Well, good morning, everyone, and thank you. Welcome to our Reviva Pharmaceuticals key opinion leader fireside chat. My name is James Molloy. I'm one of the biotech and specialty pharmaceutical analysts here at AGP. You'll see our disclosures on the screen. In this chat, we're talking with one of my coverage companies. They just had some late-breaking news: Reviva Pharmaceuticals, which we have buy rated, $16 price target. Reviva is developing, among other things, brilaroxazine, a serotonin-dopamine modulator being tested for schizophrenia, inflammatory, and cardiometabolic diseases. The Phase three RECOVER-1 trial on schizophrenia just reported positive data at the end of 2024. During the call, our listeners will be on mute. If anyone has any questions for the group, please feel free to enter them in the chat in the Zoom or email them directly to me at jMolloy@allianceg.com, which is also right up here on the screen. I'll ask the questions at the end of the discussion as we have time, and we will have a hard stop. The conversation will go one hour with a hard stop at noon. With us today from Reviva, we have the CEO, Laxminarayan Bhat, PhD, and the key opinion leaders who have been kind enough to join us today. Our doctor is Larry Ereshefsky, a world-renowned KOL in the CNS field and the chief scientific officer at SyneXEL Research, Follow the Molecule, a CNS consulting firm. And Dr. Mark Opler, who is also a world-renowned KOL in the CNS field and the chief research officer, eCOA Neuroscience at WCG, and executive director at the PANSS Institute. I'll pass it over briefly to Dr. Ereshefsky. If you could please give us a brief overview of your background in the CNS space, Dr. Ereshefsky. Thank you so much. It's a pleasure to be on this call and to be speaking to all of you. I've been involved in drug development in academics and then in the private sector for now going on almost 50 years. I started out focusing on antipsychotics and worked on getting a research unit funded at San Antonio State Hospital, where I was a professor of psychopharmacology, and since that time, I have been involved in the development of many of the antipsychotics and other treatments. I'm currently more active as a consultant, as a translational scientist. As mentioned, I am the Chief Scientific Officer for an 18-site clinical network, and I also support a variety of companies, from the largest to the smallest, in developing drugs using biomarkers and early engagement of patients into clinical trials, and I'll stop there so we can get to the good stuff. Thank you, Dr. Ereshefsky, and next, over to Dr. Opler for a brief background on his experience in the CNS space. Thank you so much. I'm definitely not the good stuff that Dr. Ereshefsky alluded to. Mark Opler here, delighted to be here. I've been working in clinical research and neuroscience for about a mere quarter century rather than Larry's half century, but during that time, I principally worked as a psychometrician trialist and designer of trials, helped many companies like Reviva execute their trials in schizophrenia, mood disorders, anxiety, and you name it, anything and everything in psychiatry, quite a few different areas of neuroscience. Among my other hats, I'm also Executive Director of the PANSS Institute based here in New York City. Among our other roles within the PANSS Institute, we help oversee the use of the PANSS as primary outcome in industry-regulated trials, so delighted to bring that experience to bear here and very happy to be part of today's conversation. Jim, back to you. Thank you, Dr. Opler. And now, if you, Lax, you have a few quick slides you'd like to run through to give sort of a baseline and a brief overview of the key points regarding Reviva and brilaroxazine that will guide our discussion, our KOL call today. Lax? Yeah. Thanks, Jim. Thanks for having me here and organizing this event. Dr. Opler and Dr. Ereshefsky, thanks for your time. And it's a great pleasure to have you here. Reviva, I give a very brief overview of our company, mainly focused on the clinical data, and then set a stage for discussion with our experts, KOLs here. Reviva is a late-stage pharmaceutical company focused on developing new therapies for CNS, primarily at this time focused. Our lead drug, brilaroxazine, is in phase 3 development. For schizophrenia, we intend to develop this drug for beyond schizophrenia to other psychiatric conditions highlighted here: bipolar, major depressive disorder, and ADHD as well. This is an in-house discovered molecule, and then we have granted patents globally. So just quickly to highlight here, we have completed NDA-enabling non-clinical manufacturing, including multiple clinical trials. Highlighted here are the clinical trials required for filing an NDA in schizophrenia. As you can see here in the first column, they are typically, we call it, clinical pharmacology studies. They are standard studies required for any antipsychotics coming to NDA approval. We have completed all those studies together, around 150 patients. The second column and third column, they are specific to the drug randomized double-blind trial. So these REFRESH studies, phase two in 234, and then RECOVER study in phase three in 411 patients. The trial designs were identical, kind of you can compare similarities. And then also, if you look at the outcome, the primary and then secondary endpoints are kind of comparable. So that makes the requirement for a randomized trial for identical or a similar outcome for filing an NDA. The last one is a long-term safety study. That's a one-time requirement for safety evaluation if you intend to develop for schizophrenia or additional indication in this class. So the FDA requirement here is a six-month completer for 300 patients completed for six months