Very much. It's my pleasure to be moderating this chat with Shawn Singh, President and CEO of VistaGen Therapeutics. Certainly timing as we await some phase three data coming up in the next couple of months. Maybe, Shawn, you can just set the stage, give a quick background on the company, and then we'll do Q&A. Great. Appreciate it. Thanks for having us. Of course. Always great to see you. I don't know how you're still staying awake. I'm all right. You're phenomenal. VistaGen is a late clinical-stage biopharmaceutical company. We've got a focus on neurocircuitry-focused drugs. We call it, they're called pherines, from a new class. We've got five assets in the pipeline focused on, at the lead end of the ladder: acute treatment of social anxiety disorder, major depressive disorder, vasomotor symptoms, hot flashes due to menopause, psychomotor impairment, and cancer cachexia. This is an entirely new class. This is a drug candidate leading the class that is focused on rapid onset, non-systemic. There's no systemic uptake. We're not seeing direct activity on any of the neurons in the brain. What we see as a result of this mechanism is a completely differentiated profile from most of the neuropsych drugs I know that you've seen and that have been in development and used by patients over time. The ability to be able to deliver on a target product profile that has rapid onset, no abuse liability potential, no sexual side effects, no weight gain, no sedation, all as a result of the mechanism. The programs have been built around the mechanism. We have one phase three study that's hit in 2023 that anchors what we hope will be an NDA-enabled program with the second phase three study that has potential to bundle up with that one called PALISADE-3. We will read that out by the end of this calendar year. There's a fourth study in the portfolio that we'll read out in the first half of 2026. Great. Yeah. Maybe help set the stage for PALISADE-3. For those who do not know the background, maybe just go through the design. What would be a clinically significant outcome on the SUDS, and what other secondaries are you looking for? Yeah. This is a public speaking challenge built as a study design around the way we think the drug works. Again, we're looking for the acute treatment of social anxiety disorder, which is fundamentally a fear of being judged, humiliated, embarrassed in what most people consider kind of ordinary, everyday work, academic, social situations. The study design is associated to measure an acute benefit in a five-minute public speaking challenge that is repeated if people are able to be randomized from the first speech to the second. Over a four-week period, the first week is simply an assessment against IE criteria. The second visit, second week, subjects are on a single blinded basis. They are setting a placebo baseline. They all get placebo. Fifteen minutes after that, they're told they have three minutes to get ready for a five-minute speech to a group of strangers in a typical conference room setting. During the course of that five minutes, using what's called the SUDS, the Subjective Units of Distress Scale, they're asked each minute how they feel on that scale. Visual analog would be thermometer, 0 to 100, where 75 on that is feeling more than a little uncomfortable. If they are more than a little uncomfortable for two minutes in the current studies, one minute in the prior study that hit, they are invited back the next week, and they're randomized one-to-one, double-blind to treatment and to placebo, and the challenge is repeated. Fourth visit, simply a safety visit. What you're assessing is the group-to-group difference between the second speech and the first. We also have secondary endpoints that are clinician-based and individual-based, patient-based, to say how they think they did, not knowing what they got in the randomized portion of the trial, drug or placebo, how did they think they did, second speech versus first. Great. And so powering, can you talk a little bit about that? We haven't really gone too much into powering. Obviously, we're trying to replicate PALISADE-2. Okay. We've done many things associated with what we think are impactful. When you're trying to control variability, of course, that's key. That's key in every neuropsych study. What we've learned a lot over time is things that seem to matter in the execution and being able to surveil rigorous execution of the protocol. That really matters. Obviously, controlling variability in any neuropsych study is what helps you mitigate placebo risk. Yep. Yep. Okay. Makes sense. As it relates to your FDA alignment on this type of design, can you maybe talk about some of the history of that? How did you actually come about using this methodology? The story starts in phase two, as it always does. We had two different study designs in phase two. One was more of a real-world setting and a crossover design where people were encouraged to engage in their stressors, and then they were crossed over, depending on what they started with. That engages a real broad diversity of stressors. This is a disorder where we'd spend hours in here to articulate the different bundles of stressors that people have at different journeys, phases of their journey in life. When they're 18 to 22, it's sort of one set if you're a young professional, a young parent. We are in a situation where the second side of it was one particular stressor that was used in phase two. There were two in one of the studies, social interaction as well as public speaking, where