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, or by emailing your questions to questions@lifesciadvisors.com. 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. Lax Bhat, Founder, President, and Chief Executive Officer of Reviva Pharmaceuticals. Please go ahead, Lax. Thank you, Tara. Good morning. Thank you each and every one of you for being with us today. Before we begin our webinar, I would like you to review our forward-looking statements displayed here. It's my pleasure to welcome everyone to our Key Opinion Leader webinar on brilaroxazine phase III RECOVER Trial in Schizophrenia. Today's webinar has three segments. In the first segment, our KOL, Dr. Opler, will present brilaroxazine phase III RECOVER Trial efficacy results. In the second segment, our KOL, Dr. Ereshefsky, will present brilaroxazine phase III RECOVER Trial safety, tolerability, and compliance results. The third and last segment is for question and answers. We will cover all three segments in 60-75 minutes. O ur first speaker, Dr. Opler, is currently Chief Research Officer at WCG and Executive Director of the PANSS Institute. Dr. Opler served as faculty member in the Departments of Psychiatry and Environmental Medicine at New York University School of Medicine and in the Department of Neuroscience at Columbia University College of Physicians and Surgeons. His academic research focuses on the etiology, phenomenology, and treatment of serious and persistent disorders. He is a co-author and developer of several clinical assessment tools, including SNAPSI, CGI, and NY-AACENT. He is a contributor to the latest edition of the PANSS Manual as well. Dr. Opler has received research support from the U.S. NIMH, the Brain & Behavior Foundation, the Stanley Medical Research Institute, and Qatar National Research Fund. He has co-authored more than 50 reviewed publications and has contributed to multiple book chapters and articles on clinical assessment, research methodology, and mental health. He received his PhD and MPH from Columbia, his BSc from SUNY at Stony Brook. He is a graduate of the Psychiatric Epidemiology Program at Columbia University and completed his postdoctoral fellowship at the New York State Psychiatric Institute. Dr. Opler's group has been associated with the development of most marketed antipsychotics in recent years. Dr. Opler has been associated with brilaroxazine clinical trials as well. Our second speaker, KOL, is Dr. Larry Ereshefsky. Dr. Ereshefsky has a PharmD degree and has over 40 years of experience as a clinician, scientist, and investigator to develop treatments and innovate clinical methodologies to make a difference in the lives of patients with neurodegenerative and psychiatric disorders. He has contributed significantly to several drug approvals spanning neurology, psychiatry, including drug development planning, and PK/PD evaluation, methodological innovation for schizophrenia, depression, bipolar disorder, Parkinson's, and pain indications. Dr. Ereshefsky is a leader in the use of signal detection strategies to minimize placebo response and ensure study designs preserve statistical power while preserving the blinding. He is a retired Regents Professor of Pharmacy, Psychiatry, and Pharmacology from The University of Texas, UT Health Science Center. He has designed, implemented, supervised, and conducted more than 100 CNS clinical trials ranging from first-in-patient through to proof of concept, and has overseen large global phase III registrational trials. He serves as Chief Science Officer for Apex Innovative Sciences, including their two 80-bed early phase research units. Dr. Ereshefsky's unique perspective as a clinical scientist helps to guide drug development from clinical to late phase. He served twice on the FDA Psychopharmacologic Drugs Advisory Committee. Now I will give a very brief overview of our clinical program, brilaroxazine for schizophrenia indication. Reviva has successfully completed brilaroxazine phase III RECOVER Trial in acute schizophrenia patients and announced the top-line data on October 30th, 2023. We have now additional data to present. In today's webinar, our Key Opinion Leaders are presenting the RECOVER Trial efficacy, safety, tolerability, and compliance data. KOL will answer any questions from the audience. RECOVER study in acute schizophrenia patients met the primary and secondary endpoints, including some of the key exploratory endpoints such as sexual dysfunction in females and biomarker-based endpoints for neuroinflammation. RECOVER Trial long-term safety study in stable schizophrenia patients is progressing well. We have enrolled approximately 300 patients so far in this study and continue to enroll patients until 100 patients complete one-year treatment. Brilaroxazine 15/30 and then 50 mg doses are being used in the long-term safety study, and the study is progressing well. We anticipate completing this long-term safety study in Q3 2024 this year and announcing the top-line data in Q4 this year. W ith this background update, I would like to invite Dr. Opler to present the brilaroxazine RECOVER Trial efficacy data. Dr. Opler. Thank you so much, Dr. Bhat. Hello, everyone. Let me start with a little background on the disease in question. As many of you know, schizophrenia is a common psychiatric condition affecting somewhere between 1%-2% of the world's population. Approximately 3.5 million people in the United States and 24 million globally suffer from this disease. This is among the leading causes of disability worldwide, with onset usually in the transition between adolescence and adulthood. T his is a disease that requires lifelong treatment. It's a lifelong diagnosis with effects throughout the lifespan. Of all the patients diagnosed and treated, approximately a third are considered treatment refractory, meaning they do not respond well or adequately to first or second-line treatments. The reasons for this are complex, probably to do with the etiology, which is also a continuing subject of debate in research. We do know, however, that neuroinflammation is implicated as a major contributing factor, possibly to the onset, certainly to the symptomatology of schizophrenia. As mentioned before, it is a complex disorder with a wide range of symptoms that vary both within and across patients and over time, from the positive symptoms such as delusions, hallucinations, and disorganized speech to the negative symptoms or deficits, including deficits in emotional expression, experience of pleasure, and social withdrawal. Again, no two patients are exactly alike, although they all do share similar diagnostic features, and this disease is rarely constant throughout the lifespan. Along those lines, let's take a look at how schizophrenia progresses over time. I n the premorbid stage before formal diagnosis, you can often see changes in patient functioning, sometimes in social withdrawal and occupational and educational attainment during prodrome. Onset tends to begin, as I mentioned before, in early adulthood and may often be accompanied by the emergence of positive symptoms and frank psychosis. This usually resolves somewhat over time, but then other symptom categories become predominant, including negative symptoms and cognitive deficits. There are probably multiple neural circuits, multiple neurotransmitters, and multiple biological systems that are involved in this complex interplay of symptom and disability. Recently, there's been focus on immune and inflammatory processes in psychiatric and in neurological disorders, and we expect to continue to learn more about this as time goes by. A t the present time, I think it's very fair to say that there's no single therapy that addresses all of the needs of any patient with schizophrenia. In addition to suboptimal efficacy of current treatments, the ability to adequately address critical aspects of the disease, such as negative symptoms, mood, and cognition, continues to be elusive for many patients. Add to that the fact that many existing treatments have limited tolerability and carry with them a range of side effects, from endocrine and cardiac to neuroleptic and metabolic side effects. There are also, because of these side effects, a number of drug-induced comorbidities that are very disabling. Some drugs cause difficulties in movement. Some are associated with obesity and dyslipidemia. Others may cause, as mentioned before, metabolic side effects, including type 2 diabetes. All of this ultimately leads to high rates of discontinuation and noncompliance with treatment, and it is one of the problems that the field continues to struggle with. Let me say just a word or two about the clinical evaluation of schizophrenia in drug trials, such as we're here discussing today. The primary outcome