and 100 patients completed for one year. We have 303 patients completed for six months and then 159 patients completed one year treatment. It's 50% more than what is a minimum needed for approving a drug. So with this, say, clinical data generated in close to 900 patients, we believe we met the statutory requirement for filing an NDA. So we reached out to FDA for a pre-NDA meeting. We have a Type B meeting scheduled with FDA. We hope to have FDA feedback sometime in December. So with this background, and then I would quickly go through a few slides just to highlight some of the background information about, very briefly, schizophrenia that lead to next data, how it is differentiated compared to other antipsychotics, the historical data. So if you look at those who are not very familiar with schizophrenia as a disease, the schizophrenia is a debilitating mental illness. Globally, around 24 million people suffer from schizophrenia. U.S. alone, around four million. Europe, around seven million people suffer. And then if you look at it, despite having multiple antipsychotics approved over the last 40 years, but still treatment has significant unmet need, around 30% patients either partially respond or do not respond to the currently available treatment. High discontinuation rate associated with currently available treatment, anywhere 30% in acute to long-term treatment, up to 70%. Most importantly, relapse rate is very high, anywhere around one year around 25% to five years at up to 90%. When I say five years, in most patients, treatment is lifelong. This is a lifelong disease, and then treatment requires lifelong in most patients. So the biggest unmet need in the treatment of schizophrenia is a negative symptom. This is one of the chronic conditions, and treatment adherence, you can list as these two are top unmet need. So if you look at on the right-hand side, that's a very important point to be discussed here in this webinar. Schizophrenia is not a single disease. Rather, it's a mix of multiple symptoms: the positive symptom, negative symptom, mood, and cognitive dysfunction. These are major symptom domains associated with schizophrenia. So by and large, currently available treatment address to a great extent positive symptom. However, the other conditions, negative symptom, mood, and cognitive, they are chronic conditions, significant unmet need with the currently available treatment. So the pathophysiology indicating that dysfunctional. If you look at the mechanism of brilaroxazine, our drug, it directly modulates dopamine-serotonin signaling cascade. And if you look at the receptor profile, and then it has a potent activity anywhere sub-nanomolar to 6-nanomolar activity for key dopamine and serotonin receptors. It differentiates from other widely used second-generation antipsychotics with strong efficacy for D4, 5-HT2B, and 5-HT7. They are implicated in chronic conditions. They are hard to treat: negative symptom, depression, and cognition. The most importantly, the 5-HT2B, that's almost three times more potent than dopamine, is also implicated, highly expressed in neural network, implicated in addressing neuroinflammation. Neuroinflammation is one of the major unmet needs, at least based on recent clinical literature. It is, if you can, if a drug can address neuroinflammation, it can treat even to a great extent treatment-resistant schizophrenia as well. So now, how this receptor pharmacology translated in clinical trials. Here is the data, phase 3 data. As you can see with the primary endpoint, PANSS. PANSS is a scale used for evaluating the primary endpoint. If you compare the gray bar that is for placebo to the solid bar, purple bar, that is for top-dose brilaroxazine, it has 10-point separation with the early onset of action. Continuity improved at day 28. This is really, to our knowledge, differentiated product data compared to historical data. Now, the schizophrenia secondary endpoints play a critical role because every single drug approved to date has a statistically significant outcome on the primary endpoint. However, not all antipsychotics showed a statistically significant outcome on multiple secondary endpoints. They are, some of them are predictive for long-term success as well as durable sustained efficacy, such as efficacy for negative symptom, general psychopathology, and then CGI and social cognition. These are not all antipsychotics showed statistically significant outcome. To my knowledge, primary endpoint and then efficacy for positive symptoms, these two endpoints have every single antipsychotic showed. So good efficacy further supported by vocal biomarkers. This may be Dr. Opler when he will make comment. He will elaborate on this. This is a unique feature what we have seen in this study evaluated good outcome. This supports negative symptom efficacy. And then also we have evaluated multiple biomarker data. They further support enhanced efficacy or a strong treatment effect, not only efficacy and then safety. Good efficacy and safety translated into 16% dropout rate for the efficacious dose. That is lower than the placebo, to my knowledge, historical data. So approved antipsychotics showed higher than placebo in general. And then they are in the range of anywhere 30%-40% discontinuation rate. This is around 50% less discontinuation compared to historical data. Now, moving on to the data what I presented that is in the hospitalized patient, acute patients, if you move on to long-term treatment, one year, they are the medication administered to these patients at home. So here, all three doses showed sustained efficacy over one year. When I say sustained, and then it's also durable efficacy. As you can see, improvement from hospitalized patient to at-home treatment is consistent and then durable, especially