know causally which domain was carrying those effects. And so we tested this hypothesis that you saw on the slide before you, that it was avolition or these reductions in motivation that were driving the global treatment effect that roluperidone had. And that's indeed what came out. If you look at these figures here on the top with the red areas that are circled, what you see is that reductions in the internal experience of avolition, meaning that subjective motivational deficit, were what separated out the treatment arm from the placebo arm. Meaning that when the drug hit motivation, when it improved motivation, what you saw were these global improvements in the other negative symptom domains. Now, critically, we wanted to see if that same effect could be replicated in the phase III trial. And here it was. This figure here is showing a direct effect. We were able to isolate using more advanced mathematical network analytic techniques. We were able to isolate the direct effect of the treatment itself and identify which of the negative symptom domains ended up having these causal interactions to lead to these improvements in the other aspects of negative symptoms. And again, it turned out to be avolition. So here, across two separate clinical trials, we found this replicated effect, that avolition was what carried the day. It is the reason why we saw these global improvements in negative symptoms from roluperidone. We know that those effects are important to people with the illness and their relatives or caregivers. This slide presents data from two separate studies, and I'll walk you through this. The first study is one that we conducted here in my laboratory at the University of Georgia, and we called this the Self-Perceptions Study, and it was constructed to understand the subjective viewpoints of people with schizophrenia and their relatives or caregivers on why negative symptoms are important to them, on how they defined them, you know, what they think caused them, and how much improvement they would need to experience for their lives to change. In other words, what magnitude of improvement would they deem clinically meaningful? You can see the results here in this table. If you look at the portion on the left, what you can see are the two higher order dimensions of motivation and pleasure, that experiential dimension, and the expressive dimension and the individual domains that fall underneath them. And what we did in this study is we essentially asked patients, and separately asked their relatives or caregivers, to tell us what magnitude of improvement on a clinical rating scale, on the Brief Negative Symptom Scale, would be considered meaningful for them. And we didn't define meaningful for them. We left it open to their own interpretation, and it could have related to social, occupational improvement, you know, improvements in school, quality of life, et cetera. So, however, they defined meaningful improvement in their lives. What we did is we quantified the magnitude of change that would be needed on the Brief Negative Symptom Scale, which has a range on the individual items from 0- 6. So in this table, what you see is, in comparison to ratings given by clinicians, which you can think of as the kind of landmark for where that patient's negative symptoms were. We looked at how much of a decrease the patient said they would need to achieve for their lives to meaningfully improve. The answer here for the motivation and pleasure dimension was about 0.65 points of improvement. For the expression dimension, it was 0.23. So on this 0-6 scale, this was the magnitude of improvement the patients deemed would have a meaningful impact on their lives relative to where clinicians rated them in terms of their negative symptoms. The relatives and caregivers also provided these same ratings on the magnitude of improvement that they thought that the patient would need to achieve for their lives to be meaningfully improved. And you can see it's roughly in the same ballpark. Now, critically, what you see here on the right is something that we can use to compare the magnitude of improvement that clinicians say is clinically meaningful with the magnitude of improvement that the patients and their relatives say would need to be achieved for a drug to be meaningfully impactful in their lives. On the right here, what we did is we took data from the roluperidone phase II-B trial, and we essentially anchored it to the Clinical Global Impression Scale. So we looked at the relationship between the Brief Negative Symptom Scale scores and this kind of anchoring method of the Clinical Global Impression score that is related to a minimum clinically important difference or minimum clinically important change that the patient identified that would need to be achieved for clinically meaningful improvement to occur on a medical definition, right? So that the treating clinician deemed meaningful. And so here again, this value reflects the magnitude of improvement the clinician deemed clinically significant on that 0-6 scale, on the Brief Negative Symptom Scale, to be deemed clinically meaningful. And the clinician here, you can see, deemed an improvement of 0.72 points change for the MAP dimension and 0.59 for the expression dimension. And these numbers are in the same ballpark. They're really pretty comparable to what you see in comparison to what the patient said they would need to achieve for their lives to be meaningfully improved. And this is something that's really critical for the FDA. This type of data on the magnitude of improvement needed for a patient from their perspective, to deem a treatment meaningful, has not really been published much in the field. So this is really important for the FDA to make this type of comparison and say that the magnitude of treatment a drug has achieved is not just comparable to what a clinician would say is important, but also to what the patient and their relatives or caregivers would say. And roluperidone does very well here. It's roughly equivalent to, and sometimes even better than, what the patient would say that they need to improve to show a meaningful change in life. And with that, I will stop my portion, and I will introduce you to Dr. Brian Kirkpatrick from the University of Arkansas. Thank you, Greg. Good morning, everybody. So I'll be talking about measuring and what to do with measurements of negative symptoms and how that applies to clinical trials. There are a lot of studies that have had industry and academic that have focused on negative symptoms as their primary outcome, and none of them have, you know, there aren't other drugs that have been well-validated for effectiveness for negative