Good afternoon, and welcome to the Reviva Pharmaceuticals KOL Webinar. At this time, all attendees are in a listen-only mode. A question-and-answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player. As a reminder, this call is being recorded, and a replay will be made available on the Reviva website following the conclusion of the event. I'd now like to turn the call over to Dr. Laxminarayan Bhat, founder, president, and chief executive officer of Reviva Pharmaceuticals. Please go ahead, Lax. Yeah. Thank you, Tara. Hello, everyone. Thank you to each and every one of you for being with us today. It's my pleasure to welcome everyone to our KOL webinar on presenting the results of brilaroxazine in phase III RECOVER trial in patients with schizophrenia. Today's webinar has three segments. In the first segment, our KOL, Dr. Mark Opler, will present a summary of brilaroxazine phase III RECOVER trial results. In the second segment, our KOL, Dr. Brian Kirkpatrick, will present the brilaroxazine in phase III RECOVER trial vocal biomarker results. The third and last segment is our question and answer. We will cover all three segments in about 60 minutes. So before I formally introduce our KOL, I would like to take a moment to, you know, introduce our R&D pipeline and an upcoming clinical data readouts. So this is our forward-looking statement. I would like you to take a look at our forward-looking statements here. Now, this is our agenda as I briefly walk through. Now, coming to Reviva's pipeline. Reviva is a late-stage pharmaceutical company focused on developing next-generation therapies for diseases of neuropsychiatric. That is our core strength and then specialty. We have two molecules in development. The lead molecule, brilaroxazine, currently in phase III development for schizophrenia. We have treated brilaroxazine a little over 1,000 patients as of today in multiple clinical trials. And based on the data in hand, we believe brilaroxazine can be developed beyond schizophrenia to other large indications in the psychiatric space: bipolar, major depressive disorder, and ADHD. And the drug has also shown good efficacy in the translational model for inflammatory conditions. So you might be wondering why we are developing this drug for inflammatory conditions. See, neuroinflammation is very well known in psychiatric patients. Our drug has potent activity. The pharmacological profile of our drug is based on the data generated to date, including the clinical data. We will walk through some of the biomarkers data in this presentation. It supports the drug's efficacy or the ability to address the decrease the inflammatory markers. So that's the connection between the, you know, common thread between the mental illness and the inflammatory conditions, the pharmacological activity, and then the drug's ability to treat both neuropsychiatric conditions and then inflammatory conditions. So this is the clear summary of the clinical trials, what we conducted so far, and then what we are finishing, and then what we intend to do for NDA. We have completed two large studies, clinical trials, randomized double-blind trial, multicenter global trial. First one is phase II, REFRESH study in acute schizophrenia. It was a dose-finding study. The study met primary and then key secondary endpoints. The second study, large study in 411 patients, it was an acute schizophrenia study. Again, the four-week study, the study met primary endpoints and key secondary endpoints as well. And currently, we are almost near completion of long-term safety study. The goal is to the requirement, regulatory requirement to have 100 patients completed of, in the schizophrenia, with the brilaroxazine. We have, as of today, over 80 patients have already completed one year treatment. We expect to have 100 patients completed in this study next month in October. So the last study, RECOVER-2, similar to what we already successfully completed, RECOVER-1. Again, trial design is four-week. Only difference is the low dose will be replaced with middle dose, thirty milligram, already tried in the phase II study. That's the only difference. Some of the few secondary endpoints we incorporated based on what we learned from RECOVER-1 trial, with a goal to appropriately, you know, if the results are positive, to go for label claims. Otherwise, we have completed all the remaining non-clinical development, including the drug manufacturing and the toxicology studies, carcinogenicity studies. Carcinogenicity studies all have been completed. This is the status where we are today. With this, a brief overview, now I would like to introduce our speakers. And then before that, as I mentioned briefly, so the RECOVER-1 trial, both efficacy, safety, and compliance was in detail reviewed in the last KOL webinar held on February 15th, 2024. The recording of the last webinar and the slide deck, they are available on our website. And in this KOL webinar, we will go through very quickly, review the efficacy of and then safety overview of RECOVER-1 trial, and then mainly focus on vocal biomarker data to further support the primary and then secondary endpoints evaluated in the RECOVER-1 trial. And then further, possibly, you know, as a surrogate outcome, you know, various biomarkers data which were not presented in the previous KOL event will be discussed in this webinar. Now, with this background, I would like to introduce our first speaker, Dr. Mark Opler. He is currently Chief Research Officer at WCG and Executive Director of the PANSS Institute. Dr. Opler has served as faculty member in the Departments of Psychiatry and Environmental Medicine at New York University School of Medicine, and Department of Neuroscience at Columbia University, the College of Physicians and Surgeons. His academic research focuses on the etiology, phenomenology, and treatment of serious and persistent mental disorders. He is a co-author and developer of several clinical assessment tools used in psychiatric studies. He is a contributor to the latest edition of the PANSS Manual. PANSS is a positive and negative symptom scale, is used in the last twenty-five years, over twenty-five years as a primary, assessing the primary endpoint, as well as some secondary endpoints as well. Dr. Opler has support from, U.S. National Institute of Mental Health, the Brain & Behavior Research Foundation, the Stanley Medical Research Institute, and the Qatar National Research Fund. He has co-authored more than fifty peer-reviewed publications, and has contributed to multiple book chapters and review articles on clinical assessment, research methodology, and mental health. Dr. Opler received his PhD and a Master of Public Health degrees from Columbia University, and his Bachelor of Science degree from SUNY Stony Brook. He is a graduate of the Psychiatric Epidemiology Training Program at Columbia University, and completed his postdoctoral fellowship at the New York State Psychiatric Institute. Now, our next speaker, Dr. Brian Kirkpatrick. Dr. Kirkpatrick is a nationally and internationally renowned expert on schizophrenia and related disorders, whose pioneering research has advanced many life-changing treatments. Dr. Kirkpatrick graduated from the University of Texas Medical School at Houston, and completed his residency in psychiatry at the University of North Carolina. After residency, he participated in the University of North Carolina Robert Wood Johnson Clinical Scholars Program, receiving a Master of Science in Public Health with a concentration in epidemiology. He also completed a fellowship in neuropharmacology at University