for most antipsychotic efficacy trials has been the Positive and Negative Syndrome Scale, or PANSS. The scale has been used in multinational clinical trials for more than 30 years and is the generally accepted endpoint for most regulatory agencies, specifically the PANSS total score. The PANSS has demonstrated reliability and validity across many languages and cultural contexts, and, as I said, is generally accepted as the primary outcome. A number of other scores and endpoints can be derived from this scale, including positive symptoms, as demonstrated by the positive factor, negative and social cognition factors, as well as agitation, depressive, and others. In addition to the PANSS, another scale used in the RECOVER Trial that's commonly used across many studies is the Personal and Social Performance Scale, or PSP. This scale evaluates interpersonal and daily functioning and quality of life. These are critical domains for patients with schizophrenia working towards recovery. Another scale I'll mention is the CGI, or Clinical Global Impression Scale. This is a standardized tool used by clinicians to summarize global patient status. In order to make sure that these scales are being used reliably and in a valid way, free of bias, and with limitations on the amount of noise and random error, the RECOVER study used a set of state-of-the-art methods developed by WCG. These methods are similar to those used in other clinical development programs, which have led to regulatory approval, and the goal was to ensure accuracy and high quality of the data. These methods included clinical rater training and calibration for all outcome measures, with significant focus on the PANSS since that was the primary outcome. All PANSS assessments in this trial were video recorded and blindly reviewed to ensure standardization and accuracy of ratings. In addition to that, we conducted blinded data analytics to monitor for and to reduce potential sources of noise and to ensure that random error was kept low consistently throughout the trial from beginning to end. Now, just to say a word about the design of the study. These were patients who were in the acute phase of illness between ages of 18 years-65 years. All of these design features are very common across many antipsychotic efficacy trials. The acute episode of schizophrenia here was defined as being of at least moderate severity according to the PANSS total score at baseline, between 18 points-120 points, and with a baseline CGI score of 4 or more. 411 patients were randomized evenly across three arms: 15 mg and 50 mg of brilaroxazine and a placebo arm. This was a 4-week study where the primary endpoint was the change in baseline of the PANSS total score versus placebo at week 4. Baseline characteristics for all three arms were roughly equivalent, as you can see here. I will mention that the ratio of patients across all of these demographic and other features were roughly similar to those seen in other acute trials of antipsychotics that we've seen in the last couple of years. I won't spend a lot of time on this. This was the main outcome of the study, the primary endpoint. As you see here in this figure, the PANSS total score actually started to show separation on the 50 mg dose of brilaroxazine as early as week one. That statistical significance was maintained throughout the trial, finishing up at week four with a very significant result and demonstrating roughly 10 points of reduction in the total score versus placebo. If you look at the placebo arm here shown in gray, you'll notice that placebo change here was kept relatively low, which is good to see because, among other things, that's an indicator of the quality of the trial that was conducted. Secondary endpoints, including the positive symptoms as measured by the PANSS positive subscale, also separated as early as week one for the 50 mg dose, and that was maintained throughout the trial all the way up to week four. The 50 mg dose was shown to be numerically superior, as you can see here, and by week four, you start to see that separation occur. Other measures and secondary endpoints also reached significance by week four, including, very importantly, negative symptoms. As I said before, negative symptoms are a challenging cluster of symptoms to treat effectively. F or any drug or treatment to meaningfully separate from placebo on negative symptoms is an accomplishment. And as you can see here, we achieved statistical separation with an effect size of 0.4 on negative symptoms as measured by the negative subscale of the PANSS. Other measures of negative symptoms derived from the PANSS, including the negative factor in the Marder model, showed separation by week 4 versus placebo for the 50 mg dose. Once again, you'll see here that the 15 mg dose also separated numerically at the same time point. Say a word about social cognition. Social cognition is generally regarded as an individual's ability to process and understand social information and to interact with other human beings according to the processing of that information. There is a factor that can be derived out of the PANSS on social cognition, which also proved to be statistically significant by week 4, both for the 50 mg and for the 15 mg dose. Social cognition is considered a very important factor in a patient's ability to maintain and continue social relationships both in social settings as well as in occupational settings. This is a nice result to see. The Personal and Social Performance Scale, which is generally considered a measure of functioning in multiple settings, demonstrated statistical improvement by day 21 for both the 15 mg and the 50 mg doses, with very significant separation from placebo by the end of the trial at an effect size of 0.5. This is very important because beyond simply achieving symptomatic remission, the other thing that treating clinicians and researchers really want to see happen with effective treatments is the ability to achieve or recover some of the occupational functioning that's been lost and some of the social functioning that's been lost in this disease. P atients coming in with fairly severe scores in this study to see this kind of improvement on a scale indicates that this treatment may have use beyond the acute phase of the illness. Excitement and agitation are symptom clusters that are often associated with emergency treatment and hospitalization. So we were pleased to see that as early as week 3, the 50-mg dose of brilaroxazine demonstrated separation on the excitement-agitation factor in the PANSS. This is good to see because, again, this is one of those symptom clusters that most often brings patients in for emergency care. Another secondary endpoint I want to highlight is the CGI. The CGI is rated from 1 to 7. G enerally speaking, a 1-point improvement in this scale is considered a meaningful improvement. A s you'll see here, by week 3, there was statistical separation on the 50-mg dose. And by week 4, we saw separation both for the 50-mg and the 15-mg low- and the high dose of this drug. The CGI is generally accepted as another important measure of overall efficacy of a drug. T his is another important result, especially in combination with the PANSS total score. I want to highlight also the proportion of subjects in each arm who actually achieved this 1-point improvement from baseline. A s you'll see here, while a number of patients on placebo do get there, possibly due to the fact that they're being put into inpatient treatment and receiving other forms of supportive care in that setting, you really do see the difference that brilaroxazine makes over placebo when you look at this proportionally. W hile we got 65% of patients on the 50 mg dose up to this level, fully 78% on the 50 mg dose got there. T his is another important metric that I think needs to be included when you consider the efficacy of the drug. Just to sort of sum up everything we've talked about here, it's a very impressive range of endpoints representing different classes and clusters of symptoms within schizophrenia that are very important to the overall success, both of the treatment and of the patient. Great to see the PANSS total score achieve such a strong reduction versus placebo. Great to see the CGI change so much, so consistently. T o see all of these symptoms improving and improving in the same direction with such magnitude is something that I think is quite significant. These results were very consistent from the phase II study that was conducted previously. Again, another piece of evidence demonstrating the quality of the data and also the consistency of the result. I want to spend just a second comparing these results to the results of other marketed antipsychotics. The overall effect size of the