symptoms specifically. There are several contributions to this. One of them is a high placebo response rate, so this is noise. And there are many things that contribute to this. One important one is simply that you have a great deal of attention in these clinical trials. You come in, and people are smiling at you and very interested in what you say, and that has an impact on people. Excuse me. This is a widespread problem. It's in other areas of psychiatry, not just in schizophrenia. And one that is particularly a problem for people who have schizophrenia in these trials is antipsychotics themselves. They're dopaminergic agents that can inhibit the brain's reward system, and so you can, you know, your attempted therapy, whatever the other drug is, may have a diminished effect or no effect, in part because of this effect on dopaminergic circuitry. So it can be very challenging to find a signal. The other one is what is sometimes referred to as pseudo specificity. So if you have improvement in a delusion, say someone is paranoid, or if they have overwhelming hallucinations, they find it difficult to pay attention to other people or other activities. If you treat them successfully with an antipsychotic, their negative symptom ratings, avolition, anhedonia, blunted affect, and so on, may go down on rating scales. But this is kind of misleading. This is not a true improvement in the primary negative symptoms that are actually just a result of the illness directly. So we're talking about primary versus secondary negative symptoms. So primary negative symptoms, in a sense, it's easier to understand if I explain what secondary are. They are due to things other than the illness itself. So for instance, as I mentioned, positive symptoms can cause these negative symptom rating scales to go up: depression, anxiety, side effects of antipsychotics, substance abuse, and then simply being socially isolated, which happens to many people with schizophrenia. So primary negative symptoms are not caused by these other factors other than a neurological, biological problem that is part of schizophrenia for many people with schizophrenia, so it's primary. It is not caused by secondary, these other things. And so far, clinical trials haven't really had the right design, the right population. So recently, Cobenfy, the new muscarinic antipsychotic, has been approved. The company said that they had improvement across a range of symptoms, including negative symptoms. And on the rating scales, yes, negative symptoms went down. But the FDA said, "Wait a minute." They said, "The pivotal trials of Cobenfy, supporting the schizophrenia indication for Cobenfy, were not designed to capture changes in positive or negative symptoms as distinct groups. In other words, negative symptoms that change whether or not there was a change in psychosis. Additionally, the pivotal trials for Cobenfy were not designed to evaluate the efficacy of drug and negative symptoms, because the patients in the studies were experiencing exacerbations of schizophrenia, which can confound the assessment of improvement of negative symptoms when the positive symptoms improve. So how would you go about evaluating negative symptoms in a way that would let you gain an indication for the treatment of negative symptoms? You, you need them not to have a change in positive symptoms, so you want people who enter the trial to have minimal and preferably stable positive psychotic symptoms, hallucinations, delusions, disorganization, and the same for dysphoria and anxiety and depression. So you don't want to use dopaminergic antipsychotics either, because the signal can be obscured by the noise or of sedation, avolition, and movement problems, motor problems. And you also may directly impact the structures in the brain that regulate emotion, and also tend to regulate negative symptoms. And it becomes impossible to distinguish why are these improving? Is it because you've improved these other things, or because you've actually done something to what's intrinsic to the disease? And so you can kind of see the advantage of monotherapy trial design. It's the best way to isolate the drug effect on primary negative symptoms if you include patients who have stable and minimal positive symptoms and anxiety, depression symptoms. And the other thing of that is, it's really to gain an indication, it's important to show an impact on function. Regulators, payer, payers, and patients care a great deal about the function and quality of life. One of the difficulties, of course, is that improvement in function is a lagging indicator. Takes a while, even if you have an effect, a good effect, for that to show up in rating scales, because you have to remember, many times these patients have lived for years with these negative symptoms, so they are tending, going to tend to have smaller social networks, fewer opportunities for socialization, difficulties with social skills, decreased opportunities of a number of other kinds, for recreation, for employment. And they're often going to have negative beliefs about their abilities. They're going to have poor confidence. Now, there are two or three scales that are accepted. The most influential for measuring this within schizophrenia is a scale called the Personal and Social Performance Scale, the PSP. I'll be referring to that in the next few slides. So clinicians rate this scale. It's widely accepted as a measure of function in schizophrenia. It has four subscales: socially useful activities, work and study, personal and social relationships, self-care, which can often be quite impaired, and disturbing or aggressive behaviors. So here we see the using that kind of design, monotherapy, stable and minimal positive symptoms, and anxiety, depression. In the phase II-B study by Minerva of roluperidone, you see... Okay, the blue is placebo, and over here on the vertical axis, they all start out at zero because this is change, decline in the negative symptom factor scale. So blue, you can see some placebo effect, and in green, you have the 32 mg dose, and it was significantly different and became significantly different, began to separate by the second week. The effect was bigger with the 64 mg dose, and it stayed, and it was constant. And you see that the effect size for the 32 mg was pretty good. That's immediate, little more than a usual definition of a medium effect size. And for the 64 mg dose, it's close to what is called a large effect size. Moreover, this is particularly, it's encouraging because this is what matters for people when they're in their lives. You saw a significant improvement at the 64 mg dose. The 32 mg dose did not separate, and we'll come, that has