with the interaction with the agency, the laboratory or the clinical-based setting where we could consistently provoke anxiety across sites with one specific stressor being the public speaking challenge, that's where we got comfort that that was the best way to assess and measure efficacy benefits in an acute setting. Again, there has never been an acute treatment for social anxiety disorder approved. There are three old-school antidepressants for the overall treatment of social anxiety disorder. That uses a scale called the Liebowitz Social Anxiety Scale. Dr. Michael Liebowitz, the Upper East Side here, he innovated that scale long ago to assess sort of like you would see a movie of a patient's experience over time using the LSAS. That is not appropriate for an acute setting. That's where we landed on if you're using the public speaking challenge design, you need something that can capture state of anxiety minute to minute. That's what the SUDS is able to accomplish. You're looking at the patients actually report the outcome to the rater, which is something we like. We think the agency likes those kinds of endpoints. Each minute during the speech, there's a rater that asks the subject, "How?" They say, "Score." They're given a number on that scale. Those numbers then drive whether they get randomized. It also drives the data at the end of the day. Yep. Yep. Okay. Makes sense. Going back to the PALISADE-1 and then PALISADE-2 studies, maybe talk about, again, your thesis behind the discordant results. As it relates to PALISADE-2, what's your level of comfort that that is going to count as a pivotal in a potential NDA? Going back to PALISADE-1, 2, we think a lot of that, as other sponsors, I think you've heard over time, the black swan of the pandemic had a lot to do with variability and the impact of, for example, masks being included in the context of the public speaking challenge. That was unlike phase two. In terms of PALISADE-2, the meaningfulness of PALISADE-2, we really focus on, well, what happened when the world changed? When did the masks come down? When were the visits allowed to be kept in and with rigorous adherence to a schedule? Things that you typically expect in an environment where you can control variability with typical tradecraft associated with trial execution. We did a lot, obviously, to look at what we think happened with PALISADE-1 during the peak of the pandemic, and then why did we think PALISADE-2 hit. Those lessons are what we bring into play when we're trying to figure out what enhancements to make for the PALISADE-3, 4 trials that we're conducting right now. Okay. Okay. As it relates to PALISADE-2, is it a robust study that would count for an FDA filing? We think so. I mean, we follow the SAP. There was no alpha cost. There was nothing unusual. That's what you look for. It was a very adequate and well-controlled study. That's important that you're adhering to the SAP. In that case, we were able to achieve stat sig with fewer subjects than we'd even modeled in the SAP. It's, again, nothing unusual about that study in terms of following the script for what we need to do. We think it anchors very nicely the program. It's a lot more like what we saw in phase two. We see PALISADE-1 more of an outlier. Just, again, contextualizing it in the period makes a little bit of a difference, especially when the masks come down and you can get into sites, you can refresh training, you can surveil execution. Right. Things that are just different, which we saw at the back end of PALISADE-2 and are certainly seeing in today's environment far more so even than during PALISADE-2 at the back end. Yep. Okay. I want to get back to PALISADE-3 and just contemplating a successful outcome. Given that the SUDS is a novel endpoint, how important is it that you also see an effect on CGI, some sort of quality of life metric that corroborates clinical meaningfulness? It's very important, and it's been consistent that we've seen with that kind of cross-validation that comes to the SUDS from the CGI. The CGI is the docs at the end of the second speech, not knowing what the subject was on, whether on treatment or placebo, is asked, "Do you think the subject was much less anxious, very much less anxious, or less so than either of those two?" What we saw from CGI in PALISADE-2 was about almost 2x, 1.8x those treated. The docs thought did better when it was unblinded if they were on drug versus placebo. You also ask the patients. The PGIC is where the patients are asked, again, without knowing what they were on when randomized, how do they think they did second speech versus first? That's a really important cross-validator for us as to the way we think the drug has potential to work in the real world, which is it's almost like having a little psychiatrist on your shoulder saying, "See, just in this acute setting, you didn't get judged. You didn't get embarrassed. You didn't get humiliated." That cognitive feedback that occurs from those acute successes, this is a disorder that the onset is typically in adolescence, 8 to 16, I think we've talked about before. The mean duration is about 20 years. It is a chronic disorder that manifests acutely. It's not like GAD. It's not all day, every day. There's without a specific trigger. These are very specific, very often predictable, stressful situations. Patients are often very high-functioning. They've built their lives around the disorder, the way where they live, what their jobs are, how they interact with people, how they negotiate that. When you