of North Carolina. Dr. Kirkpatrick joined the Maryland Psychiatric Research Center at the University of Maryland School of Medicine, and later served as Vice Chair of Psychiatry at the Medical College of Georgia. He subsequently served as Chair of the Department of Psychiatry at Scott & White Hospital and the Texas A&M School of Medicine, and the Department of Psychiatry and Behavioral Sciences at the University of Nevada, Reno School of Medicine. He joined the University of Arkansas Medical School, Department of Psychiatry in 2022. Throughout his career, Dr. Kirkpatrick has focused on schizophrenia and related disorders. He co-chaired the Consensus Development Conference on Negative Symptoms, sponsored by National Institute of Mental Health. He's received competitive funding from National Institute of Mental Health, the National Institute of Diabetes and Digestive and Kidney Diseases, the Brain & Behavior Research Foundation, and Scottish Rite Foundation. He served as associate editor of Clinical Schizophrenia and Related Psychosis, and on the editorial board of Schizophrenia Bulletin. With this, I would like to invite our first speaker, Dr. Mark Opler. Dr. Opler? Thank you so much, Dr. Bhat. Thank you, everyone, for being here today. Just to review, schizophrenia, as we're going to speak about today, is a common psychiatric condition, affecting a little more than 1% of the world's population, including 3.5 million people in the U.S. alone. It's among the leading causes of disability worldwide, with onset usually in late adolescence or early adulthood, and it is a lifelong condition requiring lifelong treatment. As of today, an estimated 30% of patients are treatment refractory or non-responsive. And while there are many putative causes of the disease, neuroinflammation is implicated as a major contributing factor. It's a complex disorder as we'll discuss with a wide range of symptoms and impairments from social and occupational dysfunction and interpersonal disruptions to impairments in self-care contributed to by a range of symptoms from positive symptoms including delusions, hallucinations, and various forms of disorganization to negative symptoms as we'll talk about further in today's meeting. As I said, it's a complex disease. It involves multiple symptoms that change and fluctuate over the course of time. Beginning at onset, in fact, even before formal diagnosis, premorbid conditions may include changes in occupational or educational attainment. As prodrome progresses into frank disease, certain symptom clusters become more prominent, and these will fluctuate over the course of time and throughout the patient's life. Positive symptoms like hallucinations and delusions will wax and wane, while other symptoms, like negative symptoms, may be more chronic and, perhaps at times even more predominant. As I mentioned before, we believe that a large percentage of patients with schizophrenia do not respond to therapy that current pharmacotherapies that we have available, and none of the current therapies that are marketed really address all the needs of any patient with schizophrenia. Suboptimal efficacy and side effects, you know, add to our already, you know, considerable burden of low treatment adherence. You know, beyond suboptimal efficacy and the poor tolerability, the fact that many patients with schizophrenia being treated fail to adhere to treatment remains a major public health problem. Discontinuation rates, as you see here on the slide, are reported to be about 30%-45% in the acute phase of illness and as much as 70% in long-term treatment. So these remain critical unmet needs in the treatment of schizophrenia. In the clinical evaluation of new treatments, there are a set of standard scales and tools that most clinical trials utilize. And in studies of brilaroxazine, including RECOVER-1, all the following have been used as well. Starting, of course, with the PANSS, the Positive and Negative Syndrome Scale, which has been the gold standard for evaluating the efficacy of antipsychotic treatment for a little over 30 years now. There are various components to the PANSS, which we'll talk about today, including the PANSS total score, as well as factors addressing positive, negative, agitation, social cognition, also sometimes called disorganization, and other factors. Next is the Personal and Social Performance Scale, or PSP, which evaluates a range of interpersonal, daily functioning, quality of life, and other domains. The CGI, or Clinical Global Impression scale, is another standard tool, used typically by clinicians to create an overall summary of patient status. While many studies utilize these tools, some have more rigor than others in terms of evaluating and maintaining data quality throughout. Pleased to say that the RECOVER study used state-of-the-art methods developed by WCG, in similar to other top-tier programs which have led to regulatory approval. These included standardized training for every rater engaged in the study and calibration for all measures, independent review of video-recorded assessments to verify the scores that were obtained, and standardized ratings across rater sites and countries, as well as blinded data analytics to monitor and reduce potential sources of error and random noise throughout the study. So we're very confident in the quality of the data obtained, and as we'll see today, it is corroborated by various forms of objective data. A quick word about the design of RECOVER-1. As has already been presented, the patients in this study, four-week, randomized, double-blind, placebo-controlled study, were between the ages of 18 and 65, diagnosed according to DSM-5 criteria, with a duration of one to 20 years. They had to be in an acute episode of schizophrenia with at least moderate severity, based on the baseline total PANSS score between 80 to 120, and a baseline CGI score of 4 or more. 411 patients randomized in equal amounts across three arms, brilaroxazine 15 milligrams once daily, 50 milligrams once daily, or a placebo arm. In this four-week study, the PANSS total score was the primary endpoint, and the scales discussed before all served as secondary endpoints. Demographics of the trial were as follows: you know, well and equally distributed across all three arms. We see the ages of the patients averaging about 38 or 39 years old. The overall percentage tended to be male. You see here the other demographic characteristics. The only other thing I'll point out, I think just to keep this brief, the total PANSS score is relatively high. These are patients who would definitely meet the definition of being at least, you know, at least moderately severely ill and in an acute phase of illness based on these scores. All right. Sorry. Let's go back. So to just remind us all of the key findings in the study, the primary endpoint, the PANSS total score, demonstrated meaningful change in the 50-milligram arm versus placebo. And you'll see here, the change, the statistically significant and sustained decrease, occurred actually as quickly as within one week. So within seven days of the initiation of treatment, we see a significant difference from placebo in the 50-milligram arm. The 15-milligram arm did numerically separate from placebo, although it didn't achieve statistical significance. Another point I want to make is that, you know, these findings demonstrate no significant difference between U.S. and ex-U.S. patients. So, you know, again, I mentioned before and will continue to mention, the consistency of the findings both within and across different cuts of the data is quite