the last two bullet points on the left-hand side. If you look at around 50 points decrease in PANSS score over one year. This is something a patient's this kind of PANSS score reduction lead to. You can compare to almost remission or near remission. They may be out of schizophrenia, but still require medication to maintain to avoid relapse. This is really, to our knowledge, sustained and durable efficacy. Again, we evaluated all the secondary endpoints evaluated in the hospitalized patients, consistent robust outcome. Then this led to good efficacy and safety led to 35% discontinuation over one year. 35% discontinuation, again, compared to historical data for other antipsychotics, this is 50% less discontinuation. This is really a good treatment outcome adherence compared to other treatments, historical data. We believe we have addressed the key unmet needs in the efficacy, safety, and then treatment adherence with this drug. To summarize the data, we have seen a strong durable efficacy from hospitalized patient to long-term one-year treatment. This is a very consistent efficacy and then treatment adherence over one year, well tolerated, and then side effects are very benign. They are transient like headache, insomnia, and sleep disturbances. No drug-related serious adverse event reported in the study. Most importantly, if you look at the remaining points highlighted here, often antipsychotics cause significant motor side effect. We don't see hardly any motor side effect in the even treating over one year. So we believe the strong anti-inflammatory effect further, besides dopamine partial agonist activity, further mitigated the motor side effects in this patient population. Low metabolic side effect, we have seen around over one-year treatment, around 1.2-1.5 kilo weight gain. That is a very, very benign compared to widely used historically data of antipsychotics. On the other hand, other metabolic side effect, the blood sugar level are normal to baseline or the placebo. And then cholesterol, and then LDL cholesterol significantly reduced. This is maintained. So this is a good profile, metabolic profile. Again, hormonal imbalance are not seen in this. In fact, imbalanced hormone, the prolactin level reduced and then maintained over one year. That's very important to my knowledge. Maintaining the prolactin level in this patient population is extremely important to address negative symptom and then depression. So that's what we believe is very, very translated. And then also reduction in prolactin or maintaining prolactin level important in the sexual function in this patient population. So that's a really good outcome to our knowledge. Lastly, we see clinically significant cardiac side effect, GI side effect with other historical data compared to other antipsychotics. But in our case, we don't see that kind of side effect. We haven't seen any clinically significant cardiac side effect, GI side effect, no drug-induced liver injury with our drug. So with this good safety and then efficacy profile, if you compare our data with the historical data of approved antipsychotics, so left-hand side shown here, treatment effect for widely used antipsychotics. And then our data certainly is comparable or even better to most antipsychotics. On the right-hand side, if you look at here, the top five drugs in 2024 antipsychotics are highlighted here. Quetiapine, aripiprazole, olanzapine, risperidone, cariprazine, they are the top five antipsychotics captured 80% of antipsychotic market. It's around antipsychotic market is around $40 billion. The top drug is quetiapine. If you look at our data compared to these top five antipsychotics, we feel very comfortable with our data with respect to efficacy and safety and then treatment adherence in this patient population. So I pause here. We entertain any questions from attendees here and then look forward to our KOLs' comments, Dr. Ereshefsky and Dr. Opler. Thank you. Thank you, Lax, for that overview. And maybe a lot of info there. Of course, it's a very exciting drug. And Dr. Ereshefsky, Dr. Opler, I'd like to start out here first with some general comments on what Lax just walked through and what stands out to you guys as you look at sort of this body of evidence that's come out on brilaroxazine, please. Dr. Ereshefsky. Thank you. Indeed, when I look at the total evidence across all the trials, there is, first off, consistency in terms of a signal for efficacy, and there is a surprisingly low adverse event profile, and I say surprisingly because these drugs have come with baggage, if you will. The pharmacology of dopamine blockade, even with serotonin too, which is what makes an atypical atypical for the most part, there are still side effects. Even the newest drugs have cholinergic muscarinic side effects. We're talking tens of% rates of adverse events, and here we're talking discontinuation rates that are lower than placebo. In the one-year studies, the tolerability of the drug is extremely good, so it has what I think is several distinguishing features that I know we'll get into some of these in more detail, so there's a convergence of pharmacology. The inflammatory story excites me a lot. I know we're going to come back to that, but I do think that is a significant additional effect that has not been brought to bear to treat this difficult illness, and I think that when we talk about a drug people need to take nearly for their lifetime, a drug that works well, we've had those, but drugs that have near zero side effects after a year of treatment is truly remarkable, so obviously, at this point, we hope this drug moves forward, and I think it will make a difference out there. Dr. Opler, maybe your thoughts sort of in general before we go into specifics. Yeah, thank you. I echo everything that