overall effect size of brilaroxazine in this study was 0.6. Compared with first-line treatments like risperidone and olanzapine, this is on par, actually a little better. G enerally speaking, it exceeds what we've seen in other marketed antipsychotics. When you consider brilaroxazine, for example, versus aripiprazole directly, when we look beyond just the primary endpoint at positive, negative, and other features of the disorder, brilaroxazine is doing actually better than aripiprazole in each of these domains. S omething to consider. I want to now just wrap up a little bit here and give you what I think are my takeaways, my conclusions. The first is we're seeing consistent wide-spectrum efficacy of brilaroxazine, reducing symptom severity in multiple domains associated with schizophrenia, positive, negative, agitation, and other. I believe this was a very well-conducted trial with very high-quality data, as we've seen through the low placebo response. We believe this is in part due to the fact that a range of state-of-the-art methods were used to ensure data quality and make sure that neither error nor bias significantly affected the results. The efficacy to side effect ratio of the drug is very impressive. I believe that because of that, brilaroxazine has the potential to address many of the unmet needs in schizophrenia, the treatment of this disorder. As I mentioned, this is one of the leading causes of disability, a very expensive disease to treat, and we need better drugs with which to do so. On that note, I'm now going to pass this back to my colleague, Dr. Ereshefsky, who will now talk to us about safety, tolerability, and compliance. Larry, over to you. Thank you, Mark. That was, as always, fabulous. Your insights and work in this field for data integrity and quality research are extraordinary. You're one of the leaders in our field. Just want to say thank you publicly because you well deserve it. High praise from you of all people, Larry. Thank you. I've been asked to cover what some people think is the more mundane part of the story when you talk about trials data and top-line data and full data reporting. I n reality, for many chronic illnesses, it isn't just that the drug works, but that it's tolerated, it's safe, and that the patient will continue to take it and derive benefit. T o me, those are significant challenges, especially for schizophrenia. H ere's a brief flyby of the second-generation antipsychotics. P rior to 1989, and I started work and research at San Antonio State Hospital in 1977, which for some people would still be considered the dark ages of psychiatry, where chlorpromazine and other drugs were the mainstay, we have come a long way. The effectiveness of these drugs is excellent compared to earlier drugs. Tolerability is better, but we have a long way to go. We've made good steps in the right direction. I f you look at outcomes data and you look at adherence rates and just look at the impact of what we know are effective therapies, they fall short of what we need. You heard a bit about the burden of illness that these patients endure. F irst off, the percentage of subjects, of patients who truly are in remission, is a very tiny number. Many will have short-term efficacy, and we talk about 20%, 30%, 40% improvements in the PANSS as being a strong effect. These are still people with meaningful symptoms. Add on the side effects, and we've changed from in the older days, tardive dyskinesia was an extreme concern. We now look at metabolic syndrome and weight gain and other adverse events. In combination, then, lower efficacy than total efficacy, and coupled with side effects, coupled with the cognitive impairment that's part of this illness, non-compliance rates are extraordinarily high, at least 30%-50% short-term, well over 50% in long-term treatment-stable patients. If we look at side effects, probably one of the most important drivers for this data, almost everyone reports a side effect, but over half report impairment as a result of medication side effects in daily living. Almost a third report moderate or severe impairment. Clearly, that's an unacceptable outcome. Waiting for the slide to move. There we go. One of the other considerations, we know, as you've just seen, it's a chronic illness with intercurrent relapses. What's also happening, if you will, is the clock is running. Early on in the illness, there's progressive brain tissue loss. It's shown on MRIs and structural assessments as enlargement of the ventricular space or cortical atrophy. In those first four episodes, most of the brain damage is done for schizophrenia. Unlike Alzheimer's, which is a progressive illness, here, up front, after first episode, you really need to intervene and attempt to reduce the risk of relapse. That's still the holy grail. It means we end up with a lot of treatment-resistant patients by the time they're age 30+. When we look at the needs, where we are, where we're going, relapse prevention is somewhere under 50% by the second year in people that are claiming to take their medications. That's not a very good success rate. 20%-30% reduction means better, but not well. The symptoms that have already been described are across a wide array of effects or deficits. T he positive and negative symptoms, mood symptoms, become important. There's clear cognitive impairment. This leads to daily functional impairment. T here's a number of domains that need to be addressed. Many of our drugs, most of our drugs do not address all of these. Talking about side effects, and this will help with some definitional terminology, the metabolic side effects are sort of the triad of weight gain, diabetes, dyslipidemia, sometimes hypertension is included in there. Endocrine side effects, especially prolactin changes, but also thyroid, may be driving the decrease in sexual function, the sexuality side effects, which are rated by patients, even though they may be psychotic and delusional, are rated as extremely important to quality of life. We have the traditional effects, the neuroleptic side effects, extrapyramidal symptoms. W hether it's pseudoparkinsonism, akathisia, which is really uncomfortable for subjects. We're talking about an urge to move, an inability to sit still that actually is highly distressful. T ardive dyskinesia, which, of course, is a potentially irreversible muscular disorder, a motor disorder. Autonomic side effects have also been part and parcel: anticholinergic, dry mouth, blurry vision, cardiovascular, such as QT prolongation or hypotension. What I also want to underscore that you heard already from Mark is neuroinflammation and inflammatory processes in the brain appear to be a common pathway associated across a large number of CNS disorders, ranging from neurodegenerative disorders such as Alzheimer's through to depression and schizophrenia. T he role here is an important frontier. I'm going to share some data from this trial that's really among the first to look at this in an acutely exacerbated phase III trial of patients with schizophrenia. A little bit on the psychopharmacology of the drug. I've presented on this before, and I've decided to keep this simpler and get to some bottom-line points. D opamine and serotonin pathways have been clearly implicated now for decades. W e're talking about, depending on the region of the brain where innervation occurs, you may have changes in reward, in cognitive capacity, working memory, mood, sleep. Y ou can see some of the key brain regions where the cell bodies for the dopamine and serotonin system are. B rilaroxazine is affecting, in a complex but positive way, multiple dopamine and multiple serotonin receptors. These, in turn, are modulating a whole series of neurotransmitter systems that together treat many different illnesses or are the cause of behavior in many illnesses. T hen you're treating the root causes. T his goes from schizophrenia to bipolar, but it also plays a role in depressive disorder and in ADHD. T hat's quite a broad spectrum. I t's tied to a pretty wide pharmacologic set of effects. A lthough the drug does not have activity at the cholinergic, glutamatergic, or GABAergic system directly, there's clear evidence that the pharmacology of this drug is influencing, in a meaningful way, these associated transmitters with schizophrenia. L ooking at that in a little more detail, so brilaroxazine has D2, D3, and D4 partial agonist-antagonist effects. It has serotonin 1A partial agonist effects. T hen it has a few other effects that I'll come back to in a moment. These effects that are at the top of this slide are important to treatment of schizophrenia and other psychiatric disorders. T hey then, by their direct pharmacology, if you will, the direct orthosteric effects, indirectly modulate through