striking. And whether we're looking within the United States or elsewhere, we see the efficacy of brilaroxazine is maintained and demonstrated. Other things I'll point out, positive symptoms and agitation and excitement, which are considerable problems in the acute phase of illness, demonstrated a great efficacy on brilaroxazine in the 50-milligram arm, as you see here. Once again, as quickly as one week, at day seven, you'll see that decrease showing up in positive symptoms for the fifty-milligram arm versus placebo, and similarly for agitation and excitement. We see similar striking effects in negative symptoms. We'll get into this in more detail later. Whether you're utilizing the PANSS negative subscale or the negative factor, utilizing the Marder model, we show clinically and I think statistically significant efficacy. Other clusters of symptoms, including social cognition, also sometimes referred to as disorganization. We see response to brilaroxazine in both arms of the study, in the fifteen and the fifty-milligram arms in the PANSS. The other thing on the right, you'll see results from the personal and social performance scale as previously presented. We're looking here at very meaningful changes in the PSP scores, both for the fifteen and fifty-milligram arms in patients showing up again as quickly as here, within fourteen days of administration of the drug. One or two other things to talk about before we get into some of the biomarkers data. First, the CGI scores. You'll see here that, you know, we want typically to see at least a one-point reduction in the CGIS, the severity component of the CGI. And, we're demonstrating actually somewhat more than that in the fifty-milligram arm by day twenty-eight. The other thing I'll point out is the proportion of subjects with at least a one-point reduction was quite meaningful compared to placebo in the results shown here. So to summarize, you know, we hit statistically significant and clinically meaningful improvement across really all major symptom domains with the 50-milligram dose versus placebo by week four. You see the p-values demonstrated here. And again, it's the consistency of the picture that is so very striking. Some other things I want to point out, first is in the surrogate outcome, efficacy, and safety group, the CSFQ, which is a sexual functioning questionnaire, demonstrated significant improvement in sexual functioning with brilaroxazine versus placebo in female patients participating in this study. You know, we saw CSFQ scores in men and women here. But particularly in women, we see this remarkable change from baseline to end of trial at day 28. And in both the 15- and 50-milligram arms, we're seeing that sexual dysfunction, which is linked to a variety of other outcomes, including negative symptoms and social cognition and functioning, really is improving quite drastically. This may be linked to other things that we know brilaroxazine does, including improving hyperprolactinemia. Again, you know, just the fact that we can achieve this within 28 days is quite remarkable. So to shift to some of the biomarkers data, you know, as previously presented, we see change in serum prolactin, which is quite striking. Hyperprolactinemia or elevated prolactin levels, a very common condition in patients with schizophrenia and psychiatric disorders that may actually be exacerbated by a number of existing marketed medications. Hyperprolactinemia is associated with a variety of immune disorders and diseases, and we think it may play actually a crucial role in pathogenesis. In schizophrenia, it may be associated with adverse effects and treatment non-adherence. So weight gain, breast tenderness and enlargement, and sexual dysfunction, as well as erectile dysfunction in men, may all contribute to an overall picture that reduces the likelihood to sustain treatment and maybe blunts the efficacy of treatment. Another piece of biomarker data that's very novel and striking is the improvements in BDNF compared to placebo. So BDNF, or brain-derived neurotrophic factor, has been reported as being reduced in patients with a variety of conditions, including schizophrenia and depression. It's been linked to negative symptoms and cognitive impairments in schizophrenia, as well as overall neuroinflammatory conditions. And improvements in BDNF, as seen here, are reported to also decrease other pro-inflammatory cytokine levels in patients with schizophrenia. Consistent with that picture, we see actually changes, decreases in pro-inflammatory cytokine IL-8. In both the fifteen and the fifty-milligram doses, you'll see these meaningful differences compared to placebo. As well as in, you know, another pro-inflammatory chemokine, MIP-1. Elevated levels of both of these drugs are associated with a variety of CNS conditions. And, you know, it's not simply intriguing, it's actually very heartening to see that at least one effective antipsychotic medication is capable of reducing rather than exacerbating these molecules. To sum up, the data on treatment adherence, what you see here is the discontinuation rates between placebo, the fifteen milligram, and the fifty milligram arms. The discontinuation rates due to side effects being meaningfully lower, I think, than placebo, as you see here on the right, and again, just overall, you know, these are very low discontinuation rates relative to what's been reported in literature, and we hope that we continue to see this data supported by future studies, so to sum up, you know, across the phase II and the phase III studies here, we see again remarkable consistency and robust efficacy on both the primary and the key secondary endpoints, lower discontinuation rates than placebo. Again, we look to RECOVER-2 to again confirm this highly consistent set of findings. To put brilaroxazine in, just in context with other marketed antipsychotics, you see here, brilaroxazine actually exceeds even olanzapine in effect size, looking at late-stage studies and published data, on both primary endpoint for, you know, olanzapine, risperidone, et cetera, as well as aripiprazole across, not just the primary endpoint, the PANSS total score, but some other secondary efficacy endpoints as well. So to conclude, we see that, you know, we have consistent, widespread efficacy of brilaroxazine across multiple domains in a well-conducted, high-quality trial. We see a very strong efficacy to side effect ratio, which may be contributing to a high level of overall adherence. It points to a molecule that may help to significantly impact unmet needs in the treatment of schizophrenia. You know, to close, one of the things that I think you're really looking forward to, I know I am, is hearing more about how an objective vocal biomarker analysis conducted by Reviva and the study team confirms the significant impact we've seen on brilaroxazine, not just on the general population of patients enrolled in the trial, but on a subgroup of vulnerable patients with schizophrenia. And to help us review that, I am delighted to pass the presentation over to my friend and colleague, Dr. Brian Kirkpatrick. Brian, the floor is yours. Thank you. Thank you, Mark, and good afternoon, everyone. So I'll be talking about a vocal biomarker and what that can tell us about this drug. A little bit of background, let's just think for a second about what negative symptoms are. So you can think of the group as being a decrease or absence of a normal psychological function, especially those commonly found in schizophrenia. And these, based on some statistical studies of factor analysis, these can be divided