Thank you so much to everyone for joining our fifth annual Novel Mechanisms in Neuropsychiatry and Epilepsy Summit. I'm Stacy Ku, one of the biotech analysts, and I'm joined by my colleague Vishwas Shah. We're happy to be hosting Shawn K. Singh, CEO of Vistagen Therapeutics. Thank you so much for being here today. Before we dive into Q&A and obviously focus mainly on the upcoming readout of your fasedienol program in acute treatment of social anxiety disorder, of course, right around the corner in Q4, maybe just provide a quick overview of your pherine portfolio and different indications being pursued. Sure. It's great to be with you again, Stacy. Thanks a million. It's always a pleasure to speak with you and the investors. We are a late-stage, clinical-stage company, as you know, and we're leveraging our very deep understanding of nose-to-brain neurocircuitry. The neuroscience pipeline that we've got includes five clinical-stage product candidates from a new class of intranasal therapies called neuroactive pherines. These are specifically and selectively assets that specifically and selectively bind as agonists to peripheral receptors in the nasal cavity. Human nasal chemosensory neurons, we see agonist activity within about 25 milliseconds for these drugs that are all intranasally formulated because the receptors that we need, on the neurons we need to activate, are only there in the nasal cavity. What we see across a pipeline now that focuses on five different indications, five neuroactive pherine assets with at least a positive Phase IIa study under our belts, and then with the lead fasedienol, a positive Phase III study. One for acute treatment of social anxiety disorder, another for major depressive disorder, another for menopausal hot flashes, psychomotor impairments, and cancer cachexia. That takes us from the top to the bottom. All of them have a very unique mechanism behind them because what we're trying to do here is accomplish these therapeutic outcomes without systemic absorption and without any direct activity on neurons in the brain. As a result, what we've seen is just a remarkable safety profile across the whole class, where you typically don't see the kinds of things associated with systemic absorption. We see rapid onset benefit because we're not too far from where we're trying to get to in the brain with neural circuits that can achieve these mood-related and physiological changes. Very excited about the platform and the progress we've been able to make. Okay. You just gave us the high-level, maybe a mechanism of action, but maybe for those that are not familiar with fasedienol, how does that work exactly in social anxiety disorder? What early work has led to development specifically? Yeah, a lot of work by Dr. Louis Monti, who's really the most accomplished scientist in this arena and researcher. Its MOA is just unique and differentiated from all therapies, approved or otherwise, that we see out there for anxiety disorders. It's a modulator of the olfactory-limbic-amygdala, fear and anxiety neural circuits. Within about 25 milliseconds, as I noted, based on EEG and nasal receptor studies that we do, and then studies with the olfactory bulb, there's a projection to about 300 milliseconds, where again, you're seeing agonist activity in the nose that starts in motion and triggers key neural circuits that, in the case of fasedienol for social anxiety disorder, really requires a modulatory activity within the amygdala. The GABAergic activity that we see within the amygdala generates that modulatory inhibitory neurotransmitter effect, doing this again without potentiating GABA like a benzo would. We've done C14 studies to associate the fact that we don't see systemic absorption. You're in a mode where you're also not generating the kind of abuse liability potential by dropping onto neurons that you don't really want to see involved in the day-to-day effect of social anxiety disorder on subjects. It's nose-to-brain neurocircuitry. The nose is a portal to different regions of the brain. In this case, the target site is the main fear and anxiety center of the brain, the amygdala. Okay. Understood. Let's jump forward. Obviously, you've shown a lot of clinical results in social anxiety disorder. There's a number of different studies that we'll call for PALISADEs, PAL. Maybe just recap the results we've seen so far from PALISADE-1 and PALISADE-2, and of course, what are the major learnings between the two studies that you're applying to your ongoing developments? Yeah, a lot of lessons learned. I don't think there's really anybody right now who's done more in a Phase III setting with this study design, which is the public speaking challenge and the unique endpoint associated with that. Because then we're looking at acute treatment, right? Historically, the basis for approval of the three old-school antidepressants were based on the Liebowitz Social Anxiety Scale, which, think about that sort of like a movie of the journey of a patient with social anxiety disorder. The endpoint involved in the PALISADE program and the study design that's associated with that is called the Subjective Units of Distress Scale. That is more like a selfie, a Polaroid of the patient's experience in an acute setting. Aligning early around what's the registrational pathway, it