Minerva Neurosciences, Inc

Good morning, everybody. It's really a pleasure and honor to have you here on behalf of the Minerva team. Most of my colleagues are here, so after these presentations, when we have something to eat afterwards, don't hesitate to go to see them, to speak with them. It's really an honor to have you here to really, I think, present you something which is very important. As you know, since 70 years, People have tried hard in order to improve negative symptoms of patients suffering with schizophrenia. And I think here today we have Roliparidone, which is really, really creating some hope for patients. And as you know, we are all here in order to come up with better treatments for patients. So this is what we will go through today to give you an update about where we are and where we are going. And if it is moving. It is moving. So because you're a public company, I have always to show this slide. But I think it's just to mention that we are a public company. And if you want to know more, you have to go to our filings, SEC filings. So I have really the great pleasure to have with us three persons who have been extremely important for the space. So I have the honor to have Dr. Strauss, Greg, yes, because we are working together since quite long, yes, allow me to call you Greg, yes, but Greg, you will see, has worked on our data, has analyzed our data, and he has obviously a very broad knowledge about the space, but I will not go more into the details because his CV is too long, and he will present his research when he will speak. The second person could not make it to today. It is Dr. Brian Kirkpatrick. And Brian will also speak. And Brian is really, I think this is really amazing because Brian is really, really an incredible researcher, but he kept really the contact with patients. He sees patients on a daily basis and he will tell us about how these patients are looking like, how he sees his patients. I mean, we are targeting with rhodoperidone in his clinical practice. And last but not least, we have Dr. Carell and Christoph is, as you know, I mean, it's no need to present him. He's an amazing person and he has really contributed a lot to the space. So we will have a Q&A session so you can ask all the questions to my three colleagues here speaking. What we will address today is a quite large program. So first, I will give you a refreshment about Roliparidone, where we are with Roliparidone. Also an update, a peak update on the C19 study because the study is ongoing. And afterwards, I hand over to Greg, to Dr. Strauss, who will speak about how important primary negative symptoms are as We will not go into the details about primary secondary negative symptoms because Dr. Strauss could speak a lot about it and he will explain how important they are in order to give some hope to patients. Dr. Kirkpatrick will speak about, again, as I said, his view on our patients, why these patients are not keen to relapse or have limited relapses, and how he sees his patients in his clinical practice. I will go quickly through some new analysis because we continue to work on our data. Just to better understand the data, to better characterize the patient population, to better characterize rhodoperidone. And you will see we have quite exciting data. And we have here in the room, Jonathan Rabinovich and Michael Davidson who have worked on this. And if you have questions, they are more than happy to answer the questions. and after that we conclude with giving you a flavor about what is a market opportunity and afterwards we open for Q&A. I wanted also to mention that we have the chance to have my friend Frank who is here because Frank has been from the beginning of this journey and he's really guiding us through how to bring over the message to the FDA, to the regulator of this paradigm shift, yes, because we are speaking here about the paradigm shift. And I hope that at the end of the presentation, you will see that indeed what you're doing here is a paradigm shift. And as you know, when you're changing something in clinical practice, when you're coming up with new ideas, it's always a little bit challenging, but we are getting there because I think Roliparidone could really be the first drug approved for negative symptoms. So very quickly, A few words about what we're doing here. So just to re-emphasize the fact that negative symptoms are really central. It's really central when we are thinking about giving a solution or providing a treatment for patients with schizophrenia. I will not focus on all these primary, secondary negative symptoms because I think Greg will cover this much better than me. I wanted to focus just on the figure on the top right, by the way, published by Dr. Carell. And just to mention that it's maybe obvious for everybody, but it's important. You have three types of symptoms when you're dealing with patients suffering from schizophrenia. You have the positive symptoms, materialized or shown by these green lines. You know, you have some acute phases of positive symptoms, what we call relapses of positive symptoms. And afterwards, when the disease is aging, these positive symptoms are less bothering, are less frequent, are really no longer really a big problem. This is what we're currently treating with antipsychotics. We are really focusing on treating positive symptoms. You see that we have two types of other symptoms, the cognitive deficit, which is materialized with the blue line here. And this is a type of symptoms which are present all along the life of the patient. And we have negative symptoms in the brown line. Again, you will hear a lot about negative symptoms, but just what I wanted to mention on this slide, look, what Christoph put is a level where disability starts to kick in. And when you see when disability starts to kick in, it is really when negative symptoms are becoming a real problem. So really, I think it's very clear to everybody that if we want to give a chance for patients to have a decent family life, to have a We need to find a solution for negative symptoms. Just to make my case here, as we know very well, it is very well described in the literature and there are some references here at the bottom. It is really