into two overall groups. One of them is expressivity. So first, there's blunted affect, and this is a decrease in the non-verbal aspects of communication that we use to emphasize or clarify what is being said. For instance, changes of facial expression, changes of vocal expression, speed, pitch, and volume of what we say, and then body language and expressive gestures. And then another expressivity symptom is alogia, which is sometimes called poverty of speech, and it's basically few words spoken and little information conveyed. And then the other large factor in here is motivation and pleasure. So first, there's avolition, which is reduced initiation and persistence in activities, excuse me, and a reduction in initiating and persisting. Then there's anhedonia, which is pretty common in schizophrenia, a decrease in the frequency and intensity of pleasure, and the expected or anticipated intensity of pleasure from future activities, so looking forward to things. And then there's asociality, which is reduced social activity, but also a decreased interest in having close relationships with others. Now, there's growing evidence that these are of a considerable importance, not only because they tend to cluster in this way into these two groups in patient populations, but there's increasing evidence that they reflect underlying circuits, and there is some difference in the underlying circuits, so we'll be talking about vocal biomarkers for schizophrenia, and specifically for negative symptoms, so vocal characteristics in people with schizophrenia have been very well documented. They've been studied for decades, especially by academic psychology. They've been evaluated using objective automated methods, such as natural language processing and acoustic processing, and these have produced highly reliable and objective data, so speech production, the most potent speech biomarker of negative symptoms, is production, how it is produced, and then speech latency, especially turns. These are very important and been widely studied as well. And this is the response time it takes to produce speech in response to, to someone else's stopping their speech. And in a clinical trial context, it's how long it takes someone to generate a response to an interview question. So you might have an interviewer saying: "How are you doing today?" And then the patient might say: "Okay, I guess. Not much going on." So the interval, the time interval between those two, is what we mean by turn latency. And we went in with an analysis, with an a priori hypothesis that is based on extensive literature, that turn latency would be an objective measure of negative symptoms. So here's the method. Turn latency taps core schizophrenia pathology, and they reflect an integration of cognitive, social, and motivational systems. Problems in any one of those systems can increase the latency of someone's response, and they're highly reliable. In one session, one interview session, you will often have more than 100 turns. They're interpretable as well. There's a clinical interpretation of this, which is that this is simply how long it takes someone to speak, and related in some ways to psychomotor retardation, more generally. It's easy to measure without testing burden, so these are based on vocal recordings of the clinical interviews that were being done in the trial anyway. It is easy and fast to compute these. It can be automated. You can norm them for international trials, and they're sensitive to change. There's high temporal resolution, high time resolution as a state measure. In the RECOVER-1 trial, speech latency had a lot of heterogeneity, as you can see in this graphic here. They range from, you know, this bottom. The horizontal axis is tenths of a second, so 100 hundredths of a second is typically how this is people speak of this. Through machine learning, this is the actual data. Machine learning learnings divided them into two groups, and there was first vocal biomarker positive. In other words, they had increased latency compared to the other group... They had slow responses, on average about 550 milliseconds, so about 0.55 seconds longer. Now, the average in that group was about 2 seconds long. They had more severe negative symptoms with a very large effect size. Effect size being a measure of no signal to noise, essentially. How much two groups actually separate? Oh, 0.2 is small, 0.5 is considered medium, and large is considered 0.8. So they were a great deal more severe in terms of negative symptoms, validating the hypothesis that we were looking at a measure of negative symptoms. This group was slightly younger, but similar in gender composition. Now, the vocal biomarker negative, they're negative, they were more normal. They had a faster response, and their average response was about 1.4 seconds, compared to the roughly 2 seconds in the vocal biomarker positive group. And interestingly, they also had more severe positive symptoms, hallucinations, delusions, disorganization. So I'll be talking about the biomarker positive group and the biomarker negative group, and we will graph them for some of these things as if those were treatment groups. Just to show you what negative symptoms differed between these two, again, we have effect sizes. The vocal biomarker group, the positive group, had greater blunted affect, emotional withdrawal, poor rapport, social withdrawal, impaired communication. They did not, they did not have more severe alogia. During these, their screening interviews, the biomarker positive patients talked much less, talked at a slower pace, had shorter interviews with fewer turns, and raters gave them higher negative symptom scores. The question becomes, did their treatment responses differ as well? Here is PANSS total score. On the left, you see the treatments, the treatment arms for the biomarker positive group in PANSS total. Here you have an effect size of 0.95. It was larger than the effect size in total score than the biomarker negative patients. I want to point out, though, that they also had a significant change in total score. About positive symptoms, again, this biomarker positive group had a significant difference from placebo in separation from placebo with an effect size of 0.82, that's considered large, and again, the vocal biomarker negative group also had a significant difference between placebo and drug, and this 0.36 is very much in the range of the effect sizes that we were shown earlier of several different currently marketed antipsychotics. Now, this one requires cautious interpretation because you want to keep in mind, the biomarker negative group had low negative symptoms. You can't show a big effect if you have- if you don't have something, but the biomarker positive group had a robust effect on negative, the brilaroxazine, excuse me, had a robust effect on negative symptoms. How about the disorganization or cognitions scale? Again, this subscore on the PANSS was significantly impacted, treated in both groups. It was a larger effect size in the vocal biomarker positive patients, the ones who had the longer speech turn latency. Now we're shifting over not to symptoms, but to two measures of function. You're probably all aware that function is an important issue for FDA approval of a drug. They want to know that you have had actually an impact on someone's real-world function. What you see is that the vocal biomarker group has a effect size of 0.74, certainly significant. It was significant after two weeks. And the biomarker negative patients also had a significant impact on their speech. I'm sorry, on their