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Great, thanks very much. It's my pleasure to be introducing Nerva Neuroscience's team. Remy, it's always good to see you. Thanks for joining. I appreciate it. Maybe I'll have you give a 10-minute overview of the company and then we'll do Q&A. How does that sound? Yeah, this sounds perfect, Paul, and really thank you for having Jeff and myself here curious to give you an update about the progress we are making with Roliparidone, which potentially is the first drug to help patients suffering from schizophrenia and having impairing negative symptoms. So again, thank you for the opportunity. So what I'm trying to do here, just before jumping into the data, is just in three slides to give a little bit of an update about what is schizophrenia and what these patients are suffering basically in terms of symptoms. So as you can see on this schematic here, which is coming from Professor Correll and Professor Schuller, you see very nicely that when you're looking to the negative symptoms here in Brown, you'll see that the negative systems are part of three different types of symptoms constituting uh you know the symptoms of patients with schizophrenia positive symptoms here in green again negative symptoms here and cognitive uh deficit in blue yeah so what what what is important to understand is that when you treat patients with antipsychotics you definitely are improving positive symptoms but you're definitely not improving negative symptoms and as you can see negative symptoms are present prodromal before you're making the diagnostic of schizophrenia before you have the first episode of positive symptoms and the things are building up over time and are present all lifelong for for these patients as you can see also what is very important to keep in mind is that in terms of severity of illness and disability you see that that what is really impairing these patients and keeping them out of any decent life are negative symptoms, clearly, as demonstrated here. Now, what are negative systems? Because we are all speaking about negative symptoms. And I think it's maybe good to have just a few words about what we mean by negative symptoms and what these negative symptoms represent for the patient. So first of all, it is clear that negative symptoms are not treated because there is no approved treatment in the U.S. for negative symptoms as of today. And I think they are also underdiagnosed. When you're going, you know, with all the consensus papers or discussing with KOL, it is clear that everybody agrees that negative symptoms is what is impacting most quality of life in these patients. Again, it presents a real challenge for treatment because, again, we have no approved treatment as of today. and what is also something we have to keep in mind is that antipsychotics treatment might even worsen negative symptoms so this is what we call secondary negative symptoms and so because of all this i think clinical practice and and the drug development efforts have obviously tried for negative symptoms they failed but i mean people are mostly focusing on treating positive symptoms coming up with a new mechanism of actions and probably also with drugs with a better side effect profile. So this is what we have to achieve here when we try to improve negative symptoms. So negative symptoms is a construct of different symptoms, as you can see on this slide. So you have two different dimensions, the experiential dimension and the expressive dimension. And without going into the details, I think one type of symptoms, which is extremely important to keep in mind, is evolution. So evolution is this lack of motivation, this lackof drive. Patients are no longer engaged in things that were engaged before they had the disease. And obviously, as a consequence, the self-care is also very limited. There are a lot of data, because we have only 10 minutes here, showing that negative evolution is probably driving not only the improvement of negative symptoms overall, but it is also heavily improving functioning and probably cognitive impairment. Because I really think that there is more and more consensus saying that if you're able to improve negative symptoms slash evolution you might also see an improvement not only in functioning but also in terms of cognitive aspects now what is the best way to to assess negative symptoms and and there have been a lot of debates obviously over the last decades and and i have been involved because i was running a research institute and had quite a lot of companies, but I think what is very clear is that, you know, using the classical trial design to assess positive symptoms is probably not the way to go, yes, and I mean, this is my first bullet point here, yes and I will not go to the upper part of the slide, but it is very clear that this is also very clear in the mind of the regulator, yes that when you bring down someone from an acute episode of positive symptoms, you bring them down to their baseline negative symptoms, to their disease-related negative symptoms. And this is what we're usually calling a pseudo effect. Now, the other way to do this is to put your drug under investigation on top of of an antipsychotic yes because uh uh you know the the belief which is which is true yes is that when you keep someone treated with an antipsychotic the risk of relapse and the hospitalization rate is is decreased but what what is is also something we should take into account when we are thinking about designing trials for negative symptoms or assessing negative symptoms is that when you treat someone with an antipsychotic slash a