have an opportunity for a patient to be able to experience a difference in their life and their rhythm from what they've typically experienced, that's the kind of thing we're looking for. That cognitive feedback that comes from these acute wins is critical to the downstream success. Eventually, you get to a point where you've sort of rewired the hard drive and you've got the right inhibitory neural transmissions of GABAergic activity around the amygdala, sort of like a protective shield where this outside noise and from your own imposed voices and the like ends up helping you engage. We're looking for more engagement. We're looking for less avoidance. We're looking for people being able to take opportunities in their life that have really they've avoided. It's amazing what you can we've seen from prior open-label studies we reported on. It's this kind of transformations that we saw people get better after one month, a little more after two months, a little more after three months in the open-label study we reported on before, which was about 481 subjects, many of them over many months and tens of thousands of doses that were administered in that open-label study. That's the kind of confidence that you get about when you've built a study around the way you think the drug works, an entire program in the case of the interactions with the agency around the mechanism that gives us confidence that we're headed the right way. Yeah. I mean, you talked about this open-label data, right, where there's tons of redosing. How does the FDA want you to actually characterize the efficacy and safety of redosing? We followed FDA feedback, and we initiated what we call the repeat dose study, small exploratory study where we have three arms where, again, the initial focus there is what happens in the real world if people think more is better and they want to dose, let's say, within 10 minutes instead of within an hour. What we've seen in terms of a safety database built over time is headed towards somewhere between a four- and six-use-per-day opportunity for people. Some days, again, people have no stressors. Weekends, far less. If you're reading a book or you're fishing, you're not going to really need the drug. During the week, we see utilization increase. You have an opportunity in the repeat dose study to get a sense of first safety. Is there a problem if somebody takes the drug twice within a 10-minute period? There's three arms in that study. It's drug-drug within 10 minutes, drug-placebo within 10 minutes, and placebo-placebo within 10 minutes. One thing it could do is inform the dose administration component of the label that says if someone takes it within 10 minutes, it's not something to worry about. Again, it's really hard to contemplate the probability that over-occupying these receptors is actually going to make a difference from a therapeutic standpoint. The activation of the neurons, the reason we're able to dose at microgram levels, it's a 3.2 microgram level dose, is because we're dropping drug and a spray directly onto the receptors that we need to activate. That's in about 150 milliseconds. It progresses through the olfactory bulb neurons to, in this case, with this drug, to the amygdala. Then there's GABAergic activity there in 500 milliseconds. Putting more drug in the nose may just cause it to drip out, but it's likely to not overexcite the neurons that we need to activate. Once that switch is flipped, the neural circuits kick into gear, and we get the impact that we've seen so far in phase three and across the pipeline. Do you have regulatory alignment on the number of redoses and the duration of follow-up needed? I mean, if this was a chronic drug, it would just be simple. Given that it's like an acute drug that's sort of going to be used chronically, how does the FDA contemplate that? You cover that in your safety studies, right? You cover that chronic use per ICH guidelines where you bump up to about 1,500 overall exposures. You get 100 subjects over 12 months. Yep. You get 300 subjects at six months. One hundred subjects over 12 months, but it's not like they're required to use it. I mean, they're all using it a lot. You encourage them to use it as needed. You encourage them to then diary the uses. In our open label, we chronicle the uses, the utilization. We typically, in studies reported, we've never seen hockey stick utilization. Again, there's no binding affinity to opiate neurons, dopamine, nicotine, none of the abuse liability neurons that you typically worry about. In fact, we went to the agency back in 2022, and we said, "Look, here's all the data we've got so far." That included the open label and all the controlled studies. The question was, "Do we need to do a human abuse liability study or any more non-clinical on abuse liability?" The answer was no with the typical comma at this time. You look at what happens after that. We will keep an eye on that. In the way the mechanism plays out, the fidelity that we have and comfort about the way this entire pherine platform works, the lock-and-key relationship between what's in our noses as a portal to be able to drive neural circuitry to different regions of the brain, a lot of work and a lot of time's gone into that. To see these different outcomes, like we have the drug for vasomotor symptoms, as I mentioned to you, that's a completely different region of the brain. We wouldn't be seeing, as we did in phase two, a reduction in the number and the severity of hot flashes in menopausal women unless it was getting to the