allosteric effects, glutamate, GABA, and cholinergic receptors. I t really is engaging multiple circuits to get to the endpoint we want. What I think is a frontier, and it's exciting, is that through serotonin 2B and serotonin 7 antagonism, there's both preclinical data and now some data from this trial to suggest that pro-inflammatory markers are being reduced, and there is an increase in the anti-inflammatory markers in the brain, meaning brain inflammation and potentially some increased neurotrophic effects are possible. Now, that could be a whole separate seminar for another day. There again, is now data to suggest we are seeing our drugs really take on not just transmitter effects, but inflammatory and neurotrophic effects in the brain. Getting back to RECOVER and looking at the data from the intent-to-treat analysis, overall, very well-tolerated safety profile. The overall treatment-emergent adverse events are basically not statistically different. Y ou can see they're all sitting in the 30%-35% range. No serious SAEs, no suicidal ideation as assessed in the trial. No statistically significant changes in body weight, glucose versus placebo, though I will come back to weight as there are some data signals that are worth exploring and explaining. There is a number of measures on cholesterol metrics that actually go in the direction of improved health. The actual treatment, the emergent adverse events, are of the kind that we would consider fairly benign and transient: headache and somnolence. On the metabolic side effect side, weight gain overall is seen in a few people where we're looking at the definition of sort of the adverse events of special interest. It's a low number. You can see the 15-mg group with three subjects in that arm, eight subjects, or 5.9% in the 50-mg arm, and four subjects, 2.9%, in the placebo arm. I'll go through that data in a little more detail. The neuroleptic side effects are really noteworthy. The rates of akathisia are less than 1%. We're talking one subject in the 50-mg, one subject with extrapyramidal symptoms in the 50 mg, none in the 15 mg, none in the placebo. Then endocrine-wise, as we might expect from the partial agonist dopamine system signal, there is a significant decline in prolactin levels. T hyroid measures are not worsened. They're actually slightly moving towards a higher number. H ere's a little deeper dive into body weight. A gain, no clinically significant weight gain in the overall analysis, and that's the global analysis, nor are there statistical significant differences in the sub-analyses shown in the graph: U.S. versus India and Bulgaria. T his is not the first drug to show regional differences in some side effect profiles. I n this case, when we're looking at the mean change in body weight in the U.S., it appears to be dose-related and up to almost 4 kg. You go to Asia and Europe, comparable patients diagnosed the same way, rated the same way, and were well under 1 kg weight gain. What is going on? Well, we know in the U.S., in general, we have a BMI overweight issue. We believe that the combination of high-acuity patients admitted into the typical research sites in the United States are basically a smorgasbord of food available to the subject. D uring that lead-up, they're acutely psychotic before they're hospitalized. They may be overactive. They may be eating less. They may have no money. Think of the U.S. social system, and it's not hard to envision that. Now they're admitted to a unit with 2,500-5,000-calorie-a-day meals, ad-lib snacks. I t's not surprising to see increases. Now, why do the subjects on drug go up slightly higher than those on placebo in the U.S.? It's probably because of response. A s these folks are feeling better, they're basically eating and driving off the queues of the unit's process for feeding. A bit complex. I f you look at rest of the world versus U.S., that seems to be a reasonable explanation. This has been shown with many of the other antipsychotics now on the market. Looking at lipids, the bottom-line message is that the lipid panel moves towards a healthier state. There's a decrease in total cholesterol. What I've been able to do is share with you the statistics, stratifying females and males and overall. Most times, you just look at the overall. You see relatively strong p-values at 50 mg, especially. Cholesterol has dropped. There's decrease in sort of the bad lipid LDL. There's increase in the good lipid HDL. Triglycerides stayed neutral in this study. Again, a favorable profile for lipids just by being on the drug. Prolactin, again, marked decrease in prolactin. D2 modulates prolactin, and a D2 partial agonist will lower from baseline prolactin. We see that is statistically significant by day 14. By day 28, that is an effect that is maintained. Prolactin plays a role in a variety of immune disorders. It plays a role in sexual function, in a variety of considerations, including weight gain. A gain, this is a good part of the story. It reduces risk across an array of medical conditions, if you will. Looking at thyroid, T3 and T4 were measured in this study. Again, clinically significant, slight increase in T3, which is considered an improvement because in patients with schizophrenia, it's been shown that T3 and T4 levels are lower than normal. T hat slight increase is considered a positive signal. You can see, again, for T4, there's no significant effects. There is not, at the doses that we're using, meaningful declines that are statistically significant. Hypothyroidism is linked to a variety of illnesses. It can make mood symptoms refractory. It can cause cognitive clouding. It also is linked to neuroinflammatory conditions and also may well influence sexual function. A gain, there's a lot of data on the role of thyroid and prolactin in the literature for schizophrenia. T alking of sexual function, the Changes in Sexual Functioning Questionnaire score is used in this trial, not the ASEX, in part because it's an inpatient study. T his questionnaire is more weighted to the desire and libido rather than to the function. R ather than look at erectile function or successful intercourse, most of our inpatient units prevent that from happening. T hat's a hard measure to assess. W hat's moving on the scale are the, "I feel more sexual. Sexual content, TV, whatever, makes me more aroused." T hat's considered certainly a positive finding. The scores, basically, less than 41 and less than 47 for males constitute sexual dysfunction. T he prevalence is extremely high, as I think we all know. I n females, the CSFQ improved higher numbers as less sexual dysfunction. T hat occurred on the 15 mg and the 50 mg of brilaroxazine. The males did not. W e're still looking at some sub-study data analyses, for instance, the number of males with marked prolactin changes versus females. Of course, the population is more dominant to male than female. W e have to recognize there are sample-size differences when we split by gender. I t's encouraging in the short-term inpatient setting that we are seeing some movement towards improved sexual function as early as, again, the 4-week point. Now, getting into what I think is an exciting new frontier, BDNF, or Brain-Derived Neurotrophic Factor, as the name of the hormone itself implies, it's a neurotrophic factor in the brain. It has been reported to be suppressed in schizophrenia and depression and has been linked to a number of symptoms such as negative symptoms and cognitive impairment and is considered a secondary target when you're treating depression or neurodegenerative disorders. If BDNF increases, as it does for many antidepressant therapies, that's considered counteracting the inflammatory stress process that we see in serious psychiatric illness. This is a first step in gaining that data. Longer-term data, we'll see if it's sustained. It's exciting to see in this population a movement in the right direction compared to the placebo-treated patients having a baseline that's lower and a slight reduction beyond that by four weeks. In addition to BDNF, there are a variety of cytokines and inflammatory factors that move as well. Some of these are shown here. Interleukin 8 is considered a pro-inflammatory cytokine, so reductions are good. IL-8 is associated with schizophrenia, with Parkinson's disease, autism, etc. These are significant reductions that look dose-related. That's one of the strongest signals for arguing that there's an anti-inflammatory effect of brilaroxazine, especially at 50 mg. We go over to the interferon gamma or IP-10. This is a pro-inflammatory cytokine. Here, reductions are also going to be relevant. You can see the 50 mg has significantly dropped it from placebo and even the 15 mg. These together are really some of the first evidence