is what's the appropriate study design where you can provoke anxiety consistently at a scaled level in a Phase III setting. What's the best endpoint to measure that minute-to-minute efficacy? The PALISADE program, again, is anchored in learning from the first two positive studies in Phase II. There have been three positive studies overall. PALISADE-1, which was conducted primarily in the peak period of the pandemic and had a lot of impacts from sort of the black swan effect of clinical trial execution during that period, did not separate from placebo, a much higher placebo rate than we had seen. We sort of see that as really an outlier in large part based on some of the excursions that you typically saw during the pandemic, no in-person investigators meeting, a lot of site turnover, CRO turnover, just different scheduling. The masks were, of course, on much different. PALISADE-2, which was anchored a lot when the world changed, and the randomized subjects that were brought into the study when masks came down, when scheduling was more regular, when site turnover was less, and staffing could get into the sites more often and train and refresh training, those make a big difference with a protocol like this because following the recipe rigorously is important. The learning from PALISADE-2, which was stat-sig across each of the endpoints, the primary being the SUDS, and then the secondary, the CGI-I, as well as an exploratory, the PGIC, all of those hit in PALISADE-2. Taking forward lessons from that whole collective experience, the enhancements that we've made in PALISADE-3 and PALISADE-4 are intended to further control or limit variability. Now that we have an environment like PALISADE-2, which was more like Phase II, PALISADE-3 and PALISADE-4 are even better than the world was in PALISADE-2. You have a very experienced now clinical trial environment who's seen this protocol, seen this endpoint, but you also have the ability to be in person. We've significantly changed part of the operating model to own psychometrician expertise internally with our own team. A lot of scrutiny is able to be applied in person now up front of even signing an ICF. The enrichment gates that are associated with the design, the first speech requiring an extra minute of stress from the SUDS. 75 on the SUDS means you're more than a little uncomfortable. PALISADE-2, we had one. PALISADE-3 and PALISADE-4, we have two minutes that you have to be at 75. You have the IP being administered by the investigator. You have, again, no masks, obviously. You have a situation where our team, our clinical trial specialists, are arm in arm with CROs, and we've unbundled a substantial amount of reliance on CROs for subject eligibility assessment. We have our own team, again, of psychometricians. Adding other things too that may or may not have impacted. No nasal swab for flu or RSV or COVID within a month. You have to pass a smell test in case there's some potential that an anosmia makes a difference. A lot of things, again, intended to enable more direct activity and insights and best practices being shared across sites, as well as we increased the size of the studies to PALISADE-3 and PALISADE-4, or 236 subjects over model 208 in PALISADE-1 and PALISADE-2. Things that are intended to, you know, again, enrich potential for the right patients being involved in the study. I can't guarantee any kind of outcome, of course, but what I can tell you is it's a much different environment to be able to execute it. Okay. Maybe before we head into, let's say, expectations on PALISADE-3 and PALISADE-4, can you also just talk about this public speaking challenge study design when you're talking about an acute stressor? Maybe in the context of that, one piece that our KOLs have found compelling is the improvement in clinical global impression. Just help us understand that context and the level of stress for the study design. Yeah. Early on, aligning around what's this disorder all about? Fundamentally, it's not GAD. This is not an all-day every day. This is not a situation where an unspecified trigger. This is a very episodic disorder that manifests associated with very predictable, in many cases, and sometimes unpredictable specific triggers and how they impact people's life. Our goal all along is to try to have an opportunity with a PRN indication where it can be tailored to fit how people experience their journey with the disorder. The typical onset remembers in 8 to 15, and the mean duration is a couple of decades. One of the things that's constant is people have a hard time talking to people. The other objective was to have a study design that had one particular stressor that could be provoked consistently across sites in the study. This public speaking challenge and the subjective units of stress, those are the married, that's the match set. The public speaking challenge is four visits after rigorous pre-ICF screening. You meet the IE criteria. You're invited back a week later, and you're given, on a single blind basis, the subjects are given a placebo. Fifteen minutes later, they're told that they have a few minutes to get ready for a five-minute speech to a group of strangers in a conference room setting. Each minute during a five-minute speech, no notes, no lectern, just sort of freestanding with the rater next