implications for future studies. And here we go to the phase III study, in which you can see this, because it didn't really improve the PSP, didn't have an impact on function. The study was solely of the 64-mg dose, and it did meet the primary endpoint. Here you see it separates, not quite significantly at two dose, at two weeks, but then it stays significantly different throughout this study. Well, how about the PSP? You also see an impact on function in their lives. Going up is good, a higher score is good, and you see there's separation at four weeks, and then at eight and 12, it stays significant. Now, I'm sorry, before I get into that, the effect sizes of the PSP are not real large, but again, you need to keep in mind a couple of things. We talked about why it was a lagging indicator. You would expect it to continue to improve as they gained confidence and began to have more success. But another thing that I think is really important is the effect, even a relatively small effect size, may make them able to benefit from psychosocial treatments. And the psychosocial treatments of schizophrenia are actually pretty powerful, especially once psychotic symptoms are relatively well controlled. So this relatively small size may have big implications for their quality of life, their level of function, because they're now more able to participate in psychosocial rehabilitation. Now, the FDA understandably had lots of concerns and questions at the beginning about a monotherapy, and they thought, "Well, these people are going to be relapsing a lot." But what you see here is something that's very interesting. This is what we call a survival curve, so it's really time to all-causes discontinuation rates. So it's for lack of efficacy, it's for side effects, it's for they're simply deciding they don't want to participate anymore. It starts at 1.0, so this is 100% of patients have not discontinued at the beginning of this study. And the lower it goes, the more have left the study for one reason or another. Now, what you see, the red line is, these are the patients who took roluperidone in the two studies. And the blue line, the comparison is really very interesting. They're large studies, one performed in the United States, the CATIE study, with something like 1,400 patients. And the EULAST study, which was a European study. What's very interesting about that is that unlike the patients in the roluperidone study, the patients in these two studies got, in both of these studies, got antipsychotic treatment. Yet you see the roluperidone group has a lower relapse rate over this, over a number of months. So the FDA is now reassured about that. They said, "Well, maybe it's partly because of the nature of this population you're studying, which is maybe a contributor, and maybe it's just that there's something about roluperidone that has an effect, perhaps directly on psychotic symptoms, perhaps indirectly, maybe through emotion. They are not discontinuing. They're not stopping. They're not being taken out of this study or leaving it on their own." So what are the overall conclusions from this? Roluperidone demonstrated clear statistical significance on multiple efficacy endpoints. Improves what we consider primary negative symptoms. It improves functioning, improves avolition. No change in positive symptoms or anxiety, depression. They started out minimal and stable, and they stayed that way. Monotherapy was associated with a low relapse rate and low discontinuation overall. There was no evidence of the well-known disabling side effects that are often observed with antipsychotic treatment. Changes in metabolic measures, so increased risk of diabetes, for instance, sedation, motor symptoms, which are common in those drugs, elevation of prolactin, a hormone that can have some bad effects if high for over a long period of time, and no, unlike the muscarinic drug, no nausea. And this is exciting. It's a novel pharmacological profile, derives differential clinical benefit in both of these studies. And as a physician who sees patients a lot, having another mechanism of action is really important for patients. It's one of the reasons hypertension and diabetes have much more success if patients take their medications, because they have multiple mechanistic classes. And so someone who doesn't benefit or can't tolerate a drug in one class may do much better in another class. And since my entire career, we've had, in a sense, one mechanistic class, we now have two. This is, becomes a third, which is pretty exciting. And I'll turn the conversation over now to Dr. Rémy Luthringer. Thank you so much, Greg and Brian. I'm sure that you will get a lot of questions because you addressed a lot of important points. So let me focus in the last few minutes about on the proposed phase III confirmatory trial. We have exchanged a lot with the FDA, yes. So here you have the study design. So sorry about this complicated slide, yes, but so basically, you know, you could cut into three pieces of the study. So first part, which is on the complete left, is the screening period. And the screening period is for one month in this study. But what is very important during the screening period is to really make sure that you get access to the right patients and that you are screening the right patient for the study. When I speak about right patients, this is where we got really consensus and discussion, which came to a conclusion that, yes, indeed, I mean, we should include, like in the two previous studies, patients who have stable positive symptoms and stable negative symptoms over a period of time of six months, and have a certain level of negative symptoms which are impairing. So it's based really on very simple criteria, but that means this is allowing to really select the right patient population. Afterwards, you have really the key part, which is in green here, or which is called Part A. This is really looking to efficacy, as to reconfirm the efficacy we have seen in the two previous studies. You see that, I mean, we will measure efficacy at week 12, like in the two previous studies. And here, the study design is roluperidone 64 mgs, so the only dose we testing here is 64 mg, which was the highest dose we have tested in the two previous studies, versus placebo. Yeah, so this is obviously double blind part. So this is really to reconfirm or to show that means the roluperidone is improving negative symptoms, and because we have as a sole key secondary endpoint PSP, to confirm that this is, how to say, transforming or negative symptoms improvement is having an impact on functioning. When the patients have completed this part, again, which is very similar to what we have