where you have 130 or so patients in a treatment arm that has moved the needle this much. Again, just to disclose, there was a wide array of exploratory markers. This is MIP, which is now pro-inflammatory. L ess is better. You can see the drops here as well. We're looking at overall signature to BDNF, interleukins, MIP, that this drug is affecting the inflammatory state of patients with schizophrenia in a way that may actually contribute to symptom improvement and long-term stability. Going back to the high level, where, if you will, the patient votes with their feet, how many discontinue the drug for all-cause? Efficacy, "I'm tired of the trial. I had a fight with the nurse." You can see the rates are extremely low. In fact, placebo higher than both doses of brilaroxazine. Then looking only at discontinuation due to side effects, it's actually lower than placebo at near-zero rates, which is extraordinary for an antipsychotic with efficacy like this. T he last element ties into the usability of a drug and what can be a major source for adverse events noncompliance, and that's drug-drug interactions. On the left side, you have a summary of the major metabolic pathways for a variety of new-generation antipsychotics. We see that CYP3A4 is considered the major metabolic pathway for many of the drugs, as you might expect, including this drug. However, what's interesting, and when you look at CYP2D6, which is off to the side, and these are in vitro preclinical data, the percent going through the CYP2D6 pathway is very small. Because CYP3A4 is a much higher capacity pathway, the FDA has indicated no DDI studies for CYP2D6 are necessary. That's in contrast to many other drugs with significant 2D6 metabolic pathways and dose reductions when you administer inhibitors or inducers. A gain, a pretty clean path for DDIs, meaning think of schizophrenia and all the polypharmacy, the multiple medical drugs these subjects are on. W hen you have a lower rate of drug-drug interaction potential, that improves outcomes and lowers cost. J ust to make the point that even though 3A4 happens to be the primary pathway, brilaroxazine, even in the face of a strong inhibitor, hardly increases, negligible, in fact. You can see both the bar graph and the fold increase off to the side what happens with a 3A4 inhibitor. I t's a multifold impact for many drugs. F or some of these drugs, they're actually contraindicated that you should not give a 3A4 inhibitor with lurasidone as an illustration. On the inducer side, there is a modest effect. It's 50% lowering of basically the blood level curve over time. You can see what that looks like relative to the others. Fortunately, there are far fewer inducers than inhibitors that we co-administer. Even so, this is as low as most drugs through CYP3A4 ever get. Most people would consider a factor above 50% to be clinically significant. We have here a drug that also is checking the box of having a fairly low drug-drug interaction profile when it's used in the real world. To summarize where we are with safety, tolerability, and other findings, it's well tolerated. The overall AE rate comparable to placebo. Discontinuation rates show that they're basically at or lower than placebo. The lipid profile moves in what I'm calling a healthy direction with those lipids that should go down going down and those that should go up going up. The thyroid does not really reach statistically significant increase overall, but it certainly goes in the right direction. T3 does show a statistical signal in the subpopulation. Prolactin clearly goes down. These, in total, may well contribute to the improved sexual function in women and have downstream other important health consequences in a positive way. The weight gain overall, not different than placebo. However, as seen in many trials, U.S. greater weight gain than in Asia and Europe. I've mentioned maybe due to healthcare, social systems before the person is hospitalized for the study. Our institutional feeding practices with ad-lib snacks and gigantic meals may contribute to the weight increase we've seen. Longer-term studies are really the only way to evaluate appropriately weight, lipids, and thyroid. There certainly are ongoing longer-term extension trials that look quite good in this regard. And again, EPS, we're at a point where EPS is basically a thing of the past, which, again, from my perspective, in 1977, when we were giving huge doses of medication and every patient on the unit had EPS and on anticholinergics, etc., that's a tremendous step forward. The anti-inflammatory possible neurotrophic effects, this is an important frontier. It deserves greater research. The Reviva folks are paying attention to it. They're looking at a variety of indications where the anti-inflammatory action may be the direct effect of the drug on the illness, like psoriasis. Stay tuned because I think a lot more is going to happen in this space. Lastly, the drug plays well with others, low rates of meaningful drug-drug interactions. T o broadly summarize, we had a presentation by Mark Opler of hitting the main primary endpoints for efficacy, a drug with a broad spectrum of effects across a bunch of major symptom domains. It's well tolerated. Side effects are low, placebo-like. Discontinuation rates are low. And indeed, as I think many of you know, next steps is a repeat phase III RECOVER-2 trial. T he open-label study that I mentioned is ongoing and running. A gain, as you can see here, with all of the gods, if you will, smiling, FDA submission in 2025. I will turn it back over to Dr. Lax Bhat. Thank you. Thank you. Thank you, Dr. Ereshefsky and Dr. Opler, for a very insightful presentation. I would like to take a few seconds to highlight what we intend to do with the brilaroxazine for beyond schizophrenia. A s I mentioned at the beginning, the open-label study is progressing very well. We are planning to complete the study sometime end of Q3 and then early Q4 this year. We anticipate giving top-line data for a long-term safety study. We are planning to start the second study, efficacy study for brilaroxazine, confirmatory study next month that we anticipate completing sometime in early Q2 next year. Our goal is to submit NDA sometime in the second half of next year. W ith this, the next step is what we are planning to develop, this brilaroxazine, beyond schizophrenia for additional neuropsychiatric conditions. Based on the safety and tolerability data in close to 900 patients from 3 different studies so far and efficacy data in both stable and then acute schizophrenia patients, we believe brilaroxazine can be developed for other major neuropsychiatric conditions, bipolar, major depressive disorder, and ADHD as well. Now, as you have seen the neuroinflammatory neurotrophic effect data here, see, in the number of translational models, brilaroxazine has shown consistently anti-inflammatory effect. B ased on that, we have filed IND for pulmonary arterial hypertension and then idiopathic pulmonary fibrosis. The program is ready to go for proof of concept phase II studies in human. W e have also very compelling data for psoriasis that we intend to start IND-enabling studies this year. Sometime next year, we would like to file IND for psoriasis. Again, psoriasis is one of the major inflammatory conditions in neuropsychiatric patients, especially in the schizophrenia patients. B ased on the clinical data, the anti-inflammatory reduction and pro-inflammatory cytokines further kind of support our notion of developing the brilaroxazine to inflammatory conditions. T hat's where we stand at this time with the development of brilaroxazine for various programs highlighted here. Th e top priority for us is to develop brilaroxazine and then complete the NDA for schizophrenia and file NDA sometime next year. W ith this, I would like to open up for questions and answers. L et's see. N ow I'll open the session for questions and answers. A ny questions from Tara? Could you open up the session for questions? Yes, thanks, Lax. A s mentioned, we'll be conducting our question-and-answer session with our speakers. Our first question comes from Ram Selvaraju at H.C. Wainwright. Please go ahead, Ram. Thanks very much for taking my questions. Thanks for this very detailed overview. I think this is a question for our esteemed KOLs. When you look at the brilaroxazine discontinuation rate in particular, what are your thoughts regarding what we might see from the open-label extension in terms of discontinuation rate? What do you think is likely to be ultimately kind of the real-world discontinuation rate on this drug? H ow do you expect it to compare to current standard of care atypical antipsychotics? T hen the question maybe for Lax is, there are perhaps some other indications