Dr. Ereshefsky said. And I think I would add to that beyond the pharmacologic uniqueness of what we're seeing in terms of side effect profile, duration of effect, extraordinarily low dropout rate on drug, which again, I think may be tied to both efficacy as well as to the lack of side effect profile. The other thing I think is worth noting is the breadth of the effect, not just the depth, which is impressive on its own, but the breadth. Schizophrenia is a disease that is extraordinarily heterogeneous, not just between patients one to the other, but within patients. It touches on so many dimensions of behavior and health and mental health. And in this case, looking across the board, we see meaningful improvement not just in broad general categories, but in very specific ones too. I know we'll get into this later, but for example, the data on functioning with the personal and social performance scale that we saw in the study is quite impressive, suggesting that patients on drug may actually be better functioning in society and be more capable of recovering those parts of their lives that they lost when they got ill. Of course, we saw findings not just in positive symptoms like hallucinations and delusions, but also negative symptoms. I think as Dr. Ereshefsky will almost certainly confirm, this has been one of the most difficult to treat areas of this terrible disease. Negative symptoms are major deficits in human experience, our ability to interact with the world around us, to express and understand emotion, to enjoy things, to take pleasure in things that we all take very much for granted most of the time. So to see improvements in this domain when so many other treatments have failed very badly in their efforts to improve negative symptoms is really heartening. So I would echo everything Larry said. I agree there is something different about this drug. And while there's always more to learn, everything we've learned so far points to a very consistent story. Jim, back to you. I said, maybe we'll just stay with you while we have you going to Dr. Opler. Let's touch on the negative symptoms, please, and as the executive director of the PANSS Institute, Dr. Opler, if you walk us through why exactly it is so important and how this differentiates brilaroxazine from the data so far, at least from a standard of care. Absolutely. Thank you. I think negative symptoms, as I mentioned, are deficits. They're absences of ordinary functions and phenomena you would expect in a healthy person, so the ability to express emotion either through facial expression, through voice, to take pleasure in things, to be motivated to go out into the world and be a part of the world. These things are often severely damaged by the pathology of schizophrenia, and you see it expressed in patients in lots of different ways, so in the RECOVER study in RECOVER-1, I think one of the things that was really fascinating, not only was the degree to which we saw improvements in negative symptoms across the board in response to treatment with brilaroxazine, but also when we look in a very specific group of patients that have a very profound deficit, we saw, again, major improvements. I'm referencing here the data that Dr. Bhat alluded to and showed in the slides around vocal biomarkers. Without going into too much detail, this is a new and very exciting area of research in mental health and in schizophrenia in particular. We believe, those of us who are working on this, that we may have found an objective way to identify individuals with schizophrenia who have a very specific and very profound phenotype. These individuals actually have what appear to be longer latencies in their speech. Along with that, a number of other symptomatic characteristics that suggest that they would be extraordinarily hard to treat in the real world. These patients, oddly enough, were exactly the ones who benefited the most from brilaroxazine. If you go back and look at the data, you'll see that the effect size of brilaroxazine in those patients, especially compared to placebo, is very high, quite a bit higher, in fact, than what we saw in the overall population of patients tested with the drug. So I believe that, again, going back to your question about negative symptoms, James, I think it's clear that while we have much to learn still about brilaroxazine, one thing I think we can say with some certainty based on the results so far is that we're seeing consistent results in an area in a deficit that many other drugs simply do not treat or do not treat well. Larry, Dr. Ereshefsky, let me get your thoughts on that. I know Dr. Opler really pulled out the vocal biomarker. What are your thoughts on that? Do you think that's a biomarker that is something the FDA will go with? And how does that, what are your thoughts sort of on his thinking there? The latter part of that question almost requires a crystal ball, but let's just say that the use of voice-related biomarkers and analysis is becoming a reality. The extent of development of digital interventions as well as digital assessment tools using your smartphone, et cetera, is exploding. The challenge is validation of these biomarkers by a very rigorous set of definitions the FDA has. I believe strongly that this data is among the most striking I have seen for any of these new tier of biomarkers. And certainly, as a supportive element in a filing, these will be strongly considered as supportive. Whether or not it leads to some special statement in a label is where I pull out my crystal ball and say it hasn't yet kicked in to tell me the answer to that. But I do want to emphasize that this negative symptom improvement is really extraordinarily important. Having spent 26 years working with patients at a state psychiatric hospital, the rate-limiting step