done in the two previous studies, part of only having one dose versus placebo, patients go into part B, or the third part of the study. And this part is mostly focused on looking to relapses of positive symptoms. So as Brian said, clearly, I mean, we have seen in the two previous studies, when we were using open label extension, we have seen a very low relapse rate of positive symptoms in this patient population we are including in our trials. And here, what we are doing or what the FDA is asking us to do, and I think it is very important, is not only not to control anymore versus placebo or to have an open label extension, but to compare 64 mg of roluperidone versus standard of care, so basically versus antipsychotics. So the study design we are using here, in order to really maintain the blinding as much as possible, is what we call a double dummy approach. So basically, each patient will get a tablet of roluperidone, active drug or placebo, and a capsule of active antipsychotic or placebo of the antipsychotic. So we are testing here, or we are including three antipsychotics to compare to roluperidone. And you see that the patients from Part A are re-randomized equally to 64 mg of roluperidone or placebo. So this is how the study will be conducted moving forward, yes. Now, going more into the details. So again, as I said, the very important part here is part A, the 12-week double-blind placebo-controlled study versus roluperidone. You see that it is a study with 380 patients. And what is important here is that the primary endpoint is exactly the same as the one we have used in the previous study, in the phase III study. And as this, we have elevated, like in the phase III study, the sole key secondary endpoint is functioning, is PSP. And so very, very, very similar to what we have done in the past. Because it is 64 mg, remember, 64 mg showed a significant effect compared to placebo. The statistical analysis is a classical MMRM analysis, which is what most of the companies are using and what the FDA likes to see as an analysis. Going now to the second part, or the part B. So again, this is really focusing on safety slash number of relapses in this patient population when you're comparing roluperidone to standard of care. And so here, in terms of analysis, you know, because we have such a limited number of relapses, you can only do a qualitative analysis of the relapses. You cannot do statistics here, and this is something we have discussed as well. And so this is, again, looking to using our drug in monotherapy, what is a long-term safety slash relapse rate, when you treat them with roluperidone, compared to having patients treated with antipsychotics? So, so this is a very important part as well, because, if we are reconfirming the results we had in the two previous studies, which were open-label extension, low relapse rate, this shows that, yes, this population exists, and this population can be treated in monotherapy, and the risk of relapses of positive symptoms is really minimal. Now, obviously, and this is a very important slide, and this is, summarizing all the attention of the team, on the executing the trial, this confirmatory trial. First of all, I will not insist too much on the number of patients and the number of sites, but here, we are really trying to limit the number of sites to 40 sites, because it's well described that having too many clinical sites has an influence on the variability of the data, and you might lose the signal, even if the signal is very present. So we really are focusing on 40 sites. You see that we will have patients coming from the U.S. and from four European countries. Now, the second aspect, which is very, very important, and, you know, we have started with this even before we were sure that we get the financing, we have started to work again on site selection, and really based on quality performance metrics. Because, you know, sometimes one site can be extremely good two years ago, and for a reason or another, is no longer performing extremely well. So we really have used a lot of criteria here to come up with the right, you know, set of clinical sites. First of all, I mean, some of the sites have participated to the Minerva trials, the previous Minerva trials, and, you know, we have data we can analyze, and we can reconfirm to see if the site is doing exactly the same quality work as before. But we have also access to other information, and you will see that the CRO in the next slide, the CRO we have selected has a lot of expertise or a lot of experience, and recent experience of running trials in schizophrenia. And clearly, their input, you know, knowledge about the quality of the clinical sites will be part of these 40 sites, was also extremely important in selecting the sites. And last but not least, our provider, who will do the online monitoring of the quality of scoring, has also a lot of experience. So we really put all this experience together in order to come up with the right sites with the appropriate, you know, staff, or people running the study, people who are used to do the rating of the PANSS scale. And they need also to have the appropriate number of patients, yes, because you know, if you have one site only recruiting a patient from time to time, each just three months, you know, the learning curve is no longer there, and they start from the beginning, and this might induce some variability. So, one criterion was also sites who have really the potential to recruit patients. Now, the last bullet point here is key, yes. Because what we have to do here is try to apply all what Brian explained and all what you have learned from the previous studies to minimize the potential placebo effect, but to maintain also the roluperidone improvement we have seen in the two previous studies. Keep in mind that when you're looking to the two previous studies, the improvement seen on negative symptoms with 64 mg is very similar between the two studies, so the drug is always performing in the same way. So what can we do in order to keep this discrimination between the placebo effect and the roluperidone effect? So the first thing, and I think Brian addressed this briefly, and this is very close to my heart, because I started as a psychiatric nurse, is a nursing effect. When you spend time with a patient, keep in mind that these patients, when they have negative symptoms, and Brian said this very clearly, the social interactions are becoming limited, very, very limited. Suddenly, they are in a trial, they see a study nurse, they see a clinician, they see the rater, and they get attention. So this might have an effect indeed, which is not sustained over time, but has an effect on