negative symptoms, not the positive symptoms, which are really the primary drivers of the disability in patients. This is a very schematic way to present things. It's clear that if you're able to improve negative symptoms, probably you're able to improve the daily functioning of these patients. And you will see that in our studies, we have really always measured the daily functioning using a scale which is called the PSP scale and obviously improving quality of life. And I think what speaks very well here, and I'm always taking this example, you know, it's now 70 years or so that we have antipsychotics. And again, don't take me wrong, antipsychotics are very important. They are very important in our ammunition in order to help these patients. But when you're looking to how many patients have a job, Nothing has changed since 70 years. And when you see that 80 to 90% of these patients have no job, compared to four or five percent to normal people, definitely, I mean, there is something which has to be done. And again, probably improving negative symptoms, but probably also improving primary negative symptoms is definitely important. Coming to Roliparidone. This slide shows that it takes a little bit of time. This is the pharmacology of rhodoperidone. I wanted just to give you the rationale how we designed rhodoperidone. The first objective was to get rid of a direct dopamine blockade. This was the first objective because we know that blocking dopamine is very important for antipsychotics to help to treat an acute episode of psychosis or positive symptoms, but we know also that by doing so, you're inducing a lot of side effects. And we're always forgetting sometimes the side effects, but when I think Michael showed me a recent study, the reason why patients are really willing to stop the treatment is because they're bothered with side effects. Obviously, they have also the psychotropic effects, but they are really bothered with side effects. So it's really a problem. Roliparidone has no direct blocking effect on dopamine. It is definitely modulating dopamine, and I will not go into the details because it would be too long, but definitely it's not blocking dopamine. The three targets we have here is serotonin. We are targeting the sub-receptors, which is called the 5-HE2A receptor. It has an antagonistic activity there. The Sigma-2 receptor, which is a less known pathway in the brain. but definitely in my opinion and based on my clinical observations you know developing quite a lot of drugs in my life the sigma activity is probably one of the key drivers of explaining why our drug is improving negative symptoms and you will see probably primary negative symptoms and afterwards you have also and Alpha-1 adrenergic activity. So it's always difficult to say this target is doing this, but I think the combination of the three targets is definitely explaining the uniqueness of Rhodipiridin. And last but not least, we have done a lot of work to better understand what is going on. So for example, in terms of nerve growth factors and For the moment, it is preclinical, but I mean, it's very, very compelling data. We can demonstrate that Roliparidone is inducing a huge increase in transcription of BDNF and GDNF and also the release of BDNF and GDNF. And think one second, I mean, these nerve growth factors are really, really important in neuroplasticity to restore neuroplasticity. So this is what is about Roliparidone. And it has been designed on purpose. Now, let's see if all these hypotheses are translating into what we have seen in clinical practice. Here, it's very summarized, because the objective is not to go through all the data. It's more important that my colleagues are speaking afterwards. But what you can see in terms of efficacy, so in all the two studies, we have run two studies, which one is called CSEROS-3 study, The other one, CSERA 7 study. We have measured negative symptoms using the PAN scale, which is a gold standard. And when you're looking to the negative score, which has been proposed by Professor Marder, which is called the NSFS score, you see that the first study, the CSERA 3 study, No-brainer, I mean, 64 mg showed a very, very strong difference compared to placebo after 12 weeks of treatment in monotherapy. So keep in mind that here the patients are not staying on antipsychotics. They are really treated in monotherapy for 12 months. What you can see is that in the CSERA 7 study, we still have for 64 mg, which was the highest dose we tested, a p-value. which is obviously going down because a larger study more clinical sites that we have still a p-value and what we also merit because this is important and we will hear a lot about functioning We measured functioning using the PSP scanner. And what you can see here, again, in the two studies, we could demonstrate that indeed, looking to daily activities, because PSP is a very practical scanner, so looking to daily activity, indeed, you can see that these patients are, when they're improving the negative symptoms, they're also improving their daily functioning. And obviously, last but not least, what is important, Is this drug safe in terms of relapses, you know, when you give it in monotherapy? Because, again, the paradigm shift here is to say there is a subpopulation who does not need continuous treatment with an antipsychotic. Obviously, the pharmacology of Roliperidone might help, but what happens in terms of relapses? So the green boxes or the green bars you can see, these are the results we obtained in terms of relapses in the two studies we have run, the C03 study and the C07 study. You can see this is over 12 weeks, plus 24 weeks for the C03 study, and plus 40 weeks for the C07 study. And Jonathan did a comparison by selecting from A database which is called the KT database. I think it's familiar to everybody. It is the largest database which has been generated in the US with antipsychotics. He extracted the patients who have the same eligibility criteria as the one we have in our two studies. And you can see what is the relapse rate you see in patients who are getting antipsychotics. So it's not the final say here, but I mean, it's clear that The patients we have recruited in our studies and the patients