that maybe were not mentioned in your pipeline slide that I was interested to know whether you think those might be development opportunities for brilaroxazine in the future, like, for example, schizoaffective disorder or those patients who exhibit mixed symptoms, i.e., symptoms of both depression and schizophrenia concomitantly. Maybe you can comment on that and what your development activities are that may be planned in those arenas? Thank you. For the long-term safety, first part of the question, Dr. Ereshefsky, could you take that question? Sure. I actually think the question is much broader than what will be the discontinuation rate in the real world of a subject back in their life, not on a unit. I think the adverse event profile will likely not be contributory to stopping. Now, adherence or taking medications for schizophrenia is a separate challenge. We believe that with efficacy and low side effects, it's better. T he nature of the illness leads to poor adherence. T here will be people who stop taking the drug not because of something you can point to like side effects, but because they believe they're better, they no longer need the drug. Then they follow the decay curve of being off of an antipsychotic, which we see for all of them, where a certain percent in six months, a certain percent in a year, and so on, will stop taking the medication or discontinue because that's part of the illness. I do think there's a variety of psychosocial considerations that go into it. There's intercurrent substance abuse when you're in the real world. I t's a multifactorial question. Having said that, my sense is the retention rates are good. T hat's encouraging. There have been some of the antipsychotics where 50% retention at a year is considered fabulous. Obviously, a far cry from at four weeks being near zero. Dr. Opler may well want to opine because it's really as much in his court in terms of the effects of the drug as well. Thank you, Larry. Appreciate that. I would say my recollection is that discontinuation rates and non-adherence rates are somewhere around 40% or 50% in schizophrenia, which is incredibly high. I think Wayne Fenton did a meta-analysis and found that for any given medication, 55% wasn't far from it for oral treatments. I would argue that even if the real world was double what we saw in this study for the 50 mg or the 15-mg dose, that would be an astonishing improvement over average for oral medications on the currently available market. W ho can say for real or for sure? T he indications are incredibly good. E ven if reality is twice as bad as what we see in the rarefied world of a clinical drug trial, that's incredibly better than what we have today. I'll stop there and pass it back to Dr. Bhat. Yeah. Ram, to answer your second part of the question, well, are we planning for developing brilaroxazine for schizoaffective disorder? If you look at our phase II data, the phase II study was conducted in acute schizophrenia, schizoaffective disorder patient population. Having seen broad-spectrum efficacy, we do believe that brilaroxazine has efficacy for schizoaffective disorders as well. C onsidering the large indication and then huge unmet need, we intend to develop this drug for larger indications: bipolar disorder, major depressive disorder, and attention deficit hyperactivity disorder in the neuropsych space. Thank you. Thank you very much. Thanks for the questions, Ram. Our next question comes from John Vandermosten at Zacks. Please go ahead, John. John, are you there? I t looks like we may have lost John. W e'll go to the next analyst. Our next question comes from Bruce Jackson at Benchmark. Please go ahead, Bruce. Thank you. Can you hear me? Yes, we can. Okay, great. V ery nice presentation. I'm very intrigued by the new data on neuroinflammation. It's some exciting area. I wanted to ask two questions about the BDNF results. First, is this the only marker of neuroinflammation? Is it the one that the FDA is going to respond to? Dr. Ereshefsky, go ahead. Yeah. Yeah, I'm chuckling because the first part is easier to answer than the latter part, which is what's the FDA going to do on any given day. The BDNF is one of several markers that are being looked at for neuroinflammatory neurotrophic effects. It's the one that's been around the longest. It has a lot of data from going back 30 years ago when it was pioneered for depression and the like. But I think it's a profile that ends up being the most convincing. I t's a pattern of these interleukin drugs, BDNF, TNF, and others moving in the right direction, which are indicative of glial and astrocytes improvements in basically the neuronal function of the brain. Depending on the mechanisms, there are a number. I know bringing this up is like stirring a hornet's nest. L ook at the data on psychedelics and psychoplastogens. These drugs all seem to modulate through a neurotrophic pathway that in part involves BDNF and these interleukins. It does it through intracellular changes. Again, there's common pathways that you don't have to be a hallucinogen or a psychedelic to modulate. That's being worked on. There are a number of companies showing neuroplastic effects without the trip. That's sort of a goal. Maybe this is along that pathway. Intracellular signaling, there's BASP, there's neurofilament light. There are a number of markers that can be looked at. Some of those may be more disease-specific, but a lot of them are common pathways. I can envision a separate study that perhaps looks at additional markers, PBMC, for instance, and changes, intracellular CSF sampling, and so on. Things are going here in the right direction. It's part of a large number of drugs talking about this space. Okay, great. T hen one follow-up, if I may. In the data that you showed, the 15-mg dose seemed to do a little bit better than the 50-mg. S hould we be taking anything away from that, or is it just a function of the sample size? Yeah. The BDNF has been a difficult assay for people to do well. I t's only been recently that technology has improved to the point it begins to be believable. The acute phase of illness is definitely playing a role in the BDNF and other cytokine elevations that are going in the wrong direction. That 50-mg dose, is it more than 15 mg? You can't say from this data, really. It's underpowered. I would hope that as additional studies are done, you can pool the inflammatory data across multiple clinical studies pretty well. W e may get a better answer. It's interesting to note that although we're focused on 50 mg because it cleanly met the primary outcomes in this study, which was more U.S.-based than not, in phase II, 15 mg clearly had an efficacy signal. I don't want to dismiss it as an ineffective dose. As Lax indicated, the follow-on phase III will include probably a 30-mg dose, which will help us understand things better. Yeah. Just to add to that, what Dr. Ereshefsky mentioned, again, the data reported BDNF is a difference from baseline to end-of-treatment. T he baseline BDNF level varies from each different group. T he delta is from baseline. It's not necessarily kind of a dose-dependent. I n the larger sample size, we may have a different outcome. 50 mg may also show statistically significant. I t's not the reflective of true dose dependence. Okay, great. Thank you very much. Thank you. All right. O ur next question comes from John Vandermosten at Zacks. Please go ahead, John. All right. Thank you. Are there any new drug delivery technologies that might help schizophrenia patients more quickly achieve therapeutic levels of drug in their system? Maybe I can quickly answer that question and then pass on to Dr. Ereshefsky. Yeah, it depends on what gets into the brain. We have seen, based on the data animal studies, we have seen almost a 3.5x higher in the brain versus outside the brain. B ased on the excellent bioavailability and then blood-brain barrier data, we believe the oral dose, it works very well. Now, with respect to compliance, of course, a long-acting depot formulation, we are currently working on it. That's the follow-on to oral medication like other options currently in the market. We are currently developing long-acting formulation as well. Dr. Ereshefsky, any comments from you? Yeah. I t's a really interesting and important question. The long-acting injectables that have loading dose strategies get to therapeutic levels within 3 days-7 days as quick as an oral medication, and yet then are sustained-release for over a month. T hat certainly shows that there is the ability with safer drugs to consider loading dose regimens. T hat's something that our earlier drugs, you just may not want to double the dose and hope for the best. I t's certainly conceivable that a dosage formulation could be