to them, they will tell the rater how they feel on that scale. The SUDS, think of it, visualize a thermometer, sort of 0 to 100, where 75 on that means you're more than a little uncomfortable in that minute. If the subject in PALISADE-2 was one minute in III and IV, if they're more than a little uncomfortable for two minutes of that five-minute speech, and the speech is from a selection of five topics, nothing super inflammatory, nothing super easy, like not what's your favorite dessert. If they're sufficiently provoked during that baseline setting speech, they're invited back a week later to repeat the challenge, and they're double blind randomized one-to-one drug to placebo. What you're looking at the fourth visit, the fourth week is simply a safety assessment. What you're assessing on the primary is group-to-group difference, drug versus placebo on the SUDS. How did they do second speech versus first? Where you then move to the CGII and the PGIC, you're actually looking at individual behavior there. The clinicians with the CGII are asking or assessing how they think the subject did second speech versus first. Are they very much less anxious, much less anxious? They do not know, obviously, it is double blind still, what the subject reporting is on or who they are reporting on. What we saw in the CGII was about 2X, 1.8 times greater the treated group over the placebo group. It was P=0.33, I think it was. The PGIC is the patients now saying, how did they think they did? They do not know what they were on second speech versus first. Were they very much less anxious, much less anxious? That is a one or two on those two scales. There we saw there was 2.2X treated group over placebo in terms of the reduction in anxiety second speech versus first. What that tells us, and especially the CGII, because that is a change in the patient's condition that integrates both symptom severity and functional improvements, which are key, right? Typically, it is a very widely used scale in psychiatric trials, considered very relevant too by regulatory authorities. What we love about it, obviously, the patient-reported outcome, and we bumped that up to a secondary in PALISADE-3 and PALISADE-4, is consistent with the way we think the drug works, which is if an acute episode is knocked down, and the more often that that acute reduction in anxiety affects the way the patients think about avoiding or engaging, it is really an important piece of feedback. We hear it in the open-label as well, as we reported in the prior open-label. The more people take it in an acute setting and get wins, it is a bit like having a psychiatrist or your mom on your shoulder saying, "See, you were not watched, you were not judged, you were not embarrassed or humiliated." That builds on itself. It is that confidence and resilience that we are really looking for to affect life-changing opportunities and engagements. You really have to embrace potentially how a short-term win, an acute win, and you add those up even over time. Even just one has the potential to change the way that someone will embrace that same stressor or even a different stressor. Tailoring that to fit how these stressors affect people episodically in their life, it is some days not at all, some days a few times, some days many times. They want to be able to use it when they need it and not have drug in their body, any kind of drug in their body. What we typically hear back is they don't want weight gain, sexual side effects, abuse liability. They want rapid onset. They don't want sedation. Basically, they want to live in a way where they have agency over their emotions. Okay. We're going to ask about the open-label extension and the usage there. As you wrap up, maybe the PALISADE-3 and PALISADE-4 expectations, results, just to kind of level set, it seems like we have one positive study with PALISADE-2 in terms of pivotal. We'll probably only need one more of the two next studies to be positive to be able to file for approval. For those that are listening in, we expect the first readout for PALISADE-3 to be Q4 this year, right around the corner. The second PALISADE-4 study is going to be in the first half of 2026. Help us understand, as we await the data, you just talked through maybe all this, all that the team is doing to make sure the results mirror PALISADE-2. Talk about what kind of placebo response at the very least. I know you all have done a lot of work there. We should be expecting to see in terms of the SUDS endpoint. I think you just take a look at PALISADE-2, right? If you can control variability and you could really do things that are associated with surveillance and training and being regularly in front of essentially the site in a customer service-oriented way, you really can do things that ensure adherence to the protocol, right? That's the best way to control the variability, to have people follow the recipe that we've been cooking pretty well over time. Here you have, again, you know, it's just a measured effect. You're going to get some, of course, in the placebo group. In PALISADE-2, I think it was an 8-point drop, and the treated group was a 13.8-point drop on the SUDS. Again, seeing a separation between the two groups, you're not going to add zero placebo. It's not the case where you have disappointment bias in a minute