Clinical Global Impression for Schizophrenia scale. And again, it's a respectable effect size. And then there is the another measure of function is a little more complex. The CGI basically has one item, one number, one score, whereas the PSP has quite a few items, and they divide into four subscales. Now, the PSP total was significant. If you took the two biomarker groups and combined, you had a 0.48 effect size, which is quite respectable, essentially a medium effect size, and it was statistically significant. It's interesting, the vocal biomarker positive group had a respectable effect size, not quite significant. What's interesting is that the biomarker negative group had significant effects in other areas compared to what is significant in the biomarker positive group. So in the biomarker positive group, you see personal and social relationships at a better than medium effect size, and it was significant. In self-care, it was significant and close to a large effect size. Where the one group had something significant, the other did not. As you can see, the total score, socially useful activities, the biomarker negative group had significant and medium or better effect sizes. Brilaroxazine causes robust improvement in this measure of function in both groups, but in different areas, and that makes sense, as these two groups have different symptom profiles when they enter the study. In summary, what does the speech latency work tell us? Well, speech... A reminder, speech turn latency is an automated objective measure with an extensive literature in schizophrenia. It has a clear real-world interpretation and face validity as a measure of negative symptoms. I also should just remind people, you had 400 patients in the study overall, but there were some people who had, a recording that wasn't clear or a recording that wasn't done for some reason. So the groups I've just compared are less than, each of them is a little less than half of the total, yet you still see all these significant effects of the drug. So what do you see? In the RECOVER-1 trial, turn latency delineated two groups that differed on the severity of negative and positive symptoms, but in both vocal biomarker groups, brilaroxazine had robust efficacy for total PANSS score, positive symptoms, and two measures of real-world function. In the vocal biomarker positive group, which had moderate to severe negative symptoms, brilaroxazine had robust efficacy for negative symptoms. I think that the other group, the biomarker negative symptoms, they didn't have much in the way of negative symptoms. They had a kind of a floor effect. They weren't able to show an effect. Turn latency also, I want to point out, turn latency measures and human rater scale scores cross-validate each other. They're finding they have a very similar pattern of findings. Turn latency overall provides further support for the efficacy of brilaroxazine for both symptoms and function, and a wide range of symptoms with quite respectable effect sizes. Thank you. Thank you. Thank you, Dr. Kirkpatrick. So as you heard from our KOLs, the brilaroxazine has demonstrated robust, strong efficacy for major symptom domains of schizophrenia, as highlighted here, and then both efficacy for multiple symptom domains, in other words, broad-spectrum efficacy, and then safety profile resulted in improvement in treatment adherence. This is one of the major unmet need, besides the negative symptom overall. So, and then this data, you know, demonstrated by brilaroxazine in this pivotal study, further supported by biomarkers, blood biomarkers, highlighted here, a few of them, and then also the digital biomarkers. So to my knowledge, even with the blood biomarkers, you know, there are not many literature available for statistically significant outcome for blood biomarkers. And then with respect to digital marker, I think, again, there are very few in this space. The data presented here that is supported by biomarkers that further supports and validate the overall efficacy data generated and then presented here. So with this, I would like to open the floor for questions. Tara, you can take it from there. Thank you, Lax. So to our audience, at this time, we'll be conducting a question and answer session with our speakers. As a reminder, if you'd like to ask a question, please use the Q&A text box at the bottom of the webcast player. And to our analysts who are joining us live. To indicate you have a question, please use the Raise Hand feature under the Reaction button on the bottom of your Zoom screen. Please hold for a brief moment while we pull for questions. So our first question comes from Jason McCarthy from Maxim. Please go ahead, Jason. Hi, guys. Great presentation. I have a question, more of a broad question. So when you're thinking about the vocal biomarker test, is it available or would it be available to some percentage of schizophrenia patients, and what percentage would that be? And could it be used to bifurcate, really, which patients may benefit more from drug or in different ways, meaning on that slide you showed towards the end of your presentation, Dr. Kirkpatrick, where you had VBM negative versus positive, having differing benefits, significant in one but not the other? Dr. Kirkpatrick, please. I'd like to take that last part first. You know, one interpretation of the data is that really, brilaroxazine is treating all of these areas, but if you don't have one, you're not gonna show improvement, and if you have a lot, you're more likely to show an improvement. So I don't think that the evidence are really saying that. I think it's doing the same things potentially for everyone, but you're not gonna see a change in the score if you don't have much of that problem. That's the sense I make out of this. The other question you asked is availability of this biomarker. Widely available right now, no, but this is the kind of thing that could certainly be turned into a phone app if there's, you know, in- Yeah. So, period. Just to follow on what Dr. Kirkpatrick said, I absolutely agree. You know, I think it's pretty clear from the data that the brilaroxazine is, you know, effectively addressing the major deficits of all of these patient types, depending on what they are. You know, as far as the interpretation and the availability of this biomarker itself, you know, we are launching this in clinical trials, utilizing, you know, very highly calibrated methods and techniques to make sure it's being done correctly. So I expect we'll see it there first. But I agree with Dr. Kirkpatrick that in you know the coming years, it could be utilized as an application for clinician to help identify a specific phenotypes. They know who they've got in front of them. And as Dr. Kirkpatrick presented, the vocal biomarker-positive patients presented with a very specific set of negative symptom deficits, and I think being able to tell that in a reliable, automated way could be very important for the therapy of this disease going forward. And just a general question- And speaking- Oh, sorry. Speaking as a clinician, I'm not sure it would make sense to use this to decide to exclude somebody. I mean, I don't really think that that's where the data points us. I don't think it should be a, you know, in a clinical setting, should be a barrier, a gate to this drug. Got it. And just a real quick general question, there's a number of other people in the queue. Lax, maybe for you. Is this something that the company using a VBM to really have a much better objective view of what's happening on negative symptoms that Reviva may leverage to