hypothalamus, different part of the brain, similar with the other pherines. Makes sense. Any questions from the audience? I can keep firing away then. This will be a drug-device combo. How buttoned up are you on the regulatory side with that, like human factor studies and things of that sort? Human factor studies ongoing. It's part of the typical package, this standard amber vial and a standard pump. We get to cross-reference DMFs from those providers. We're at the point where you teach people, and then you have another phase where you got to say, "Did you remember what we taught you?" Here, it's a pretty easy configuration, the container closure that we've got with the REG batches and the like. That goes, again, with all the final study reports from CARC study, repro tox, everything that's in the typical bundle. A lot of those things we're working on already. I think there's no measurable PK for this drug, which is pretty atypical. Does that matter from a regulatory perspective? If the FDA says, "How do you know people are reliably getting the same amount of drug?" What do you say to that? Yeah. The challenge is you can't detect these drugs in plasma. These are human species-specific receptors as well. There are not animal models for efficacy. You converse about it. If you say, "Look, the typical PK chapter isn't something that applies with this class," certainly from the CMC perspective, you have to make sure that you're producing the same thing over time and that there's no impurities and the like. Clinically, you cannot detect the drug in plasma. Yep. Yep. Okay. We do a lot of work upfront to get to the dose. I mean, you start with human subjects coming in, harvesting nasal epithelial cells, sticking them in a dish. You did some like electrophysiology work, right? Do that after. The first phase is you take a look at calcium channel flux, and then you move to the point we call them EGNR studies, electrogram and nasal receptors. Setting up a situation in human volunteers where you're setting, again, a baseline with a spray, and then with electrodes that are placed in the nose and up near the bridge of the nose where the olfactory bulbs are, we'll spray different levels of active to see how that's how we get the 150 milliseconds and the 500 milliseconds, which you see whether there's activity across different concentrations. Of course, the phase one studies, we've seen different dose levels used in the earlier phase one and phase two studies. We landed on 3.2 micrograms with the FDA based on one of the phase two studies, including men and women. We're comfortable that that's a dose that anchors the entire phase three program. A question here. Yeah. Are you going to be required to do long-term studies for tachyphylaxis? That's a great question. We get that a lot. These cells turn over quite a bit. Again, we're not in about three weeks that we think. Tolerance issues, tachyphylaxis issues just don't—they're not really biologically possible with the way that the mechanism of this drug activates the neurons in the nasal passages that we see. We do know there's a little bit of metabolic activity in the nose, but that's not been the typical concern across development conversations, tolerance or tachyphylaxis. Again, you're not getting in the brain. You're not bathing any of these receptors or neurons that typically cause issues with tolerance, at least in particular. It's part of the reason why part of the IE criteria is you've got to follow. You can't have a COVID swab within the last month. We make people take a quick olfactory test that we've created to make sure there's no anosmia, so there's no neuropsychiatric irritability that might be factored in. There's a lot of things that we've been able to do over time to enhance subscalability assessment and just making sure that you've got people that have a solid history of at least moderate to severe effect by social anxiety disorder, again, which starts way back. The psychometric scales that come into play, even before signing signs in ICF, are pretty critical. You get very high-touch clinician eyes on things too upfront of even signing an ICF. That's a really nice change that we've seen throughout the clinical trial universe these days at sites, especially network sites that are very sensitive to screen fails. They do a lot on their own to even make sure they can suss out patients that might not be so friendly on their screen fail rates, especially if they've been private equity funded. Yep. Not something they like to see. Got it. As it relates to PALISADE-3, we're getting close to the study completion, excuse me, and data. Anything you can say about just what you've observed related to the conduct of the study? I'm assuming you have a very good idea of the types of patients that have gotten in. I'm assuming you've seen blinded data. Again, I don't know how much you want to comment, but as we approach this top line, what's your comfort level that this was a really well-run trial? A lot of things drive the confidence. It really started as we took a look at the PALISADE-1 and PALISADE-2 experience and all the way back to phase two. What's essential is rigorous adherence to the protocol. You got to follow the recipe. We did many things in terms of enhancing the approach to PALISADE-3 and PALISADE-4 that were not part of PALISADE-1 and PALISADE-2. For example, we have our own team of psychometricians that are really heavily involved in subscalability review, totally unbundling the reliance on CROs for that. That was in the context of PALISADE-1 and