and you know these drugs are odorless and tasteless, so there's no functional unblinding. At the end of the day, too, though, you do expect some. You just do what you can do to execute and make sure that the rest of the study and all throughout the process, starting very beginning before ICF, making sure that you have patients suitable, they really have been chronically affected by the disorder at high levels of assessment severity using all the scales. That's why the psychometricians are so important, because there are enrichment gates built in. If someone, you know, for example, if they, you can tell by voice tremor because we're audiotaping these speeches now, and that gives us a lot more insight into the surveillance as to whether the sites are executing the protocol properly, as well as whether or not they're training subjects up properly on the SUDS, for example. You want to build efficiencies in. You want to not waste time. At the same time, the quality of the subject assessment is critical, and especially if it's from assets internally, our headcount that is experienced in assessing that suitability. Okay. How is enrollment progressing, and where are we in completing enrollment? We're on track to the guidance that you just gave and we've given. We will announce LPO when the last subject in PALISADE-3 and PALISADE-4 hits the last appointment, which would be the visit IV of the last subject randomized. Remember, only those who make it to and through visit III are included in the dataset, the randomized subjects only. If they are not sufficiently stressed at visit II, the first speech, they have an opportunity to move to the open-label. It's a very nice throughput, both those who aren't qualified to be randomized as well as those who complete the whole randomized study, moving into the open-label. It's encouraging to see that. How long does it take to analyze between last patient out and top line results? Typically, it's about eight weeks. Sometimes it depends on the number of queries. We're doing a good job of managing queries throughout the process. I think six weeks would be really aggressive. Eight weeks would be more normal. It depends how well your sites are and how efficiently they're uploading the data. DBL doesn't take forever these days, given electronic capture of data and sites behaving. We have a really good relationship with our sites. There's the cooperation among our clinical trial specialists and our subject eligibility review teams. People are on top of it. We're working with a really good CRO with accessibility. I think eight weeks is probably the best thought there right now. Okay. To the extent that you can, as we await data, what are you seeing in the open-label extension trial these days that you view as encouraging? What type of efficacy should we expect based on prior open-label extension study results? Maybe talk about efficacy from the LSAS endpoints. I don't have any of that from the current open-label, but I can tell you back to the old open-label. That's what we've reported on. What we typically see there, again, the more often people use it, they're better one month after two, two months instead of one, three months over two. It's the willingness to engage in things that many of us take for granted that are life-changing to a lot of them. Things that you hear from the reported open-label tell you that little things make a pretty big difference. What they're trying to really get to is a mindset where, you know, they'll go and eat in a restaurant rather than DoorDash. They'll stand in an ATM line. They'll not have to sweat their palms when they're presenting to a large group at work. They will not cancel dates and things that they've scheduled that they typically for their life have thought, "I better do this because I need friends and I need dates," but yet don't follow through. They'll go to concerts. Things that are the kinds of stories we get to understand and read from the diaries from the reported open-label, they're key. They're very important. We encourage in the open-label, people get to take whatever they need to take besides our drug. At the same time, you're monitoring utilization. That gives us a lot of insight on the commercial side. We're not seeing the kind of hockey stick utilization you'd expect with abuse liability. Remember, we went to the FDA early on and said, "Did we have to do a HAL, a human abuse liability study?" The answer to that was no. There's no binding to opiate, nicotine, dopamine. There's none of those things. No drug-drug interaction. This is totally different in terms of the way we're trying to achieve these outcomes with neurocircuits rather than drugs that have to race through your body, your blood, and into your brain. Okay. Understood. You also have a Phase II repeat dose study ongoing with potential results in the first half. I think that also includes an open-label extension component. Please provide more details there. Our understanding is that it's mostly to satisfy the FDA requirements for safety. In light of that, is there anything else required for submission to the FDA? Any details would be appreciated. We will also do just a basic human factor study. It's sort of associated with the final container closure. The repeat dose study could inform labeling that there's no worry if in