we are currently recruiting in our C-19 study seem to be less keen to relapse. And we'll hear much more about it, why we might think that this is the case. So this is a study. So I think everybody has seen the study design. This study is really coming out of all what we learned from the previous studies with in-length and very productive discussion with the FDA. And I have to say that we had really, really good interactions, good advice. And I think it's fair to say that this is somehow the consensus of what we have to do here. So the first thing we have to do, because keep in mind that this is a large patient population we are addressing, we have What is called phase A of the study, the first 12 weeks, you see, this is to really confirm what we have seen in terms of efficacy with the two previous studies. The big difference here compared to the two previous studies is that we are focusing on 64 mg, which is the dose for which we are seeking an approval. and we have no longer 32 mg in this phase. So the objective here is really to demonstrate that indeed using the NSFS endpoint, so the negative symptom endpoint we have used in the previous studies, we show a p-value between placebo and treatment and 64 mg. What we call phase B, this is really different from what we have done in the two previous studies. In the two previous studies, the patients were allowed to go into an open label extension, so everybody was switched to treatment. In this case, and this is really something which has been discussed with the FDA, and I think it's very important. Also, it will be purely descriptive because the number of relapses we have does not allow you to do any formal statistical analysis. It will be purely descriptive. but it's a comparison between our patient populations, the patients we have recruited in our studies, the patients we are recruiting in the C19 study, when they are receiving an antipsychotic, we will check the relapse rate and we will compare it to the relapse rate we see with Ronyperidone. This is important to reassure patients to reassure the patients, to reassure the prescriber, to reassure the agencies that indeed, I mean, there is nothing severe which happens when you take off this patient population from antibodies. And we will hear much more about this from Dr. Kilpatrick. So this is basically the study. So I will not go into the details of where we are with the study. We are really enrolling the patients. The study is going according to plan. As we have disclosed, we really hope that we will have the results in the second half of next year. Today, definitely, we are on track to have the results coming out. I'm speaking obviously about the first 12 weeks, that's about phase A, during the course of second half of next year. I will be not very long on this slide just because this is too complicated, too busy. But it's just to say that the study design we have implemented here is not just because we wanted to do it in this way. It was really done by really thinking what we are trying to achieve here. First of all, we wanted to demonstrate that we have an effect on primary negative symptoms. So primary meaning disease-related negative symptoms. and so here you know you need to avoid patients who are fluctuating too much and so you're looking to stability of these patients over the last six months before there are candidates for the studies they need obviously to have negative symptoms which are impairing in order to be to be part of the study but just to mention that the You go to the literature, and I'm using the word Michael is always telling me, and he knows the literature in and out, Dr. Davidson, it's a graveyard to put drugs on top of antipsychotics because you're blocking dopamine and the things that are likely to improve negative symptoms is difficult. I'm not saying that it is not possible, but we have decided to focus on a subpopulation where we think that there is more stability in order to really demonstrate that first ronipiridone has an effect on primary negative syndrome. When the drug will be approved, we can really think about moving forward. So when you're looking to the conclusion of all this work, and even there was a committee at the IACTM meeting who was working on study designs, I think it's fair to say that probably the best study design is monotherapy, long period enough, stable patients. And because there is no approved drug, in terms of negative symptoms, the comparator is placebo. The last thing which is coming on the last slide before I hand over to Dr. Strauss, I wanted really to make something very clear because I'm obviously reading all the reports, I'm reading all what is published and a lot of people say, okay, I have an effect on negative symptoms. This slide I think is to explain that you have Two things. You can improve primary negative symptoms. So this is a brown line. So basically, you're reproducing the brown line, which was also in the slide from Dr. Carell. So this is what we call, technically, this is a trademarker. So this is a marker. These are symptoms which start very early on and are present all lifelong of the patient's life. and afterwards you have what we call state markers. These are markers or symptoms when you're looking to the patient today. So one day the patient can show some depressive disorders, one day he can be bothered with extra-premordial symptoms, his motor symptoms because his treatment is not completely adapted and sometimes these patients have an acute relapse of positive symptoms which is a green light at the bottom. When you bring down from this acute episode the patient, this is what we call a pseudo-improvement. So you're improving or you're bringing back the patients to the level of their primary negative symptoms, of their disease negative symptoms. So I think the only way to claim that you have really an effect on primary negative symptoms is to do what you're doing. Stable patient, long-term effect patient. and all the rest is all maybe to improve negative symptoms, but to bring someone down from an acute episode is to the effect, to the improvement of negative symptoms. So it's very important so that we understand about what you're speaking. I think it's time now to hand over to Greg.