improving negative symptoms. So this is what I call the nursing effect. So what we have decided in this study is to reduce interactions with the patient. You know, compared to the previous phase III, the interaction is really reduced to when the patient has to be scored with the clinical scales. So this is one aspect which is very important. The other aspect is intensive training of the raters for the PANSS scale, and I could also put here the PSP scale. Keep in mind that, I mean, most of the trials are done for antipsychotics, so where patients have an acute episode of positive symptoms, and so this is quite easy to score, whereas scoring negative symptoms using the PANSS scale is a little bit more challenging. So here, really, we also are focusing a lot of our efforts to really help the raters to understand how to use the part for negative symptoms from the PANSS scale. The other aspect, which is not really related to the execution of the trial, but which is important, is that it is very well described in the literature that if the expectation to get active drug is high, you know, you have a tendency to have an inflation of placebo effect. And keep in mind that in the two previous studies, we had two doses of roluperidone versus placebo. So 2/3 of the patients were receiving active drug versus 1/3 placebo. So the expectation was higher than in this trial, where you know, the randomization between active drug and placebo is 1 to 1. So this is a very important aspect, not specific to our trial, which is well described in the literature, but which is important. The other aspect is, you know, again, coming to the selection of the patient. Getting the right patients into the study is very, very important to reduce the noise. And this is a difference compared to what we have done in the previous trial. In the previous trial, it was purely the decision from the PI. It's still the decision from the PI in this trial, but what we are doing here, and this is more to help the PI to take the right decision, we will have a small committee discussing each patient's inclusion to the study. It's just to say: Are you sure about this aspect? So just to enhance the quality of the patients going into the study. The next bullet point is key here, is to use, you know, this service provider, who has a lot of experience, in order to monitor the blinded data once they are generated online, to monitor the data. And here, we are going down not only to the level of the clinical sites, but we are going down to the level of the person who is doing the scoring, yes. So we will have such kind of monitoring of the rating or the quality of rating from each scorer at each site, yes? This is very important, but what we have added here, and we have really the chance to have someone who has joined our team, who is one of the world-leading experts in overseeing clinical trials, yes. And so in combination between the service provider and the person who has joined our group or company, you know, we have a really very strong tools to really assess online if someone is deviating from the standard deviations of scoring, which is allowed in this, in which case we are using here the PANSS and the PSP. We have also, we are using also e- tablets here, which are very important because they are prompting the person who is doing the scoring about discrepancies, yes. I'll give you an example. If you score worsening of negative symptoms and you score improvement of PSP or CGI-S, this is not completely accurate. So the tablet is not correcting what the scorer is doing, but is asking the question, "Are you sure about what you have done here?" So all in all, this gives more help to the scorer to do the right thing. And last but not least, you know, because we have only one dose versus placebo, you know, we do not care about the type one error correction we had in the previous phase III trial, you know, where we had to use the Holm-Bonferroni correction. And you know, to claim that you have a positive study, you need to have the two doses showing a p-value. In the previous phase III, it was only the highest dose. In this case, we're only testing the highest dose, so no concern about the type one error correction. So, I think when having all these, you know, things in motion in order to come up with the highest quality of execution of the trial, I think the probability of success is really enhanced. Now, this is the update on where we are with the study. We have appointed Syneos as a CRO, and I was saying in my previous slide, that Syneos has a lot of experience in running trials in schizophrenia. They have been involved, or they have run, with the help of, obviously the sponsors, they have run the Karuna study, the studies of the first drug with a new mechanism of action. So this is very recent experience Syneos has in running clinical trials in schizophrenia. So really, we are really happy that Syneos is our partner to run this study. We have already activated multiple sites, and as I told you before, this is a long process. I mean, we have worked on this over the last few months, quasi one year, in order to come up with the right sites, you know, to participate to this trial. We will have a first patient in Q2 2026. All is moving according to plan for this. And afterwards, based on the feedback from Syneos, based on the feedback from our previous experience and from different sources, we estimate that, I mean, we will have the top-line results of the primary efficacy endpoint, the... So the week 12 efficacy endpoint, we will have this in the second half of 2027, and the results of, you know, the relapse part, in the second half of 2028. And so what we are doing, and this is ongoing, yes, I mean, we continue our dialogue. We keep the a-agency, the FDA, informed about progress, and when we have the top-line results of the 12-week primary endpoint, we will obviously share this with them and discuss about what is the best way moving forward in terms of resubmission of our NDA. So this is just to say, again, we are so proud that, I mean, we have all these top-tier investors who have really done a lot of due diligence on our data and came to the conclusion that it is worthwhile to finance us. So before handing over for Q&A, let me just just summarize again, the Minerva confluence. I think here we are in a, in a, in an exceptional good situation and unique situation. First of all, we have the pharmacological tool, we have the drug, which is really what you need. And we have already, you know, clinical data, the truth is in clinical data. We have two studies where we could really demonstrate that the drug has an effect, and has an effect also on primary negative symptoms, which is