human nature takes over and people think more is better. You do two doses within a 10-minute window, which is how that study is designed. We don't see any safety risk associated with that kind of utilization. It's just, again, when you activate these receptors, it's pretty fast. There's only so much volume the nose can hold. It's not necessarily a case that more is better. We're not worried about a safety-related issue. With this whole PALISADE program, one of the reasons for doing two studies in addition to needing one of the two to hit and having a hedge there is to aggregate additional safety exposures over time, number as well as 12 months and six months. All three of those studies feed into that safety database. What we've experienced so far is consistent with what we've reported. It's just mechanistically driven in ways that you're not going to see, similar to what we saw in the reported study. I think maybe where we end up here, very low prevalence of TEAEs, nothing over 5% except headache. We'll see when the study reports out. Okay. Understood. You briefly touched on the commercial work that you've done, but we appreciate that you spent a lot of time trying to make sure everything is very much commercially ready. Just help us understand what's currently being used in terms of treatment of SAD. Is it a big% of patients that are receiving treatment? What type of clinicians do they see? Are they being treated for comorbidities? Of course, obviously, this is all in light of what we understand is the current use of benzodiazepines. You got a lot on me right there. I know. We only got three minutes left. The standard of care, I mean, there really is not any recommended expert guidelines around the acute treatment of SAD. It's not benzos. It's not beta blockers. Neither of those has ever been in a controlled Phase III study for the acute treatment of SAD. We all know how they work. We all know all the side effects and safety concerns associated with those. Our TPP is remarkably different from anything that anybody's ever learned about those. There really are 30 million adults in the U.S. with about 10% of U.S. adults affected by SAD. It's a population right now that's probably about 30% treated. There's definitely some upside there for under diagnosis and under treatment, mostly because the options are suboptimal. What we see here, commercially, when we talk to KOLs and a lot of the plans that we've had relating to the kind of outreach and digital impact that a drug candidate like this can have, it's just substantially different. Having the ability, we've seen a lot of increase in digital psychiatry. We've seen a real reduction in any in-person treatment or appointments by psychiatrists. We see a lot of conversation that's consumer-driven, especially similar to maybe like the GLP-1 drugs and weight that's related to anxiety. There's quite a bit out there. Telehealth and mental health, we've had real good outreach there about the marriage and how we see, especially if the drug is unscheduled, is where we would, we would so far believe is possible based on what we heard from the agency and what we typically see. Even DTC, I mean, some of the things there, if you look forward, you don't need 30 seconds of fair balance, just given what we have typically seen as the safety profile here. Very consumer-driven, very, even the psych-like PCPs that are general practitioners, NPs, PAs, certainly the psychiatrists. The psychiatrists are sort of like, "What do you need us for?" because digitally, you've got consumers coming to you. Medical education will be important on the MOA. Safety will be very important. Psychiatry will sort of be the beachhead, but it's a very broad market out there that's associated with PCP, psych-like PCPs who will write scripts for anxiety and depression. Maybe not something more complex than that. We're in a nice lane at the right time with a target product profile and a massive TAM associated with even a reduced headcount associated with conventional launch strategy. We'll see how that goes, but a lot of that effort is a pre-commercial effort stage-gated, and things will change as we see success and on our way to an NDA-related submission if we're fortunate enough to have that capability. Wonderful. In the last few moments, maybe you touched on your portfolio behind fasedienol. Just remind us the timing of potential next catalyst in the last sentence. For fasedienol? Beyond fasedienol. Oh, you know, we should have an IND in place in the fourth quarter for PH80, the drug that's non-hormonal, non-systemic PRN for menopausal hot flashes. Very excited about that one, especially the demand and what we're hearing associated with menopause and mental health. That's a study design that we're working, and we think maybe a little bit less than a year from now, we'd like to see our first patient in with that. iTRUVON for major depressive disorder, again, there, you're talking about a non-systemic rapid onset opportunity with no sexual side effects, no weight gain, no sedation, the kinds of things that really depart from what we see as approved antidepressants, but also those in development, especially on the safety side. Wonderful. Thank you so much, Shawn, for your time today, and thanks to everyone for listening in. You bet. Always a pleasure. Thank you.