Good morning, everyone. It's a pleasure to be here. I'm Dr. Gregory Strauss. I'm a professor of psychology and neuroscience at the University of Georgia. And my research over the last 20 years or so has focused on negative symptoms, in particular, the phenomenology or how we conceptualize them, developing new assessments for negative symptoms, understanding their mechanisms from a neurobiological perspective. and of course working on new treatments. And there's also always a beautiful irony of having negative symptoms be your scientific expertise. I'm very motivated to study the lack of motivation. I enjoy studying the inability to experience pleasure. And of course, I'm excited to talk to you about some of our new work on this today. So as Dr. Luthringer set up so beautifully, Negative symptoms are heterogeneous. In other words, you can have two patients with the exact same score on a negative symptom clinical interview scale like the PANS for very different reasons. For example, they may both have a score of 20 on the PANS. One patient may be predominantly apathetic. We call this primary negative symptom. It's something that's assumed to be a direct manifestation of the illness of schizophrenia itself. You can have another patient who looks identical on paper, but their negative symptoms are secondary. They result from other factors. And this is not a concept specific to negative symptoms or even psychiatry. It's known throughout medicine. I'll give you a brief example. Last summer, I took my daughters to Orlando. We went to Disney World. We were very excited until we got home to this rental house at the end of the first night. My younger daughter, seven years old, wanted to go downstairs and get a drink. Daddy went downstairs with no contacts in. I went one way. My body, my ankle went the other way. Snap, snap, later. I can't walk for a few days. Fast forward a couple of months. I go to the doctor and I say, my knee is hurting. And looks at the knee. Nothing's wrong with the knee. She says, this is secondary. You need to improve your ankle. You've not rehabilitated your ankle. You went back to your normal level of exercise too quickly. In psychiatry, it's a similar idea. The idea is that there are common problems There are common secondary sources of negative symptoms. Sorry, screen went forward on me. There are several common secondary sources of negative symptoms, and two of them are depression and anxiety. For example, someone may be incredibly sad, feeling worthless. They may have sleep problems. These may cause them to have a lack of recreational activity, goal-directed social behavior. Another person may be very worried. They may be very tense in their expression of emotion in the face and look very blunted. They may be so concerned about the things they're worrying about that they don't seek out social or goal-directed activities. This is very different from someone with true or primary negative symptoms. These patients will not feel depressed or anxious regardless of what is happening to them, regardless of the stimulus. For example, a case where a patient's brother passed away. They were living with sharing a room with the brother. They did not feel sad. They did not feel depressed at all after losing the brother. Anxiety, same thing. Another patient with this primary negative symptom profile was held up at gunpoint. Remarkably terrifying experience for anyone. Did not feel fear in this situation. No anxiety, right? So this is a very different profile, this secondary negative symptom profile, than what happens with primary negative symptoms. Similarly, positive symptoms can induce negative symptoms as a secondary cause. for example, hallucinations. So when they hear a voice telling them, don't get up off the couch or the FBI will come and chop your legs off and you'll die. So they sit on the couch, they don't engage in activities and They're behaviorally delusional. Same thing. They may be paranoid, thinking others are out to harm them. So they withdraw socially as a protective mechanism. Or they may be so disorganized in their thought that they can't execute goal-directed activities to engage in motivated behavior. This is not a primary negative symptom. People with primary negative symptoms have very low levels of positive symptoms, low levels of hallucinations, delusions, disorganization. So without having any of those positive symptoms at a severe level, they still have negative symptoms. They still withdraw socially. They're not interested in the social interactions. They could take it or leave it. They don't feel lonely, even though they've spent the majority of their time alone during the day. This is a very different profile. Similarly, medication side effects. Someone might be sedated due to the effects of their antipsychotic. This may cause them to have less behavioral activation. Someone with primary negative symptoms, they continue to show the lack of behavior even in periods where they're medication-free. So their negative symptoms persist even into these medication-free periods. So Creating, importantly, there are a couple of very critical things to know about this primary-secondary distinction. The first one is primary and secondary phenotypes have distinct underlying mechanisms. We have estimated that primary negative symptoms largely result from disrupted corticosteroidal circuitry. that is driving this apathetic profile. Secondary negative symptoms, on the other hand, have different underlying biological