dopamine blocking molecule you induce sedation you increase evolution you increase the movement disorders eps akathisia so so definitely this does not help and this might induce secondary negative symptoms when you go a little bit more into the the how the brain is functioning and particularly in terms of emotions, in terms of things which are probably involved in negative symptoms like the limbic structures, going to block dopamine can definitely not help us in order to see an improvement. And last but not least, because we have primary negative symptoms, disease-related negative symptoms which are really the impairing part of the negative symptoms. And because we are secondary negative symptoms if you're doing this on top of antipsychotics, you cannot discriminate between primary and secondary negative symptoms. Hey, Remi, can I chime in with a quick question here? Sure. I think, and we can get into the data and make it, like, more interactive, too, but, like if you're a clinician and you have someone who has stable positive symptoms but, you know, residual negative symptoms, like how do you know that it's safe to take them off the antipsichotic, that the probability of a positive symptom relapse is low, right? I mean, this will kind of get into, you know, how your drug could be adopted in the real world for patients with negative symptoms, but they use that as a monotherapy. They need to be comfortable, right, that the positive is not going to sort of spike, or at least confident that your drug can maintain stable positive. But how would a provider do this? So, in your question, there are several responses and several elements to take into account. So first of all, I mean, it is very clear that you have different subtypes of patients inside the ecosystem of schizophrenia. And it is VeryClear, and a lot of people are working on it and publishing on it. And you have also long-term data, even going to 20 years, I'm in follow-up of patients where you clearly show that, yes, maybe acutely, maybe sub-acutely in over one year, antipsychotics are protecting against relapses and hospitalization but long term if you're going beyond one year if you are going to five years to ten years definitely there is a population who does not need antipschotics because relapse rate is very similar between treated patients and non-treated patients and what is also important to keep in mind is that when you're looking to functioning these patients who are not continuously treated basically are functioning better. So this is this notion of intermittent treatment, which is now becoming more and more popular, and bringing back the antipsychotics to why they have been developed. They have been developed as major tranquilizers. And so if you have an acute episode of psychosis, there is no discussion. You need definitely an antipsycotic to bring down the patient to his baseline, let me put it like this. So the second reason why I think the the prescriber can be reassured is the pharmacology of the drug. So this drug is not blocking dopamine, rhodoperidone, and this was intentional because of all the reasons I was just giving in the previous slide. But you need nevertheless to have a drug which is not only improving negative symptoms, but which is also keeping patients stable in terms of positive symptoms. So basically, when you're looking to the pharmacologist, this is a drug having a 5-HE2A antagonism, a sigma 2 antagonism and some alpha 1a antagonism. But it's very well described in the literature that 5-HE2A antagonism is definitely helping to keep someone stable in terms of their positive symptoms. At minimum, in the patient population we have targeted, which is a patient population where we are looking to stability of the positive symptoms over the last six months before thinking about monotherapy with Roliparidone. And obviously, they need to be pairing negative symptoms. And last but not least, we have more than 800 patients who have participated to our trial. I can also mention Lundbeck, who did a trial with the same patient profile. And what happens is very clear, is that the relapse rate is extremely low in this patient population. And last but not least, and I will come to this when I speak about the trial design we are currently working on, and we agreed with the FDA, definitely we will get some additional data to reassure the prescriber about monotherapy. But just coming to the fact that if you want to demonstrate an effect on primary negative symptoms, you probably have only one way, which is monotherapy versus placebo, because there is no approved treatment currently for negative symptoms. So because we have not a lot of time, I allowed me to put here the integrated analysis of the two studies we have carried out, registrational studies. And this is the primary endpoint, which is coming out from the pan scale, which is called the modern negative score. And the data I'm showing you here are the ITT population. And the way this is analyzed is the MMRM approach. So these are changes from baseline. Primary endpoint of efficacy was week 12. And what you can see very nicely here is that already after week two, you start to see an improvement compared to placebo for the two doses. Blue being placebo, green being 32 milligram, and red 64 milligram. Things are building up over time, and at the end of the 12 weeks, you have p-values for the for the 2 doses. You can also see that 64 milligram is definitely having a stronger effect than 32 mg, and this is also seen in the effect size here, as you have with the two doses. Just one word about the two studies. So, the first study was extremely