developed that put, and I'm not saying this should be done, but puts 100 mg or 125 mg of brilaroxazine in a sustained-release tablet that's released over 24 hours. Y ou may well have an acute treatment that lasts for the first 4 days-7 days of therapy. I think that's well within the realm of possibility. Obviously, people have tried sublingual drugs. We've had those around. Slightly faster blood levels are achieved. A dherence in an acute population isn't always easy to achieve, having someone hold a tablet under their tongue for a couple of minutes. That's not likely when you're psychotic and paranoid. T here are ways to go. Obviously, we've got injectables for PRN agitation. That's the fastest into the body. I t's realistic. I think we're at a point that it needs to be explored. I'm not sure it has been explored. T he way we talk about more rapid-onset antidepressant effects within 3 days-7 days, I think that is a goalpost that we should be shooting for. Thank you. Thank you for that. A second question is regarding the RECOVER-2 trial. I'm wondering if there's any modifications to trial design that could help isolate a little bit more the placebo effect. I think we noticed that at week 4, some of the placebo effect was reversed on some of the metrics. T hen also perhaps maybe a modification to adjust for that weight gain that we saw in the United States. Are there any modifications like that or trial design adjustments that could potentially help improve those metrics? Maybe the first part, Dr. Opler, regarding the trial design and then placebo effect. Sure. Thank you very much. First, I just want to say, as a rule, placebo response has tended to increase over time in schizophrenia trials for the last couple of decades. T he fact that it was kept actually quite impressively low for the RECOVER trial is an accomplishment that we shouldn't minimize. That said, it's been asked, "What are we going to do differently in RECOVER-2?" I think the answer is nothing. We achieved pretty impressive success. I don't think we want to mess with that recipe. M y advice would probably be to conduct the same rigorous training with the investigators to make sure that they are administering the scales that they need to administer accurately and reliably every single time. The use of audiovisual recording to have blinded evaluation of those assessments and ensure that they look accurate as well is also important. Finally, the blinded data analytics at a study, at a site, and at an investigator level, again, to continue to monitor for sources of noise and potential bias and error is another methodology that I don't think we're going to change at all for RECOVER-2. That said, sure, there are probably other things we could try. There are some very clever and innovative designs out there. Unfortunately, I don't think any of them have been proven to be a silver bullet for placebo effect and placebo response. I t pains me to say we're not going to do anything different. No clever additional tricks beyond those we're already using. If I can jump in with part of a comment. With every successful trial, expectation bias goes up. Word on the street, investigators, clinicians, patients, "Oh, the phase III had great results." Well, as soon as that word is out, and it will be out, then you are attempting to contain expectation bias. T he methodology that was just outlined by Mark is state-of-the-art to do that. Part of it is on the sponsor and the CRO that they go in acting a little humble about their drug. Y es, you want excitement. You want enrollment. Y ou don't want to bias people into believing this is the answer because that can come back and affect you in ways that are hard to always contain, although I think one of the best systems is in place with Dr. Opler. I don't know if you have any comments, Mark, about your experience in seeing later-stage trials get tougher to perform. Yeah. It's a great point, Larry. I think, well, you said it exactly right. I think we simply have to reemphasize to everybody, all stakeholders in the study, that no matter what, this is still research. This is still an experiment. W e need everyone's involvement in that and ensure that they're approaching this with the understanding that this is a confirmatory study. W e need to keep that in mind. Thank you. Thanks for the questions, John. Our next question comes from Jim Molloy at AGP. Please go ahead, Jim. Hey, guys. Thanks for taking my questions. Thank you for the excellent call. I had a question for the doctors. Presuming the phase III data looks good, and ultimately, the drug, brilaroxazine, is ultimately approved, where would you see this fitting in the treatment algorithms in your practice? H ow would you see the compliance rates potentially versus current standard of care? I know you touched on it briefly, the awful compliance rates currently. H ow would you potentially see brilaroxazine hitting those compliance rates in the real world? Thank you. Same here. Dr. Dr. Ereshefsky, would you like to take that call? Okay. Well, so in the real world, and depending on the country, you get into what is the economic value of a drug against predecessors with regard to use. W hat we have here are a profile of substantial efficacy against placebo across multiple domains of treatment. T hat's going to be a plus. A s the AEs are confirmed to be as low as they appear to be, I think the long-term data will be pivotal in moving this up towards, if not first-line, second-choice therapy. That will be from the economic perspective. Is it going to be a better drug than some of the less expensive drugs that are generic? Well, we don't have head-to-head comparisons. T his certainly is looking promising. Y our question has two parts, the science and the economics, and then the regulatory systems. The EMA is a little different than the FDA with regard to how they look at drugs' value. I'm not sure how that'll pan out. I think that Reviva is going in the right direction to generate the data that will convince the payers, ultimately, is where I'm coming from. Mark, do you have any comment? Sorry. Just come off mute. No, I agree absolutely, Larry, with everything you just said. I think a lot will depend on the data generated by the next study as well as what comes out of interactions with all of the stakeholders, from regulators to payers. I do think as far as where this drug fits in the armamentarium of treatment, again, the hope, I think, is to find a treatment that actually works across the lifespan for patients in different phases of disease with minimal side effects, low discontinuation, and really targets the symptoms, both that lead patients into the hospital, but also that keeps patients out of the hospital. I f we can achieve that with brilaroxazine, that would be a meaningful accomplishment. Okay. From the Reviva management side, as our KOL pointed out, so there are two aspects to that. One is the efficacy based on the endpoints. It's a really very robust data. What we have noticed in this pivotal trial, functional outcome for the efficacy, as well as especially the mechanistic angle of neuroinflammation, we believe when we complete the second study, additional data coming in from the total clinical development, that would further strengthen the differentiated profile of brilaroxazine. Yes, there are drugs currently in the market. S till, the benefit of what brilaroxazine can bring to these patients, that should make a difference in overall market access. Great. Thank you. Maybe a quick follow-up, if I could, please. Knowing that predictions are hard, especially about the future, looking at the next phase III and going from the 15 mg and 50 mg to 30 mg and 50 mg in the second phase III, anything that you guys anticipate potentially seeing different in the next phase III? I s there anything else down the pipeline that you guys are keeping an eye on as well outside of brilaroxazine that's looking interesting? Thank you for taking the questions. Yeah. No, no. With respect to brilaroxazine and the second phase III study, we are putting the low dose, 30 mg, and then top dose is 50 mg as in the just completed study. W e are very optimistic about the outcome of the 30 mg because 30 mg dose, including the 15 mg and 50 mg, all three doses have been used in stable schizophrenia patients in the long-term safety study. All three are very well tolerated. We haven't seen any relapse symptoms in this patient population. We are very encouraged by the data generated to date so far, the way it is progressing. N ow coming to the other indications, other drugs currently in pipeline, we do have drug RP1208. This is a triple reuptake inhibitor. We would like to develop this drug for weight management, obesity, and depression based on the mechanism of