differentiate itself, either with regulators or providers, should the drug be approved, versus other drugs in development, where they've had good effects on total PANSS scores, but when you, you know, kind of parse that data apart, it doesn't seem to be as robust in the negative symptoms for other drugs? Yeah, certainly, yes. And then again, that table highlighted here, what this biomarker data provides us. We have significant number of patients with a good negative symptom. That's the first thing. To see the data, real efficacy, you need to have right patients enrolled. Our study had right patients. Now, we have seen good data with this vocal biomarker, and we. The next one study, we are completing long-term safety study, one-year data. There also, we have vocal biomarkers. So once we complete the study, next month, 100 patients, and then we will have close to 400 patients, vocal biomarker data coming up. That should further strengthen the data, what we have. And then in the last study, registrational study as well, we will be implementing this. Overall, we believe once we complete the development, we will have more than thousand patients' data to support the negative symptom that we believe it's a strong evidence if the upcoming data is also positive. Got it. Thank you, everyone. Thanks for the questions, Jason. Our next question comes from Laura Suriel at AGP. Please go ahead, Laura. Hello, this is Laura Suriel for Jim Molloy. Thank you for taking the questions, and congrats on the continued progress of this trial. So continuing with the speech latency biomarker and considering the significant findings already found and how brilaroxazine addresses this biomarker, how do you plan on applying this biomarker to the RECOVER-2 trial and further studying it? And if there's also any other related biomarkers that you're looking to address in the protocol, that'd be well to address as well. So just to quickly highlight the RECOVER-2 protocol, identical to RECOVER-1, what we completed. As I briefly mentioned, some of the new findings, what we have in this study, RECOVER-1, what we learned, we have put that one as a, again, as some of the exploratory endpoints. We graduated to secondary endpoints with a intention, with an intention to go for appropriate label claims. Yes, RECOVER-2 has a, you know, all the endpoints, what we, biomarkers, what we discussed here, it has much more than what we presented here. Understood. And then just one more from me, probably addressed to Dr. Opler. As you mentioned, that brilaroxazine might be better in comparison to other marketed antipsychotics, specifically with the lower discontinuation and disappearance rates. How do you think that brilaroxazine might fit and be integrated into the overall schizophrenia treatment landscape? It's a great question, and I think it's pretty clear that, you know, in addition to being a good and effective general antipsychotic, you know, we're learning more, and I think we're gonna see that its ability to address multiple domains that other drugs don't may prove useful across the lifespan of a patient, right? I mean, one of the challenges, of course, with this disorder is that it's not simply heterogeneous across patients, but that the disease evolves within patients as they age and continue dealing with all that it presents. So I think we're going to find that it's both broadly efficacious, quite potentially useful as an early treatment choice, but then may help provide patients with more stability over time as they age and as the disease evolves. Got it. Thank you for taking the questions. Thanks for the questions, Laura. Our next question comes from Bruce Jackson at Benchmark. Please go ahead, Bruce. Hi, thank you for taking my questions. First question is about the use of the vocal biomarkers. You've already alluded to the ability to kind of get some better nuance on the subgroups. What are some of the other advantages of using the biomarkers? So, for example, is it faster, easier, cheaper to conduct a clinical trial if you have these biomarkers available? Dr. Opler? I'm happy to try to address that. So, you know, I think at this stage, it is quite useful because it's very low burden. We extract this from recordings that we're already collecting for quality purposes. I think in the future, you know, when we start to look, let's say, at studies of specific phenotypes, we might be able to use this approach to actually reduce the overall sample size that's required to conduct the trial. By having studies that are better powered, potentially utilizing it as an objective measure, with remarkably low noise relative to other traditional measures, I do think that this approach could have a pretty significant impact on the clinical trials landscape. I think for now, what it's doing is it's enabling us to collect, you know, further data about the efficacy of brilaroxazine and further understand how it's treating, you know, treating the disease at different levels, from the molecular to the clinical, and now into the domain of, voice and vocal biomarkers. Okay. Okay, great. And then, you sort of alluded to the fact that you've got some additional measures in the RECOVER-2 trial, including the vocal biomarkers. Have you had any conversations with the FDA about how to use these new biomarkers in a clinical trial setting? So, Dr. Kirkpatrick, would you like to take this? he might have to address that to you. I was thinking he had to address that to you. Mark. Actually, all three of us were at a meeting sponsored by the FDA in August, and they are very interested in seeing these, seeing what can be done with digital measures. They actually have pretty, pretty good publicly available information on the things that would worry them about, about digital measures, and they are pretty consistent with the same. They're really kind of the same issues that they worry about a great deal, understandably, with non-digital measures. What is the context of use? What does the patient think of it? Are you affecting function? Things like that. And just to second what Dr. Kirkpatrick said, you know, data actually on the vocal biomarker in brilaroxazine was presented at a public meeting at FDA last month in August, and the response was actually quite favorable. You know, further in a review of the available novel measures to assess negative symptoms, we saw that, you know, speech latency, as Dr. Kirkpatrick discussed, actually met already many of the standards required for acceptability of a measure. So we look forward to further developments on this and further discussions with different stakeholders, including those in the regulatory sphere. Okay. Just to add that, Bruce, you know, we believe there's a great potential with this biomarker as an objective biomarker. So in the next two studies as well, one, as I mentioned, when completing the long-term safety, we have put this biomarker. We will have the data in the coming months, and then also in the upcoming study, RECOVER-2 as well, we will be implementing this. One other thought about the FDA meeting. One of the higher-ups in the FDA talked about the cliff that people do. Things look great in phase II, and then in phase III, you don't have success. Maybe the first study works, the second one doesn't. And one of the points, discussion made was you probably don't want to proceed unless you have quite a bit of consistency of finding an effect across your various measures. And this, it seems to me that this can very quickly play a role in that. This is by... It is an objective measure. It's a very different kind of measure, and I