were really two things. One was treatment resistance, but especially if we got the positive symptoms under control and you discharged these folks, they bounced back in because they wouldn't take the medications causing side effects. They didn't have the capacity to actually live a life. So they ended up in board and care facilities in these less-than-ideal housing situations that are impoverished. The environment is under-stimulatory. It encourages patients to sit in their room and smoke cigarettes and watch TV. And that's not a key to either a healthy or a successful life. And we're now raising the bar. It's not sufficient to treat acute psychosis short-term. To me, the short-term data is striking and positive, but the open-label data takes you into the real world of a year's worth of therapy, and having these remarkable outcomes sustained, both positive, both negative symptoms, to me, is exciting, so going back to just the vocal biomarker, the vocal work being done, there's a lot more that has to happen, but I believe that this drug and Reviva have moved the field forward with some extraordinarily strong data, and when we say strong, when we talk about an effect size of 0.9, that is extraordinary. Most antipsychotics, effect sizes of 0.3, 0.4 maybe is what you see, so this is a large effect size. It's the kind of effect size that doesn't just move the needle. It flips the person from not functioning to really having the potential to move on into a real life. Maybe just to follow up on that, then I'll toss it over. I'll ask Laxminarayan a question after this. One of the things that you've touched on in the past is the low drug-to-drug interaction and the lack of side effects. If you talk a little bit about the importance of that, you touched on it there, but if you expand a little more on that, please. Absolutely. So wedded to that question is also the fact that even the best drug stops working if you don't take it. And in the outpatient area, side effects especially are going to drive people stopping their medication or changing the dose on their own, which will limit what the drug ultimately can do. So if you look at treatment emergent side effects in the long-term study, when you can talk about discontinuation rates due to side effects in total under 2% is remarkable. That is an extremely low number. When you can talk about extrapyramidal symptoms, these are the Parkinsonian behaviors and akathisia being near zero changes in rating scales, literally zero changes. Again, that's remarkable and adds to the quality of life. And the fact it's true in the long-term data really is a telling story. Now, when we go into the pharmacokinetics, the drug-drug interaction piece of your question, first off, tied to adherence, more complicated drug regimens will reduce successful adherence to therapy. So think of that as does the drug get dosed once a day. Many of the more popular drugs are dosed more than once a day. And so that's a barrier right there. Additionally, it's very common when we treat patients that we need to use multiple medications. Now, whether you want to call it smart polypharmacy or just polytherapy, the reality is most patients are on three, four drugs to treat symptoms and side effects. So that complexity of regimen alone reduces adherence and is reflective of the limitations of current therapy. Now, when we get into drug-drug interactions, what that basically means is when you add an antipsychotic to medications people are on. And many people are not just on an antipsychotic historically. They're on an antidepressant. They may be on a mood stabilizer for a variety of reasons. And when you add a drug that changes metabolism, inhibits metabolism of another drug, you basically have set the apple cart and it ripples through. You either have to reduce the drug dose, switch drugs, et cetera. Additionally, it goes the other way. So a drug can be, if you call, we call it a victim or a perpetrator. And those are not my terms, so don't read into them. But the point of this is that many drugs are metabolized through Cytochrome P450 enzymes that other drugs we use either stimulate or block. And more commonly, it's the blocking of metabolism. It's been shown in studies that you do not see a meaningful inhibition of metabolism for brilaroxazine whether you give a 3A4 inhibitor, which is a common drug, and they've done the clinical testing. They received an FDA waiver. They didn't even need to look at cytochrome P450 2D6. The preclinical data showed that it was negligible, so in other words, this drug can be added to regimens and not upset the apple cart, and the only drugs that can affect the metabolism are drugs that induce the enzyme cytochrome P450 3A, and that's a relatively rare occurrence. The inhibitor drugs are the ones that really cause difficulties, and in fact, some of the antipsychotics need drastic dose reductions or are not indicated for use in the presence of strong inhibitors of cytochrome P450 3A4, and this drug does not have that as an issue. The changes are negligible. So, I know that's getting complicated when you start to spout cytochromes. We're in another world, but I hope that made the point of some advantages for this drug. No, absolutely. Thank you very much. And that's, of course, the reason your expertise is the reason. It's lovely to have you on the call. Lax, maybe you can walk us through some of the unique dual mechanism of action for brilaroxazine that sort of drives these excellent results. Yeah. You know, the brilaroxazine, particularly when we designed this molecule, to one of the things often when we typically design, we mainly focus on pharmacology, receptor pharmacology for the target. But the ADME-PK profiles are kind of the secondary in most of the design. But we particularly addressed these