action. Then, preclinical data in hand, we would like to develop this 1208 to obesity and depression. Thank you. Next question. Our final question comes from Soyoun Shim at UBS. Please go ahead. Hi. This is Soyoun on for Ash. I actually have a few questions. I don't know. You might have already addressed it. I n the phase II REFRESH study, 15 mg, 30 mg, 50 mg dose group, it does seem to show any dose response activity. A ctually, the 15 mg seemed to have efficacy that was comparable to the 50 mg in that study. However, in the phase III RECOVER, the 15 mg did not have statistically significant improvement over placebo, while 50 mg showed remarkable activity. What do you think led to these differences? Al so for the phase II REFRESH study, I recall there were side effects of EPS about 9%, akathisia of 10% for the 50 mg brilaroxazine, which was also higher than the active control. I n the phase III, those side effects were less than 1%. What do you think led to such differences? Sure. It's a great question. Maybe I can quickly answer that one. I will open to KOLs. With respect to the first part of the question, efficacy, we believe this is related to disease severity. If you look at our REFRESH study baseline PANSS score somewhere in the 85-87, they are much milder acute patients. With the low dose, 15 mg showed efficacy in those patient populations because they are slightly milder patients than the patients in the RECOVER study. RECOVER study baseline was around 99. They are acutely severely ill patients. This is a dose proportional. This is proportional to disease severity. That's why low dose took a week more to start showing the separating from placebo if you look at on the primary endpoint graph. Now coming to the side effect, again, it's the same. There are two components to that. One is the low baseline score are less severely ill patients with the high dose. Once they get quicker, better, then you expect to see for the mechanism-based some side effects in some patients. T hat's what we have seen in the phase II study, slightly higher EPS because they are milder patients. T hen also, the patients demographic-wise, as we have seen in the weight gain, U.S. patients tend to have around a 35% higher body weight. H igher body weight at the dose, often, it gives a slightly less effect that also might have contributed to seeing a higher EPS or a neuroleptic side effect in the REFRESH study compared to RECOVER study. I'd like to Dr. Ereshefsky, do you have any comment on it? Well, I think you're covering the most important considerations. We've known for a long time that the severity of the patient influences the observed side effects, especially extrapyramidal symptoms, that a healthy volunteer, given an antipsychotic, they're frequently a very unhappy person, if we go back to the original drugs, whereas acutely psychotic, they were reasonably well tolerated. Here, the drug is well tolerated across an array of subjects, frankly. Even the phase I data showed that it was tolerated quite well. I do think that the geographic distribution is really getting at not just PANSS, but, as you said, body weight. T he proportion of people in the phase II study were different in terms of U.S./ex-U.S., if I recall, than in phase III. I t's not apples to apples comparison. Okay. So So Dr. Opler, do you have any comment on efficacy and then especially the EPS measurement, what we do, akathisia and EPS with respect to severity, what the question came in? Thank you, Dr. Bhat. O nce again, Larry said it quite brilliantly. I think that the severity does ultimately affect both how the patient responds as well as their symptom profile. With regard to EPS, I think that there are often, in some studies, potential confounds between psychotic agitation as well as extrapyramidal symptoms. O ne of the things we were very careful about in this study was checking to ensure that that wasn't happening. I think we can say with great certainty that the lack of extrapyramidal symptoms we see is real. It's not a confound from psychotic agitation. It's not one symptom being confused with another. I t's a very clean safety signal as well as a very clean efficacy signal. I think other than that, everything Larry said, as always, is exactly right. Thanks, Dr. Opler. There are no other additional questions. Are there any other questions? Yeah. W e had a follow-up question from John Vandermosten at Zacks. P lease go ahead, John. Great. I'm here. Thank you. Am I coming through? Yes. Yes, we can hear you. Very good. Very good. There have been some acquisitions recently that, after a long dry spell of no acquisitions in the space, there have been a couple of big ones in the last few months. B oth of those were before approval. I'm wondering, it's just a few things of the team's thoughts on what that means in terms of maybe the risk profile of what Big Pharma is looking for in a new drug, and then also what that means for Reviva and their differentiated, I guess, from those other assets, their differentiated product and what it might mean for interest from others in the space, other Big Pharmas in the space. Okay. Dr. Ereshefsky, any comments on the general interest? What's coming up with the recent interest? Well, I was going to say it sounded like this one was in your court. I certainly am familiar with the other companies that are being acquired and have worked closely with them and their assets. W hat I see is an awakening of psychiatry being a viable and important space for new drug development, especially schizophrenia. We went through a bit of a drought. I f you go back even just five years ago, people were predicting a tremendous falloff in research. Y et here we are with a number of novel mechanisms. T his, I think, fits into that camp. T otally up to Dr. Bhat and his B oard as to what they do. T his is a strong-looking candidate with a growing body of data. I would think that by the start of the next phase III trial, if someone's going to make a move to buy you before approval, that's going to be the timing. Again, I'm out of my expertise space. I find this drug exciting. And It's in the same kind of profile, generally speaking, to the drugs being acquired. Okay. Dr. Opler, any comments? Yeah. Just briefly, I think to paraphrase Mark Twain a little bit, the death of neuroscience has been greatly exaggerated. I've seen these predictions come and go that there's nothing new under the sun. This is a dead area. Let's shift all of our focus and attention to something we can actually do something about, like oncology or cardiovascular. I have to say, I'm continually surprised at how much neuroscience still has to offer us. W hat we're finally seeing now, I think, is the convergence of new mechanisms, new efforts to improve our methodology, and just the bravery and the continued perseverance of innovators. W hat I would say is I can't predict what Big Pharma is going to do on any given day any better than I can predict the movement of electrons or the FDA. I will say that a confirmatory study is looking pretty good to me for this molecule, especially if the same methodology with the same rigor is applied. If I were on the side of Big Pharma, I would want to get in on this before it was too late because these opportunities don't come along every day. I think while there will be more innovation to come down the line, something exciting is happening now. We would be foolish to miss out. Thank you, Dr. Opler. From Reviva, what we believe, again, in the historical data, if you look at the drug development, regardless of the mechanism, if a drug delivers the good efficacy and safety and the tolerability, that matters to the patients and then physicians. Based on the data, I think brilaroxazine, to my knowledge, has a robust efficacy and then safety data. That makes this drug differentiated when it comes to market. Thank you. All right, Lax, I think that was the last of the questions. I'll turn it over to you for closing remarks. Okay. Thank you. Thank you, Tara. I f there are no other questions, I would like to thank our key opinion leaders, Dr. Opler and Dr. Ereshefsky, for sharing their very insightful opinion comments on schizophrenia and presenting brilaroxazine phase III RECOVER trial results and answering the audience questions. Thank you, Dr. Ereshefsky and Dr. Opler. I want to thank you all for taking time out of your busy schedules to attend this event. I f you have any additional questions about anything discussed in today's webinar, feel free to send us an email that's displayed here in our webinar. The recording from today's meeting will be posted on our website, www.revivapharma.com, soon. Again, once again, thank you all for taking time to attend this webinar. T hen thanks again for our key opinion leaders. Thank you.