think it's the kind of thing that could help a drug company decide whether or not to proceed with the next study. Okay, great. Last question from me, and I'll hop back in queue. You mentioned earlier, the efficacy of the drug in both a US and international population. Is the voice biomarker something that can be used in both US and international populations? Yep. Yes. Yes, delighted to say, and look for future publications on that very subject. It's remarkable how well it works across cultures, languages, and countries. Okay, beautiful. Thank you. Thanks for the questions, Bruce. So our next question comes from Ram Selvaraju at H.C. Wainwright. Please go ahead, Ram. Can you hear me now? Yes. Yes. Firstly, I wanted to ask whether, in your estimation, Dr. Kirkpatrick, we have sufficient information to indicate clearly that the 50-milligram dose of brilaroxazine looks like it would be the optimal dose. To what extent do you think additional dose finding appears warranted at this juncture? I wouldn't want to underestimate the effect of the fifteen-milligram dose, truthfully, and I believe the plan, correct me, Dr. Bhat, you're thinking of perhaps adding a thirty-milligram dose. Is that correct? Yes, correct. You know, just to add to that, we see quite heterogeneity in the severity of these patients. So, you know, the dose response is proportional to, to a great extent, severity of these patients. So, you know, this is quite normal in the schizophrenia trials to have this kind of pattern. So having said that, we remain very optimistic to, you know, getting the this drug approval, all three doses, 15, 30, and then 50. Okay, and then secondly, when we look at this vocal latency measure, can you comment on potentially its applicability in other areas of neuropsychiatry, where a drug like brilaroxazine could be tested, for example, in patients with mixed symptoms of depression and schizophrenia or possibly other neuropsychiatric conditions outside the schizophrenia setting? I'm delighted to say we already have published data demonstrating the utility in mood disorders. And we have evidence also of its impact in other, you know, CNS conditions, including neurodegeneration. So I think we're going to see this approach and similar approaches appearing as part of our armamentarium in the study of brilaroxazine's efficacy across a wide range of conditions. So, for instance- Uh, thirdly- ... cognitive- Go ahead. If you give someone a cognitive load, they're likely to have some delay in latency. People with schizophrenia, as a group, have some cognitive impairment, as well as being upset when they're in a relapse. That's very helpful. Thirdly, I wanted to see if you could maybe elaborate on your comments earlier on with respect to the impact of brilaroxazine on sexual dysfunction and the extent to which you look at this as potentially differentiating for brilaroxazine specifically versus other approved atypical- Yeah ... antipsychotic drugs. I'll say just a quick word. You know, given that a lot of pharmacotherapy is actually associated with sexual dysfunction, I think it's heartening to see a drug that not only doesn't impair but may even improve this important domain, which, you know, again, I think goes widely under-recognized and under-addressed in this population, so you know, I'll stop there. Brian, I don't know if you or you, Dr. Bhat, want to add anything to that. Dr. Kirkpatrick? Yeah, please go on. Well, I was thinking about one of the differentiating issues is, most present antipsychotics increase prolactin, and that one of the problems of that, you listed several of the side effects. Another one is definitely osteoporosis in women, and that's a significant when you consider that people are taking these drugs for years and years. And then also, one thing to remember: majority of patients, the onset of schizophrenia, early, teenage. So this is a sexual dysfunction is one of the major unmet need. What the data, what we are seeing here is, very encouraging. Then last question from me is more broadly with respect to the evolving treatment landscape in schizophrenia. Maybe Dr. Kirkpatrick or Dr. Opler, you could opine on where you see a drug like brilaroxazine fitting into this landscape, given its similarities as well as differentiators versus more traditionally typical antipsychotics, which are currently the backbone of therapy, but also looking ahead into the potential advent of M1 and M4 receptor agonist drugs. We don't know. It's a little difficult. We don't know yet whether some people respond better to muscarinic than they do to dopaminergic drugs or serotonergic with dopamine, serotonin, and vice versa. I would be surprised if we found that everybody did better on muscarinics. That just seems very unlikely to me, given the heterogeneity of schizophrenia. So I think that the dopamine slash serotonergic agents, this one's rather different in how it affects those, but I think that there's going to continue to be a place for those, and, but we shall see. And so then the question becomes, how, what is the effect size? What is the acceptability? What are the side effects of a dopaminergic, serotonergic drug? And right now, this, this drug looks pretty good. You know, I would also add just, you know, to what you said, Brian, you know, I would be remiss if I didn't mention, we don't completely understand why many of the drugs we use actually work. You know, we have strong suspicions. We can see in binding studies where they go and what they do, but, you know, the picture is often much messier than that. I think to simply categorize brilaroxazine as another, you know, dopaminergic, serotonergic-acting agent might oversimplify the case. There clearly is, you know, a neuroinflammatory component that we shouldn't underestimate, and I think we'll learn more about as time goes by. So I think it's going to fit. It's going to have a very unique place in the pharmacotherapy of schizophrenia. We look forward to learning more in RECOVER-2 about, you know, all that it can possibly do for us in the future. I think you would probably both agree with the following broader statement, which is: It does not appear likely at this juncture, given how little comparatively we know about M1 and M4 receptor agonist drugs relative to traditionally typical antipsychotics, that they would replace a typical antipsychotic that's the backbone of therapy. Yeah. Clearly, given the complex neurochemistry of schizophrenia, in all likelihood, a drug like brilaroxazine, which, as you said, additional features to its pharmacology beyond the typical antipsychotic impact on the serotonin dopaminergic system, would potentially be applicable whether you have a future landscape dominated by atypicals or dominated by muscarinics. So yes, just to quickly add to that, the pharmacology-wise, basic pharmacology, I believe there is no dispute there. Schizophrenia is primarily caused by dysfunctional dopamine and serotonin. But to my knowledge, that the pharmacology, muscarinics are other agents that indirectly modulate dopamine, serotonin to balance. As we know, when we have an indirect modulation, there are limitation what to expect with the efficacy outcome. That we have seen in recent, you know, clinical trials, dose response. High dose may not work, low dose may not work. There is a narrow therapeutic window that is uncommon to see with the allosteric modulation. What brilaroxazine does is a direct modulation of the primary dysfunctional pharmacology. So that is proven approach, and then there is a better handle to manage the dose response in that. So, having seen