drug-drug interaction-related issues in these patients that is a polypharmacy or patients who live with multiple medications. That's the reality. We believe with our design, what we addressed in this molecule that translated very well in the clinical trials. Now, coming to the efficacy, the molecule has a very potent activity for 5-HT2B, 7 and D4 compared to other atypical antipsychotics, especially 5-HT2B is a receptor considered as an upstream target that mediates downstream cytokines that is implicated in the mediation of neuroinflammation or pro-inflammatory markers. So we believe that is translated very well, not only in the preclinical models, but also in the two trials, double-blind trial in 400 patients for a four-week trial, hospitalized patients. And then 440 patients in one-year treatment, we have seen consistent reduction in pro-inflammatory markers that we believe are one of the key differentiating factors, not only enhancing the efficacy as well as mitigating some of the key side effects what we see historically with other treatment options. There are a couple of points I want to follow up on. Can I jump in there? Yes, please. Because this is an area that I really believe is a change in paradigm for treatment. And I'm involved with a variety of treatments, developments for neurodegenerative disorders. And this concept of neuroinflammation, inflammatory responses is tied tightly to symptom severity, progression of illness in Parkinson's, for instance. I did one of the first studies with cerebrospinal fluid from Michael J. Fox Foundation. And these same cytokine markers, when elevated, demonstrated more severe movement impairment. And so here, it's a strong signal. The cytokines, these interleukins, all come down. And these are sort of the bad guys in your body. And the consequences are damage to the structure of your brain, damage to cell function in neurons, firing, and resilience to other trauma that may occur. And then it increases BDNF, Brain-Derived Neurotrophic Factor, which has been implicated again in positive outcomes in depression, in psychosis. There's a lot to digest here, but it's a strong, sustained signal. And when I look at the pharmacology of this drug and I try to understand why it certainly seems better than the average drug we use in treatment, I think this inflammatory biomarker story is a key part. Sorry to jump in there, but. No, no, please. People want to hear your opinions, not mine. Dr. Opler, what are your thoughts on this? I will never achieve Dr. Ereshefsky's pharmacological eloquence. But I think a couple of points that I would like to reflect on that may or may not be related to the neuroinflammation story and some of the other points made around the biology of this molecule. We do see some other unusual features of the drug that are worth pointing out from results of the RECOVER-1 study. One, I think, is the remarkable improvements, in fact, in sexual functioning. And that's a very key quality of life. Historically, studies show that patients with schizophrenia experience really extraordinary decreases in sexual functioning. And as part of the human experience, it's hard to underestimate how vital that really is to people's health and well-being. And I think even what we know from our studies is probably underreported. The epidemiology of this really does sort of indicate that patients with schizophrenia get a double hit, first from the disease, and secondly, most of our treatments actually add to that burden rather than take away from it. To actually not only see no worsening, but in fact, meaningful improvements in men and women in these studies, especially in the RECOVER-1 study, it's really very heartening, and my suspicion as rank amateur when it comes to some of this is that the neuroinflammation story and some of the metabolic uniqueness of this drug may have something to do with that, so I just wanted to point that out. From From a softer and perhaps more quality of life perspective, there are a lot of tie-ins to that story. No kidding around, that's an important part of treating this patient population. Lax, over to you for a couple of quick thoughts. One of the things that really jumps out on brilaroxazine is the long-term durability, the lack of relapse, which is key. Then I also want to talk about the prolactin levels on the biomarkers and your thoughts on that. Then I'll bring it around to the docs for their thoughts. Sure. The long-term durability is very important. That is hard to see with the current treatment options. See, most patients get stabilized with the currently available treatment in four to six weeks of treatment, but when they continue the medication for beyond that, and then many patients start discontinuing because one reason is a lack of efficacy to treat multiple symptoms associated with that schizophrenia, and maybe the side effect related, but the combination of these two led to discontinuation or going with the add-on another therapy for antidepressants. It's very common in the antipsychotic treatment. At least to my knowledge, one-third of the patient population are using two antipsychotics to treat these multiple symptoms associated with that. See, durable efficacy toward treating multiple symptom domains, at least the key symptom domains, are very critical for patients to be on drug for a long time that is needed in these patients. So what we have seen in this study, especially the long-term treatment, one-year treatment, we have hardly seen patients got relapse on treatment. But if you look at the historical data, around 20%-25% of patients discontinue on treatment due to relapse or we call it exacerbation due to increase in severity that we don't see in these patients. That we believe is a sustained and durable efficacy. The second part is