PALISADE-2, especially because what we saw at the back end of PALISADE-2 is when our teams got to be really heavily involved with the retraining. We are audio taping each of these engagements, each of the speeches. That's really helpful to surveil whether or not there's unwanted chit-chat, whether anybody's there are any excursions from the protocol. The IP is being administered by the investigators as opposed to the subject. So no one's administering it up in the sinuses potentially like an inhaled drug. We've got the QOT where people have to pass a smell test in order to be eligible. We've got some additional comorbidities that we included: ADHD, MDD, and the IE criteria. Mostly overall, the confidence is always driven by sort of the surround sound, right? How I go to a lot of the sites, our teams at sites, CROs at sites, you're always trying to stay top of mind. Having the open label extension has also been helpful to drive kind of enthusiasm. People get through the four-week study pretty quickly. They are experiencing what they might see or not see in the open label. We are anxious to see how that unfolds at the end of the day. If it is similar to what we saw in the reported open label study before, that is going to be something we like. I think it is overall really the ability to surveil, the ability to get in person, the ability to see the routinized systematic march through the four-week protocol, and knowing that this is really the third and the fourth lap for this protocol and this endpoint in the research committee, not like in PALISADE-1 where it was the very first time. No masks, of course. That is a big difference in PALISADE-3 and PALISADE-4. You cannot really ever guarantee an outcome. You know that from doing this a long time. What you can get comfort on is what's the effort and what does that mean at the very site company-to-site level without reliance on somebody in between having to give you their take on it, as opposed to our team being able to be comfortable that people have been willing to be trained up. They were willing to be refreshed whenever needed. They're being enthused about keeping this protocol top of mind. Many protocols, you got to wait a long time until you see who was on what at the end of the day and sites sort of move on. This one here, I think it's nice for them. Depending on how they see things happen in the open label, it keeps an engagement. Plus, you get an economic driver that allows you to get varsity sites. Yeah. Yeah. Any other questions? Shawn, anything else you want to talk about in the last couple of minutes here? I know you have a pipeline, but obviously with the phase three coming up, I'm just trying to hit that from every angle. No, I think you should. Look, it's a program intended to be executed all the way through. We had the second study, of course, not only as a potential backup if III doesn't hit, but we also are aggregating the safety numbers that we need for that study. At the same time, it's tremendously exciting for us to be at a point in time to hopefully repeat history that we made before with PALISADE-2 at a time where, if anything, we've seen things get worse. Certainly, as people have re-engaged at work, at school, we're seeing the year-over-year continuing to increase, especially in the younger demographic, 18 to 22. Unfortunately, you see a lot of the match set going from social anxiety to depression to suicidal ideation to suicide. We want to get in there and knock that out. One of the interesting things I hear sometimes these days is not only that psychiatry psychiatrists do not really see patients in person anymore, and patients do not want to be seen in person anymore. The digital psychiatry component is a really good fit for where we see this going at the end of the day: telehealth and mental health. The consumer conversation out there about anxiety is very similar to what we hear and see on the socials with GLP-1 and weight. If we have a drug candidate that we can deliver on some of these declaration calls of patients, which are, again, no weight gain, no sexual side effects, no sedation, no cognitive impairment, no risk of abuse, these are the kinds of things that allow compliance to actually be steady. The ability to potentially have impact, one of the main things that social anxiety patients do is they cancel. They cancel dates. They cancel health checks. They cancel things that are really their own well-being. We may see improvements in people going to get their heart disorders checked, their diabetes. They may be getting better dental care. These are all kind of collateral benefits of just simply engaging and not worrying about sitting in a conference room or a waiting room, having people look at you and feel like they're judging you and you're embarrassed, and you leave and you don't go to your appointment. That's the kind of things that we typically hear when we're talking with psychiatrists and nurse practitioners and PCPs. Again, it's encouraging that we think we may have a treatment alternative for people who just don't want to lean into benzos. They don't want to lean into beta blockers. They don't want to lean into alcohol. I heard one psychiatrist say, "You know, you're going to see fewer DUIs because people aren't going to drink heavily to go to a social party." Again, we're trying to deal with allowing people to have confidence in acute settings, whatever they are, social or performance, vocational, and allow that to build on them over time. Yep. Yep. Okay. Great. Best of luck. This presentation has been.