extremely important. I think, with all the very important and constructive exchanges we have with the FDA, and this is still ongoing, I think we are coming up with the right phase III trial design to confirm that, I mean, roluperidone is really the right molecule for patients with negative symptoms. Again, I think it is really the right moment, as I was mentioning in one of my previous slides, because here we have really the alignment of the regulator, who is really open to a paradigm shift, and to approach the treatment or the assessment of negative symptoms of roluperidone in the way I was just describing. I think the medical and scientific community is making a lot of progress, and is ready, you know, to such kind of paradigm shift. And indeed, I mean, having these top-tier investors who really help us to go to the finish line with roluperidone is obviously important. This is what I wanted to tell you, and I think I hand over to Corey for Q&A. We'll have Tara handle the next segment of the Q&A, and then I'll do the written section. But go ahead, Tara. Great. Thank you both. Yes, so at this time, we'll be conducting a question and answer session with our speakers. Please hold for a brief moment while we pull for questions. Our first question comes from Andrew Tsai at Jefferies. Please go ahead. Hey, guys. Thanks for hosting this. It's very informative, and congratulations on the progress. So, first question is just around powering assumptions for the 12-week portion. How did you power this study? What kind of placebo-adjusted Marder score change would you like to see? What did you assume for placebo, for instance? And then the same for the 40-week portion as well. You know, I'm assuming the end goal is to show no significant increase in relapse versus an antipsychotic, but is there some leeway here? And can you maybe talk about what the qualitative bar for success would be? Thank you. I think this is for me. Yes, so thank you, Andrew, for your question. So, you know, the first 12-week is powered 90%, yes. So it's powered 90%. You know, we have estimated a difference between placebo and treatment of 1.8, 1.5, 1.8. And these are the assumptions. We have also taken the same relapse rates we had in the previous trials. Sorry, not the same as, the same dropout rates, excuse me, of the previous trial. Because these are the three criteria used in order to power the study. So this is what we have done. What I can tell you, because this was important discussion also, not only with the regulator, but with our investors. The study is overpowered, yes. Basically, it is more than 90% powered, because the powering assumptions I was telling you was with around 300 patients. So we decided to go with 380 patients to have the room left, you know, to have enough patients to go to the week 12. Now, concerning the second part, as I said in my presentation, we had really very limited relapses in the two previous studies. Also this said, it was an open label extension, yes. If you remember, in the phase III study, you know, we had less than 15% of relapses over a period of one year, yes. When you're looking to the meta-analysis which have been done on antipsychotics, the relapse rate is about 20%-35%. Yeah, so clearly, because of our patient population, and I am also very convinced that our drug has an effect on keeping these patients stable in terms of positive symptoms. Think one second about the in vitro activity, yes, I mean, which has been demonstrated in the past by several people to be protecting against, you know, worsening positive symptoms. I think, you know, this explains why we have this low level. Now, what the FDA wants to see just is, you know, head-to-head, yes? I mean, in the same study, with the same patients, how it looks like. We already have data, as you have seen the data presented by Brian. Yes, so we have analyzed the CATIE and EULAST database. We have extracted the patients who have the same eligibility criteria as our patients, and, you know, the relapse rate is very similar between the two, you know, patients treated with antipsychotics versus patients treated with roluperidone. So long story short, just to give the context that people understand that what we are doing here, I think what the FDA is looking for is something which is very similar between the two groups. As there is some room left. Obviously, if one group, I mean, say, goes to 50% of relapses and the other one is at 10%, this is a problem. But, I mean, if you are, you know, in the ballpark and with some variability, I think this is what you need. And again, because we have such a low relapse rate, you cannot do some form of statistics. You cannot do, for example, an inferiority study. It's just impossible, because we have not enough cases. This would be a 2,000 patient study, and so clearly it is purely descriptive. Thank you. Can I just one quick follow-up, then, I'll be mindful of, like, acquaintances. Can you file after the 12-week data as the 40-week data is being produced? Is that basically a rolling kind of NDA possible, for instance, or do you truly have to wait for every patient to complete all 52 weeks before filing? Thanks. It's a great question, yes, and so I can obviously not decide for the FDA. Yes, I mean, the FDA has to decide. But what I can tell you is that you know, we have really this very constructive dialogue going on with the FDA. We have a plan to share immediately the 12-week data, primary efficacy endpoint with the FDA. And you know, we will see what is the best way to resubmit our NDA. Yes, this is just my personal opinion, but, this is such an unmet medical need, yes, if I think the 12-week data are showing that, I mean, we have a good discrimination between placebo and treatment, that we have a P value, and that PSP is also improving. I hardly see that we have no room left in order to negotiate things with the agency. And keep also in mind that we will already have also some data about the relapses. We will not have all the patients, but we will already know, blinded, how many patients are relapsing. Yes, so I think we will have a lot of data in hand. And last but not least, I think it's also important for people to understand this is a resubmission of our NDA, and so the review time is six months and not 10 months or one year. So this is a six-months review time. Thanks very much. Appreciate it. Thanks for the questions, Andrew. Our next question comes from Douglas Tsao at H.C. Wainwright. Please go ahead. Good morning. Thanks for taking the questions and congrats on the progress. I guess a question to Dr. Strauss and Dr. Kirkpatrick. You know, I can understand the need to sort of have a monotherapy study to sort of really