factors that travel with the secondary sources. They travel with mood, anxiety, positive symptoms, et cetera. Now, because of these distinct underlying mechanistic profiles, point number two is really critical. Treatments targeting secondary sources. often reduce negative symptoms in patients with secondary phenotypes. In other words, if you have a patient who's depressed, treat the depression. If their negative symptoms are driven by anxiety, give them an anxiolytic. Not in every case, but a good percentage of the time, the negative symptoms will improve as these secondary sources improve. This is the pseudo-specificity that Remy was talking about a moment ago. The negative symptom effect is essentially a byproduct, if you will, of improving these secondary sources. The third point is that treatments targeting secondary sources do not reduce negative symptoms in patients with primary phenotypes. Treating patients with a primary phenotype with antidepressants, anxiolytics, will not improve their negative symptoms. It's the wrong mechanism. The mechanism is distinct and not being hit by that compound. Fourth. treatments targeting primary negative symptoms are not expected to reduce negative symptoms in patients with secondary phenotypes. Essentially, again, another mismatch between mechanism and mechanism of action of the drug and the underlying mechanism in the patient. So what does this tell us? The treatment of primary negative symptoms is the holy grail. This is something that has not been addressed in the literature to date. There are strategies for addressing secondary negative symptoms, But not primarily. And they're critical because, of course, for many reasons, but they're tied to lower rates of recovery, poor functioning, lower well-being, greater stress on the family and caregivers. So this is really, as others have termed, the holy grail of psychiatry, is to find a treatment for primary negative symptoms. So, of course, the critical question becomes, is Rolo Peridon doing this? The short answer is yes. On the screen in front of you, what you see is data from a probability calculator that estimates the extent to which someone's negative symptoms reflect primary or secondary causes. Now, if you look at the figure on your left, primary negative symptoms are displayed. And what this is is an algorithm we developed called the primary stability weighted score. And what this is is essentially an estimate of the severity of someone's primary negative symptoms weighted by How persistent they are over time from baseline to the end of the study. So here, higher values mean that the negative symptom is more primary and more persistent, right? What you see here is that placebo has higher primary and persistent scores. then Roloperidone. This is exactly what you would want if the drug is treating primary negative symptoms. Placebo is going to be consistent across time. Their negative symptoms are not changing. They're primary. They don't fluctuate. They're enduring trait-like features. When given Roloperidone, the patient's who are responding are the ones with this primary phenotype. Their negative symptoms become both less severe, the primary negative symptoms become less severe and less enduring. So you can see that indicated by the lower scores there for roloperidone than placebo. Now, if you're not familiar with looking at these types of charts, a handy way to know if something is statistically significant is to not just compare the height of the bars, but also to look at the overlap in the standard error bars. So you can see the error bars here have minimal or potentially no overlap. And that is indicating a greater likelihood of statistical significance. So you can see in this particular metric, the p-value is 0.03, so less than 0.05. In contrast, the secondary score did not significantly differ. So you can see here the p-value is 0.61. Now the secondary score is a little bit different. First thing to know is that it's on a different scale than the primary score. The figure is also very zoomed in. So it's also on the axis is a little bit centered differently. But what this scale score represents is essentially the likelihood that someone's negative symptoms are driven by secondary factors like anxiety, depression, paranoia, hallucinations. and how dynamic they are over time. Because remember, secondary negative symptoms are transient. They fluctuate a lot as those secondary sources vacillate across time. They're inherently unstable. So this score weights not only how secondary the patient is, but how inconsistent or unstable their scores are across time. And what we see here is that placebo and riloperidone do not differ. And that's suggesting that the drug is not having an effect on secondary negative symptoms, but of course it is on primary. And again, this is really the holy grail of psychiatry, of showing an improvement in primary negative symptoms. Now, importantly, that's not a given. I would argue that prior studies, if they have reported an effect on negative symptoms, many of them have, if not all, have been really driven by pseudospecificity and these improvements in secondary factors. So this is something that is really an important finding. Now, another key thing that we have found with Roloperidone is addressing what is driving the effect. And I don't mean at a neurobiological level. We know the components of the drug. I'm talking about in terms of a symptom network level interaction. Many clinicians think of