positive, with p-values of 0.0001, with effect sizes of 0,6007, and what happened in the second study is that, and I will come to this in a second, placebo picked up a little bit more, and I'm not blaming placebo here. I'm just saying that placebo picked up a bit more. The effect size of the improvement with treatment was the same, but what happened is that only the highest dose was hitting a p-value in the second study. And because we were optimistic, maybe too optimistic, we used to control for type 1 error. We used the Hochberg correction. We did not a top-down analysis like you might do in phase three. We wanted to have the two doses hitting. Unfortunately, only the highest dose was hitting. So we can only speak about a nominal improvement of 64 milligram in the second study. So again, maybe a statistical artifact, clear that we have a real treatment effect for 64 milligram for the two in the two studies but so this is what we have as of today no what is important and what i was telling you in the last previous slides functional improvement is important and here i'm just showing you the and i could show you exactly the same for the first study yes but this is a the psp result which which by the way was a sole key secondary endpoint in the second study, you see that when you're looking to PSP total score, you see that these patients are really improving in terms of functioning. And best of my knowledge, I think rhodiperidone is the only drug in the space improving patients' functioning. And if you would have time, I could go into examples of patients who have dramatically improved and were able to go back even to have a small job. Yes, I mean, which were observations which came out from the studies. But just to mention that definitely the 64 milligram is improving functioning as well. So this is a quite quick summary of all what we have seen with the two studies. Improvement of primary negative symptoms, improvement of functioning, improvement of evolution, which has been demonstrated in several ways, in several approaches, several analyses. this. No increase in terms of positive symptoms. Monotherapy was associated with a very low relapse rate. But what is also important, I think, to keep in mind is that we did not see all what you see with antipsychotics, particularly dopamine-blocking molecules in terms of side effect profile. So the drug is extremely well-tolerated. No sedation, no EPS, no prolactin increase no nausea so so i think it ticks a box about the pharmacology we are using here and as a patient population uh you know who has participated to these trials so based on this i mean with after you know several uh back and forth with the other agency and i wanted to thank once more the agency about all these very helpful discussions we had remember they even organized a public meeting in august 2024 to speak about how to design a negative symptom study how what would be the endpoints i mean we came to to this overall agreement yes and and as you know there is always a discussion going on uh with the fda but uh but clearly we came through to this conclusion so the first thing is that uh we agreed uh that uh the primary endpoint should be at week 12 like in the two previous studies with the same primary endpoint which is the modern negative score coming out from the pan scale and like in phase three studies the previous phase three studies the sole key secondary endpoint is psp is is looking to functioning so this is a double blind placebo controlled in monotherapy so before including the patients same elements as in the two previous studies patients need to be stable in terms of positive symptoms they need to be stable. In terms of negative symptoms over the last six months and they need to have a minimum score of negative symptoms in order to really quantify impairment. So this is really let me put this in brackets but this is quasi a copy paste of the two previous studies the big difference here is that we are only testing 64 milligram versus placebo yes and not the two doses versus placebo now afterwards and this is i think the the one part also of the answer to your question uh you know we have we have already a lot of data analyzing existing databases like the kt database showing that the patient population we are targeting is definitely not keen to relapse a lot. And it confirms what we have seen also with our data. But so what I think the agency would like to see, in addition, our data in this study, where we are comparing really the relapse rate of Roliparidone over a longer period of time compared to antipsychotics. So we came up, I think, with a very innovative study design here. Yes, you can see that patients are re-randomized to either rolyperidone or antipsychotics. So basically, we are using three antipsycotics. The three most prescribed antipsykotics are in this arm. And because even the agency recognized that, I mean, the blinding is a little bit complicated due to the side effects of antipsytotics, we came up with a double dummy study design. So really to try to blind the study as much as possible. So this part is purely here on a descriptive level to check relapses in these patients over a longer period of time. So primary endpoint of efficacy, week 12, 64 milligram versus placebo, and afterwards, you know, a comparison on a descriptive level between relapsis of antipsychotics versus 64 milligram. Can I chime in and ask a couple of questions? Sure. Sorry, sorry, sorry. I didn't mean to interrupt. So just a couple quick things. So one, do we have a good understanding of what is a clinically meaningful effect size for the FDA? Like, do you just need to