isolate the effect of roluperidone, right? Versus what may be sort of the confounding factor introduced by antipsychotics. When we think about the sort of natural history of those patients, and I think Dr. Strauss, you sort of showed a curve showing the relationship between the positive and negative symptoms. How do you anticipate the timing or the best time or sort of the relevance of roluperidone in terms of an intervention? I can see in the early stages before you have the significant number of psychotic events or later, right, when the positive symptoms sort of really sort of seem to go into a quiescence period, the roluperidone would be a and negative symptoms persist, that roluperidone would be perfect. But what about this time period when we still see a lot of sort of psychotic breaks, or psychotic episodes? You know, I know there is evidence that roluperidone shows improvement in terms of relapses, but, you know, how should we think about the potential use of roluperidone as a monotherapy in those, that population? What was the proportion of people in your studies who were, for instance, below the age of, say, 35? Below 35? Yeah. What would you guess? It was around, so don't blame me if it is not completely correct, but I think it was around 15%-20%. Okay. I don't think there's reason to believe it would not be effective for the same if you use the same criteria for picking them. I think, you know, in patients with psychosis, age may, has made some difference with regard to side effects in children, but we're not proposing for children, and I think young, young people respond to antipsychotics well. I don't think there's a strong reason to believe that it has to be restricted to people who are thirty-five or above. So the other thing is, I would not be surprised. American psychiatrists tend to like to do things separate from guidelines. I would not really be surprised if they ended up combining, saying: Well, this person doesn't really have motor side effects or anhedonia because they're antipsychotic, so I'm going to add it on to an antipsychotic. Well, I can add to that. I would even say we know that as the illness becomes more chronic, the environmental influences on negative symptoms do strengthen. So the fact that roluperidone has shown an effect in these highly chronic patients is really as reassuring. You know, it should be less likely to show an effect on people whose environments have become entrenched and are less likely to promote change. And I would think that people earlier in the illness, you know, first episode, early course, you know, even the prodromal phase, who've maintained their social networks, who have more supports, you know, the environment's not become as degraded. They may have more plasticity, if you will, to show these effects. If you allow me, Doug, to add something here. You know, all is about how you label the drug, yes? And again, for the moment, obviously, we have not a final conclusion about the labeling, but so what we are proposing here and what we are doing basically in the trial, yes, I mean, is the following, yes: We take patients who are stable over the last six months. You know, afterwards, the clinician will decide what is stability, yes, but, I mean, we take patients who are stable, and here, the clinician can take the decision if he wants to treat or to stop the antipsychotic and to treat with roluperidone. And so what we are suggesting, or what we are proposing, because, you know, the people should not understand that we are against antipsychotics. I think antipsychotics are useful, but as major tranquilizers, for the reason for why they have been developed, yes? So what we are proposing here is that, I mean, if we have a relapse, again, it is limited with the roluperidone, but if we have a relapse, you stop roluperidone, and you treat the relapse with an antipsychotic, yes? And afterwards, when the patient is stable again, indeed, I mean, you can think again about putting roluperidone in monotherapy, you know? And, I like, something which has been published by someone who is important at the FDA, which is to say, "Look, you know, positive symptoms is like having fever in an infection, yeah? Whereas, the deficits are negative symptoms. So I think it's a quite nice picture of how you could think about using roluperidone in the case, in the case of clinical practices. You're on mute, Doug. Well, thank you very much. That's very helpful, Rémy. All right. All right. All right, thanks, Doug. We'll go to some written questions now, being mindful of time. I want to try to wrap this up in six minutes or so. We've got some great written questions here. Hopefully, we can get through all these. The first one is, many symptoms of psychiatric diseases occur in multiple diagnoses, and is, is that true also with the negative symptoms of schizophrenia that you describe here? In other words, if it works in schizophrenia for these negative symptoms, what are the other indications that might be possible to take roluperidone into? I can start that one off. So we know... I would say the markets for this would be, psychotic disorders other than schizophrenia. So there are other psychotic disorders, like schizophreniform, schizoaffective, that display negative symptoms. The prevalence rate for schizophrenia is 1%. The prevalence rate for all psychotic disorders is about 3%. So that's number one. Number two would be the prodromal phase of illness. So in the DSM, there's a condition called the attenuated psychosis syndrome, and this is people with this pre-illness presentation, who have, attenuated positive symptoms, but often have negative symptoms that are fully fledged. And the third would be neurological disorders. We know that a range of neurological disorders do have clinically significant negative symptoms. So, for example, Alzheimer's, Parkinson's, traumatic brain injury would be some common ones. So I think we know that the mechanisms underlying negative symptoms are cross-cutting corticostriatal circuitry are going to be involved across diagnostic boundaries, and so I think all of these would be relevant targets. Great. Next question gets to avolition. So maybe sticking to you, Greg, is that you're showing avolition as the centerpiece of capturing that effect on negative symptoms. But can you elaborate a little bit more on how the primary endpoint that's being used in phase III is configured to be able to ensure that you do capture that effect on avolition that roluperidone has shown in the previous studies? Yeah, that's a good question. So the primary endpoint, the PANSS Negative Symptom Scale, has a range of items related to negative symptoms, including multiple that tap into