you asked about the prolactin. Prolactin, in a decrease, because before coming into the trial, we see the elevated prolactin level in this patient population. Some other drugs currently in the market known to decrease in the short run, but after six to eight weeks, prolactin starts going up. But some other drugs increase the prolactin throughout the treatment. That's another side effect. But in our case, we have seen after four weeks of treatment, up to six weeks in the long-term study, the prolactin level reduced and then maintained to normal healthy patients' level throughout the one year. That is a key to my knowledge. We have seen, noticed the patients who get relapse symptoms, one thing we notice in that prolactin fluctuation. Prolactin fluctuation also related to hypothyroidism in this patient population. That's one of the biggest challenges to address. And then hypothyroidism further relates to metabolic diseases and the cardiac QT prolongation as well. So, we haven't seen that kind of side effects with our drug because the consistency is there, decrease in prolactin and then maintain the normal healthy level throughout one year, improvement in thyroid hormone, and no cardiac side effect in the study. All these things are tied up with the prolactin. They interplay between the prolactin and thyroid hormone. So overall, we have seen durable efficacy that is further supported by prolactin is one of the markers. We have around a 40-year history in psychiatry evaluating prolactin-related to the treatment. Dr. Ereshefsky, what are your thoughts? First, I do want to shout out that my fellow KOL, Dr. Opler, is the godfather of the PANSS. And I say that in the sense that the quality of the use of that scale is something he has spearheaded for most of his life. When you talk to investigators, regulatory agencies, and you have a question about the PANSS, Dr. Opler is the person who does the heavy lifting, the interpretation, the training of raters. And so it's exciting for me to hear him excited about things like negative symptoms and sustained effects here. Having said that, going back to the question, prolactin was well described. Not only is prolactin lower than it was at baseline, but prolactin is actually normal. It's within the limits of normal. And that's extraordinary. Patients on many of the more common drugs, risperidone, paliperidone, prolactin easily are three to five times above normal based on that drug's effect on the dopamine system, and that long-term elevation of prolactin ripples through your body in a variety of ways, including immune diseases, adverse events. It can contribute to metabolic syndrome, risk of type 2 diabetes. I mean, it's really important that this has come down and stays down, and then the thyroid, to me, is an understudied, not well-appreciated challenge in treatment. If your thyroid is low, we know for depression, check thyroid, treat thyroid. For schizophrenia, it's not an obvious thing that people do. And the research that's emerging that thyroid is basically modulating the effects of the neurotransmitters we think are important in schizophrenia, that without thyroid, your signal from the receptor where the dopamine, the serotonin hit into the cell and the subsequent actions that are therapeutic is dependent in part on thyroid being normal. So again, this is worthy of further assessment and evaluation. And it is another new element to our thinking about schizophrenia. Maybe over to the godfather. I know that the long-term durability and the PANSS score looked very good in this data. Could you walk us through that? And then how does this, if this holds up and it gets approved, ultimately, how does this change the treatment algorithm in the space? It's all good questions, James. I think let me just start with the overall improvements in the PANSS total, which are on their own extraordinarily impressive. I think it was mentioned before that many patients in the study achieved or came close to achieving remission, which is a long-sought goal in patients with schizophrenia, and a big part of really achieving remission is not just improvements in total severity of symptoms. It's the maintenance of that state over the course of time, so just wanted to mention that, but the other point, I think, is that beyond the total score, there are also all of the individual components, and one of the things I think that we're starting to learn about schizophrenia is that as a lifelong disease, it changes over time. It evolves in patients over the course of their treatment, their struggles with the disease. And you see some domains become modulated over time, somewhat less severe, while others persist and are really intractable. One of the things I think was very exciting for me to see and start thinking about vis-à-vis the treatment paradigm is very often people's pharmacologic history with schizophrenia evolves. They may start off on one set of treatments to address the acute symptoms. They may be shifted to others. They will have lots of additions as people engage in polypharmacy with them. My hope, and maybe this is pie in the sky, but I don't think so anymore, is that we may finally have a drug that actually is there for the long term and perhaps may actually be a good lifelong choice. As people's disease evolves, they're going to need a drug that actually treats multiple facets, not just in name only, but well and in a sustained way. I believe it's possible that brilaroxazine may be that drug. And it's my hope that as we see more data and more evidence coming out on its efficacy, we'll learn more about how it works over the life course of patients with this disease. Well, Lax, we're getting down towards the end of our KOL call. We have a number of questions that have come in. We can't get to all of them. I