hit a P value in the acute portion? Or do you need to show something above a certain threshold? And then second, maybe just talk a little bit more about the relapse assessment portion. Like, what constitutes qualitative non-inferiority in this context? Yeah. So, clinically meaningfulness. So, this was obviously a debate since we received the CRL, because it was written in the CML. And it is true that the FDA was writing this in the serial. And this was one of the discussions that we had over the last quasi two years with the FDA. The first thing you have to keep in mind, and what I'm saying here is something we have discussed and we have agreed. So just to be clear. But so the first thing is that because there is no approved treatment, so it is extremely difficult to have any benchmark. And I allow me to take always the same example. I was involved in trying to demonstrate clinically meaningfulness of SSRIs and SNRIs. And guess what? It took us 10 years to come up with some consensus after the molecules were on the market. So it is extremely complicated to come out with clinically meaningfulnes when you have the first drug improving the symptoms you want to treat. But this is one aspect. The second aspect is that having all these interactions with the FDA, we were able to to share with the fda a lot of data first set of data was the responder analysis you know this is what is usually done when when a drug gets approved and when you're looking to our responder analysis it is largely largely in favor of of the drug yes so much more responders with roly perry in the two studies by the way yes so it's uh not specific to to the to the first study in the two studies we did also an anchor analysis anchoring as a primary endpoint to cgis which which is well recognized one point improvement of cg is recognized to be to be clinically meaningful as when you're doing again this analysis highly significantly in favor of of the drug yes so so we have shared all this with the fda and and they they really agreed that we have already a a lot of data here and what we need basically is a p-value and you know we will do this responder analysis the classical thing you're doing and last but not least i think there is an external source which also was is very helpful to keep in mind is that you know we have published i think no 12 papers on on the data we are very open we have shared the data with care wells and professor gregory strauss has published on this yes and what he did he did an analysis between the BNSS scale, which was a scale we used as a secondary endpoint in the first study, and was asking the patients and the caregiver what for them on the scale is clinically meaningful. And when he is comparing this outcome of this study to our data, rolyperidone is as good or even better than what the patients or the caregiver are expecting. So So, this is an important piece of information. But long story short, the answer is a p-value is enough in this case. No, that's great content. Concerning the relapse. Yeah. So, I guess a question you have. First of all, non-inferiority to do a formal statistical analysis is impossible. Why? Because the number of relapses we had was a handful of relapsees. And if you're doing a calculation of number of patients you would need, it is between 2,000 and 3,000 patients. So we agree that, I mean, this makes no sense. But what is interesting here is what we agreed with the FDA is that we will use some psychometric endpoints coming out from the pan scale. Like, you know, this consensus, there are a few papers which have been published recently, Ciafis, for example, where they explain that an increase of 12 points and more on the total PANS score is probably signaling a relapse and is also related or correlated, I would say, with a number of hospitalizations. So we will have these psychometric endpoints. And because we're measuring PANS, we're measuring CGI, we are measuring PSP, you can analyze this psychometric part as much as you want in different ways. So for the moment, what we are going after is consensus currently in the scientific community and the medical community. What the FDA also wanted, and I think it's completely fair, They want also what they call hard clinical endpoints, in addition to psychometric endpoints. So basically looking to hospitalization, looking to, you know, attempt of suicide, aggressivity towards a caregiver. So all these daily, you knows, things which might happen when a patient starts to get worse in terms of the positive symptoms. So this is what will be, you know, monitored in this part B of the study. Okay, great. We are out of time, but maybe just very quickly, the timing of this readout, Remy? Yeah, so I'm switching. So this was a slide which I think was an important slide. Why? I think it's not, how to say, testing that we have a drug. It's to execute in order to demonstrate again that we Have a Drug here. But so the timing here. So, as we speak, we have, you know, obviously selected a CRO to help us. Multiple sites activated. First patient will be in the study very soon, in Q2 of this year. And top line results of week 12 will be second half of next year. And relapse assessment will be obviously a little bit afterwards. And we will keep the FDA, you know, updated as much as possible. And when we have the top line results of week 12, we will definitely reengage about, you know, NDA submission. So this is what are the timelines, Paul. Okay, great. Awesome overview. Thank you guys very much for joining. I appreciate it. We'll have to end now, but look forward to catching up soon. Thanks, everyone, for listening. Thank you.