avolition, and some that tap into the other domains, asociality, blunted affect, et cetera. And so it definitely enables the proper type of mathematical approach to be applied, like we did before, using network analysis, to see if that centrality effect replicates from a network perspective. And there would be no reason to think that it wouldn't, since it replicated once already from the phase II to the phase III trial. It raises an interesting possibility that really the strongest effect would be a drug that is relatively specific for avolition, and that could change what kind of animal models you use and what kind of preclinical human models you used for drug discovery. Yeah, right. Next question on mechanism of action, and asking you to start, Dr. Kirkpatrick, is can you elaborate more on just your view on this mechanism of action as the mechanism itself, as important now that we have clinical data, but just speak to that in relation to the other classes of drugs that act in dopamine and the muscarinic receptors? Yeah, it's, I mean, there are a number of things can be said. I'll try to be brief. The, the 5-HT2A, the serotonergic effect, is really very interesting, because there's another literature that's been, didn't lead to drug development particularly, but, that, drugs for that receptor are actually antipsychotics, which is very interesting, and that's, that's one of the- certainly one of the important mechanisms that's going on with roluperidone. And we have a hint that it might act as an antipsychotic. But I was talking more generally about the clinical efficacy of having multiple mechanistic classes, and that's, that's very helpful for patients with a wide variety of diseases, because efficacy is going to vary from person to person, to some extent. In other disorders, it, it, the efficacy is better for one mechanism than for other, for the individual. And also, side effects are a big issue, especially metabolic side effects these days. So having medications that have... even if they have the same overall prevalence of significant side effects, having different ones, really, that's a real advantage for patients, because patients, one patient may be sensitive to A but not B, and another patient, the exact opposite. So it's interesting theoretically, in terms of pharmacology and also just practical use for patients to have a new mechanism of action. Great. All right, last question, and then we'll wrap it up, and after this question, we'll turn it back to Rémy for some closing remarks. But this comes from Tom Schrader at BTIG, who's asking about the placebo rate in the upcoming phase III. You spent a lot of time elaborating on things you're going to do to minimize the placebo effect, but he asked, "Do you agree that a key to being able to separate active from placebo is how fast the placebo patients decline? Do you agree to that?" Then, second part of it is: "Is that rate that you expect, in the placebo arm, consistent other trials in schizophrenia? So I'm not completely sure that I understand the first part. Yes, the decline, you mean improve, yes, I guess. So this is because they do not decline, they improve on the placebo, yes? They're just not improving as much as with treatment, and in addition, the effect is not really maintained over time. Yeah, so but clearly, you know, all what I described here, I think will definitely help to bring the placebo effect to a level which is probably closer to the phase II-B's than to the phase III trials. Because keep in mind, one second, that here we have a drug, and Brian just said it, without side effects like what we have with antipsychotics. You have a very, very successful phase II-B study, and you propose this trial to, to patients. So, so, so clearly, and also having two doses, you know, the likelihood to get active treatment, all this is described in the literature to make the, the placebo effect bigger. So, so all this is no longer present in this new trial or in this confirmatory trial. So, so I think really, you know, we will really be able to control much better the, the, the improvement of placebo. Now, concerning the second question about comparison with, with other trials, I think the, the, the short answer is, you cannot compare our trial with all the trials which have been done, yes? Because, first of all, if you compare to trials, which are looking to, acutely relapse patients for positive symptoms, Brian, I think, explained this very well, and the FDA even pointed it, this is a pseudo improvement, that you just bring maybe your patients back to, to baseline, of, you know, the course of the disease, in terms of, of negative symptoms. So, the only company who has done something very similar in terms of study design like we have done is, Lundbeck, and they have even published the data, which I think it's a PDE10 inhibitor, but unfortunately, the drug did not work, so they used exactly the same study design. So, long story short, today, we have no comparison. All right, fantastic. I think we'll wrap it up there. And on behalf of LifeSci, I just wanted to thank Greg and Brian for all their insightful comments today. And thank you all for listening, and I'll turn it back to Rémy for some closing remarks. So I can only echo what you're saying, yes. I mean, Brian and Greg, really thank you for being here today, and also having already published on our data and continue to help us doing the right things and analyzing hopefully the right in the right way the next study. Yes, and thinking about how large and how what is next after this trial. Yes, because as you very well said, I mean, this is a transdiagnostic problem, yes, so negative symptoms, it's not specific to schizophrenia. So thank you again for being here. I would like also to thank once more, you know, our investors. Believe me, they have done a lot of due diligence and they helped me even to analyze the data through different angles and always, I mean, you see that you have a drug effect, so thank you to all what they have done and their support. I'm really looking forward to this continuous dialogue with the FDA. One aspect I would like to highlight, you know, I had the chance to interact quite often with patients or with patients' associations, and I'm really thinking about patients. Patients really deserve a treatment for negative symptoms. As you heard, this is what is impairing their life and making their life difficult, so this is what is driving Minerva and all the people who are helping us to bring roluperidone to the finish line. So thank you for your time, and we will keep you updated about progress. As you have heard, we are close to start recruitment, so stay tuned. Thank you for your time.