individual symptoms as being distinct entities, but that's not correct. Just like almost any other element, of the environment, things interact, symptoms can interact. For example, why would someone not show emotion in the face? Why would they not speak? Why would they not engage in social activity? Maybe they don't enjoy those things. Maybe there's an underlying factor driving. Maybe it's a hedonic deficit. Maybe the way to treat that deficit would be to hit that component, right? And you would see a cascading effect temporally where all the other domains would improve. You could make another hypothesis that maybe it's social function. These are people who've been devoid of social interaction for years. and maybe the drug achieves its effect by making them more social. So then they have more opportunities to speak, become more expressive, more motivated in general. So there are many possible interpretations. The one we hypothesized, however, was neither of those. It was that the drug achieved its effect by hitting a key mechanism of abolition or a reduction in motivation, right? So what actually was found here using these network analytic approaches is that when the drug improved the negative symptom constellation, it first hit motivation. Once motivation improved, there was a subsequent cascading effect across time where all of the other domains improved. So motivation is highly central to the improvement of the entire negative symptom constellation. And this was data from the C03 study. We subsequently replicated this effect in the C07 study. This is a similar but more recent network analytic approach and intervention network analysis. These algorithms are changing every six months. There's something new out there, so we applied one of the newer ones. And what we found is that there's actually a direct effect of the treatment on the PANS item most similar to avolition. which is called emotional withdrawal. So in other words, the drug effect was hitting this item related to abortion. And again, it produced this cascading effect where you saw subsequent improvements in the other negative symptoms. So a replication of the phase two C03 study findings. Now hang with me. Why does this matter? Why do these network approaches matter? Who should care about this? I would argue that these are perhaps some of the most critical findings. Why do any of us do anything we do throughout the day? Our motivational system is functioning. Why do you change your clothes? Why do you go to work? Why do you have romantic relationships, friendships? write checks, motivation is a critical component of this. Without it, these activities become much more difficult to activate. One reason that this network finding matters is because of this graph here. In both the C03 and C07 studies, what you see is an improvement of functioning, of role and social functioning for roloperidone compared to placebo. So it improved these aspects of daily life, such as doing chores, getting to your appointments, having friendships, romantic relationships. And this is not a given, right? It's possible to change motivation, but not change these critical behaviors. It may be that someone wants to do them, but they don't do them in the real world. And that was not the case here. With Rola Peridot, you see You see that with this effect that happens on motivation, there's a subsequent effect on functional improvement. So motivation may be important to change because of its critical relationship with functioning. To give you an easy way to remember this, What is the importance of abolition or motivation here? Why does the entire constellation of negative symptoms improve? You change motivation. You make people want to speak more. You make them more likely to be expressive. You make them more likely to interact socially, to engage in pleasurable recreational activities. Interestingly, you can also improve their cognition. One of the key findings previously published on roloperidone is that it also improves basic neuropsychological test performance. And motivation is also a critical aspect of cognitive impairment. You have to be motivated intrinsically to do well on these tests to have a good performance. So changing motivation may be critical. Improving cognition in tandem may actually also be critical for improving motivation. It may allow you to have better executive functioning to execute goal-directed activities better. So why is riloperidone important from a clinical perspective? it's improving all of these aspects of negative symptoms that are critical through this effect on motivation that has the subsequent improvement on the two critical unmet needs in schizophrenia therapeutics, cognitive impairment and functional outcome, right? These are really important for improving the quality of lives that patients have and making them more likely to recover and do better in life. So again, Primary negative symptoms are really important as one take-home message, and roloperidone is indeed changing primary negative symptoms but not secondary, and it's achieving this effect through a direct improvement on motivational processes that are important for improving functioning. And I will stop here and pass it back to Dr. Luthringer.

Thank you so much, Rick. Yeah, so now it's my pleasure to introduce Brian. So Brian is sitting in a very nice location, yes? Brian, the floor is yours, so I don't know, do I have to change the slides? Okay, so Brian, you tell me when I have to change your slide, yeah?