robust data from the two large randomized trial, consistent data, we believe this ultimately benefit patients with the direct dysfunctional pharmacology. So Dr. Kirkpatrick and Opler- I think there's an unexamined assumption that many of us have about the role of muscarinic drugs, and that is you will take a muscarinic drug or one of the drugs that impacts on dopamine and serotonin, but there's increasing evidence. Psychiatrists, at least in this country, are becoming increasingly comfortable with the idea of adjunctive medications. For instance, often using certain antipsychotics as an adjunct to depression, to antidepressants. So I would not at all be surprised if in five or ten years we were thinking many people benefit more from a combination of those two very broad classes than they do from either one of them. ... and certainly, given the safety profile of brilaroxazine so far, we could eminently envision a future in which brilaroxazine could be seamlessly combined with any number of other existing agents, correct? Yeah, it will be very interesting to see the results in mood disorders. Thank you very much. Yeah. Thanks for the questions, Ram. So our next question comes from John Vandermosten at Zacks. Please go ahead, John. Thank you, and good afternoon. What about the regulatory recognition of these biomarkers? And then if you look back to other recent trials, and I'm not familiar or I'm not sure how familiar you are with them, but like Caplyta or KarXT, what biomarkers did they use, and were those recognized by regulatory authorities? Just to speak to the regulatory outlook right now, you know, there, there's a lot of, you know. There's a lot of guidance out already on the use of different methods, you know, either to enrich or to, you know, provide corroborative data. As of right now, you know, the attitude of the FDA on any specific marker will probably be dependent on the context of its use. So, you know, I think we've seen great supportive data already presented to FDA at the meeting in August on a variety of novel measures. And, you know, I believe that going forward, we're going to see greater, a greater willingness to engage on novel methods of assessment and measurement based on the outcomes of that meeting. But I think we will have to see on a case-by-case basis by study, you know, how well different pharmaceutical company sponsors do in getting the agency to accept this data for different intents and purposes, and it will depend on context. So, you know, I would say as far as your other question about, you know, what have other folks done, to my knowledge, nobody's done what our colleagues at Reviva have done on RECOVER-1 with vocal biomarkers. I haven't seen any data that comes anywhere close to looking at, you know, efficacy. There is published data from a study conducted by Sumitomo Pharmaceuticals on a drug for bipolar depression that was published. That is... There's a pair of publications, one by Cohen et al., and another by Segal et al., I believe, in Psychiatry Research, that I can refer you to, but that is specifically about mood disorders. In schizophrenia, as far as I'm aware, Reviva is far and away the leader. Brian, I don't know if you want to add to that. No, I think that's right. Great, thank you. And I'm also thinking of these biomarkers as a way to diagnose early, and I'm not sure how difficult it is to diagnose a schizophrenia patient, you know, when the symptoms are first suspected or the, you know, the disease or condition's first suspected. But is it difficult to do that? I mean, perhaps they have to come in a few times, and you look at it over time. Yeah. And if you use these biomarkers, it might actually allow for a faster diagnosis and a more certain diagnosis. Is that another way they could be used? I would say it probably will not replace, you know, the clinical diagnosis conducted according to DSM criteria anytime soon. I believe that information that we can extract from voice and from other domains could be very helpful in characterizing patients and understanding them better. As far as diagnosis goes, I will have to defer to Dr. Kirkpatrick, who, you know, does an awful lot more of that than I do. Yeah, I think. I doubt that it will be a great deal of help. I bet that if you take a large sample of clinical high-risk subjects, it will be a significant predictor of transition, eventual transition to psychosis. However, lots of things. That's true of lots of things. They're the kind of problems that people have premorbidly before the psychotic symptoms clearly declare themselves, are very non-specific. And we've already said, to some extent, this is vulnerable to emotion, to cognition, so, and motivation. It's. I think it will predict, but it probably won't do it well enough, with good enough sensitivity and specificity to be a practical tool, is my guess. Yeah. I mean, and just to build on that, you know, while it may not replace traditional diagnosis, I think it does have a lot of potential as a high throughput tool to help characterize patients and identify those with specific deficits. Okay, that makes sense. Yeah, because I think I have heard of similar things being used in neurodegenerative diseases such as Alzheimer's, so you don't want to confuse what the actual diagnosis is by using that tool, and what we- I just... If I could add- Oh, I'm sorry. Go ahead. I'm dying of curiosity about the relationship of these things to a variety of, for instance, blood-borne biomarkers, and that will be an exciting chapter, I think. And when we look at the magnitude of the biomarker change and compare it to severity, as I guess measured through PANSS, is there an association there, where the higher score for the vocal measurement and the PANSS score are correlated? There is a relationship. It's not adequate yet to completely abandon the PANSS. I'm both delighted and sad to say. But we're learning more, and I think as time goes by with more data from studies like RECOVER-2, you know, we'll get a better sense both of how brilaroxazine directly affects these endpoints that we're developing, as well as how better to use these endpoints to understand the changes that we see in patient symptomatology. Okay. Have any of you seen if there are any nuclear imaging options that can be used in schizophrenia to identify the presence of receptors or dopamine or other items of interest? Certainly such studies have been done. They're not of practical clinical use at this point. Okay. Great. Thank you for taking my questions. Thank you. See, there are no more questions or. Yeah, I think we can wrap up here. Okay. Thank you. If there are no further questions, I would like to thank our key opinion leaders, Dr. Opler and Dr. Kirkpatrick, for presenting brilaroxazine phase III clinical trial results, sharing their insights on schizophrenia and utility of vocal biomarker in clinical trials for schizophrenia, and further validating clinician-assessed outcomes in schizophrenia studies, especially negative symptoms. So I would like to thank you all for taking time off your busy schedule to attend this event. Also, I would like to thank our investor relations from LifeSci Advisors for their assistance in conducting this event. If you have any questions about anything we discussed today, feel free to send us an email to shown here in the last slide, ir@revivapharma.com. The recording from today's meeting will be posted on our website, www.revivapharma.com, maybe later today or by tomorrow. Once again, I thank you all for attending this event and especially for our KOLs, and then thank you all. Thank you.