apologize to listeners, but a number of them focus around the upcoming FDA meeting. So I thought I'd start with you. What are your thoughts? One of the key concerns is, well, with 800 patients, is that enough? Not run another phase 3. Is that going to be enough? And I guess this much will depend on what the FDA says when you meet with them. Could you walk us through sort of the scenarios potentially? Sure. We have close to 900 patients treated with this drug. Historically, back in the olden days, early 2000 or late 90s, used to be around 1,500 patients. At that time, there are failure rates that were very high. Phase 3 used to be three to four trials. But lately, that number, total number of patients treated, maybe with the quality of the trial, the number has approved drug, the total number of patients treated dropped to around 1,150 to below 1,200, between 1,100 to 1,200. So again, to our knowledge, there is no hard and fast rule. It has to be the magic number 1,500. As I highlighted, to our knowledge, that is a two randomized trial, identical, similar comparable outcome efficacy standpoint. And then one year treated with the schizophrenia patients, six months completed 300, and then 100 patients completed one year. These are kind of a non-negotiable type requirement. The remaining one, we believe, based on the overall outcome and the safety profile, I think an agency may make a decision. Again, that's what we are meeting FDA to ask to get FDA feedback. So again, 1,500 patients, to my knowledge, this is not a kind of hard and fast guideline you have to meet. Below 1,500 also got approved. Do we have the date of that meeting yet? Sorry? Do we have a date for that meeting yet? Yes, we have already received a Type B meeting confirmed, and then we hope to get FDA feedback in December. December, that's right. Okay. Well, doctor, and this may be a little outside your guys' field, but Dr. Ereshefsky, any thoughts on the size of the trials and your perspective on the potential to go to the FDA with less than 1,500? So the FDA is an interesting body. I served twice on what was then the Psychopharmacologic Drugs Advisory Committee and was involved in looking at the internal process for a number of controversial drugs, some approved, some not approved. And what strikes me here that is going for, I think, the FDA accepting less than two phase 3 trials is consistency of the data. There is a defined dose response, which is one of the bugaboos the FDA really wants to know. And arguably between 15, 30, and 50, if you take a look at that composite of data, it emerges that 50 is better than 30, then 15. And I mean, that's answered already. Most people don't deal with that this early in development and have to do another trial with a lower dose to prove where is the floor for efficacy. We've crossed some T's and dotted some I's that occur. I know from working with a number of companies across the neurodegenerative space that certainly the FDA can accept one well-controlled clinical trial in phase 3 for approval. Now, they don't usually do that, but there is precedent for congruent supportive data between biomarkers, phase 2, when you have a large study like this, and a single phase 3 that drugs can be approved. Again, the FDA is really hard to predict, but my sense is this drug has some strong advantages that it may well be able to do something very few drugs have done in psychiatry. And my apologies is exactly right in your wheelhouse. I apologize for saying it wasn't at the start. Dr. Opler, what are your thoughts? I'm not going to presume to be able to predict what anybody's going to do, particularly our colleagues at the agencies, and I do think that they will have a hard task ahead of them evaluating this and evaluating it well. It's always a difficult thing to do, I think. I will say, though, that like Dr. Ereshefsky, I am struck by the consistency of the data that we're seeing. Speaking as somebody who saw this study up close and very personal, the quality of the data is extraordinary, and I think there were a lot of things that were done on the trial to ensure quality that are in its favor. As I and Dr. Ereshefsky have seen over the last few decades, it's become very standard, in fact, to check every data point, to evaluate all the evaluators and make sure that everybody's doing a good job. And I think to that end, I can say that Reviva as an organization did an extraordinary job being thorough and careful with the quality of the data. I think the results speak for themselves. So we'll see what happens, James, but I am optimistic. Thank you, Dr. Opler. We're coming up on the last couple of minutes. Lax, I'd like to hand it over to you for any closing comments, please. Yeah. I think this KOL webinar went extremely well, and then some of the difficult questions answered by our KOLs here, so thank you, Dr. Ereshefsky and Dr. Opler, for taking time to come to this webinar and then addressing questions, and then Jim, again, thank you for organizing this event. I hope some of the critical questions the investors are looking for, and then maybe they reached out to you as well. You are one of the covering analysts for us, or some of the questions we have addressed in this webinar, so thanks to all the viewers who are attending this webinar, and then once again, thank you, Dr. Ereshefsky, Dr. Opler, Jim, for organizing this event. Thank you. Thank you. With that, we've come up on a one-hour hard stop at the end of our KOL call today. I'd like to thank our listeners as well for joining us in our KOLs, Dr. Ereshefsky, Dr. Opler, and Laxminarayan Bhat, for taking the time to join us today and walk us through this very exciting story. We'll see what happens in December. Everyone may now disconnect from the KOL call. Thank you very much for joining.