Afternoon. Welcome to TD Cowen's 46th Annual Healthcare Conference. My name is Stacy Ku. I'm one of the Biotech Analysts at TD Cowen. I'm joined by my colleague, Vishwesh Shah. With us, we have today, CEO of Vistagen, Shawn Singh. Thanks for being here today, and take it away. Great. Thanks, Stacy. It's, it's great to see you and Vish again. Thanks for having us. It's always a pleasure to be at this conference. It's super well run and we're happy to be part of it. First and foremost, the housekeeping. As you all know, I'll be mentioning forward-looking statements today, so please have a look at our SEC filings for more information on risks associated with our business. With that, we'll get right to it. Vistagen is a company with a pioneering technology related to basically using the nose as a portal to achieve different therapeutic outcomes based on neural circuitry. Right now, as a company, we sit with five assets that have been advanced from that pherine platform, which we'll get to in a bit. Each of those, five clinical stage candidates has seen some success in the clinic. One in phase III, that's our lead asset for the acute treatment of social anxiety disorder. We'll spend a fair amount of time about that today. Four others that are across different therapeutic areas involving different regions of the brain, we've seen in exploratory and pilot studies, again, how this new class of candidates can actually make a difference non-systemically, which is really the most remarkable aspect in addition to rapid onset. These are all very large market opportunities that we're focused on in areas where we have, we think, significant opportunity across different options to be able to move not only the assets through development, but also into the market, should we be able to get across the line for approval. A little bit about the platform. Pherine's really the hallmarks would be the fact that they're non-systemic. The fact that we are dropping microgram levels of drug directly onto receptors in the nasal passage that are called chemosensory neurons. All of the assets in the pipeline currently are formulated as nasal sprays for that particular reason. These are receptors and neurons that are only in the nasal passage, so drinking or any other typical delivery mechanism is not really effective other than nasal sprays that go right on top of the neurons, the receptors to the neurons we're trying to activate. Doing this in a non-systemic way, obviously, there are much significant distinctions between just about every drug in every therapeutic area that we are dealing with. You'll see that most remarkably, obviously, in the most advanced program, which is relating to social anxiety disorder. We've got an asset class that doesn't even penetrate into the brain for the neuropsychiatric and other therapeutic areas that we're trying to deal with. Abuse liability becomes something we don't have to worry too much about. We're not dropping drug directly on opiate, nicotine, dopamine receptors that are associated typically with the kind of side effects and safety concerns we worry about with current generations of drugs. Standards of care have potential to be significantly disrupted longitudinally based on entrance into these classes of these therapeutic areas with the pherine pipeline. At the top of the ladder, we have Fasedienol. That is our intranasal drug candidate for the acute treatment of social anxiety disorder. That's in our ongoing phase III program, which we call the PALISADE program. Second asset in the neuropsychiatric arena is Itruvone for major depressive disorder. We also have what is currently labeled as PH15, focused on psychomotor and cognitive improvement in mental fatigue, patient populations. Shifting to women's health, our drug candidate Refisolone, a non-hormonal, non-systemic approach to very large women's health disorders. First, for vasomotor symptoms or hot flashes related to menopause and also, premenstrual dysphoric disorder. We've had positive phase II studies in both of those indications. Finally, at the bottom in the cancer supportive care arena, we have what is currently called PH284, and that is for cancer cachexia. The three lead pherine candidates at the top of the pipeline, Fasedienol, Itruvone, or Refisolone, each is attacking what we think are suboptimal treatment options in each of these very large markets. Therapeutic areas for social anxiety disorder, and major depressive disorder, tens of millions of patients right now who are not currently, in our opinion, adequately well-served with the current treatment options. For women's health, it's really a radical shift. You have with Refisolone a non-hormonal and non-systemic PRN approach to treating vasomotor symptoms or hot flashes due to menopause, giving women, just like in social anxiety disorder, really agency over the use, tailoring it to fit how the condition, or in the case of social anxiety, the disorder affects their life on a day-to-day basis. Fasedienol, we'll park on this a bit. Again, this is a very large market, typical onset of social anxiety disorder, which is fundamentally the fear, and anxiety about being judged or humiliated or embarrassed in many, what we would consider ordinary, everyday social and performance situations. The onset's typically in adolescence. In the duration, the mean duration's about two decades. You have a situation where a lot of people are affected, over 30 million in this country alone, adults, for a disorder that really impairs many, of what folks with this disorder are affected by in their daily life, things that they'd want to pursue, relationships, job opportunities, academic advancement, things that, again, you need to really have the kind of confidence to deal with people. Fasedienol brings an optimism to this space that we haven't seen in a long time because what you're trying to do again is give people agency over a condition that affects their lives on a day-to-day basis in real-world settings that are social and performance-oriented. Fasedienol, within seconds, within one second even, based on applying a microgram-level dose directly to the neuron, the receptors of the neurons that are in the nasal passage, projecting to the olfactory bulbs and then to the limbic amygdala, is able to knock down these fear on feelings that people get when they are provoked by the social or performance situations that affect them in daily life. Rapid onset is very key. The ability, from what we have seen, these are not systemically absorbed, so you're not seeing absorption or uptake into the brain. The ability to have that kind of a product profile where you're not concerned all day every day about the side effects and the safety concerns that are often more debilitating in some cases than the underlying condition is a big deal. We've seen favorable safety and tolerability now across nearly 1,500 subjects, and the ability to use it when needed up to six times a day is what we have been studying. To be able to tailor it to fit the way that social anxiety disorder impacts lives on a daily basis and not use it on days when it isn't the case that you feel the onset. You don't have to have an old-school antidepressant in your body all day, every day, if you're not dealing with the stressors that are causing you acute social anxiety disorder. We've set up the PALISADE program really around a public speaking challenge paradigm. What we are, again, looking to is to try to knock down the acute episodes associated with social anxiety disorder. A public speaking challenge design that consists of four visits over a four-week period. First visit, simply a screening visit. Second visit, subjects are coming in, and it's a baseline setting visit, single-blinded. If they're sufficiently stressed in that first speech, they advance a week later, and they're double-blindly randomized 1-to-1 drug and placebo. Fourth visit, simply a safety visit. What you're assessing using an endpoint called the Subjective Units of Distress Scale is you're looking for a difference, a group to group difference, those randomized to treatment versus those randomized to drug against a baseline that is set in that first speech. It's a minute-to-minute measurement. Each minute during a five-minute speech to a group of strangers in a conference room setting, the subject will tell the rater how they feel on that scale. A 75, for example, would be more than a little uncomfortable on a scale that visualize a thermometer 0 to 100. The subject will rate how they feel each minute during the speech, and again, you'll compare the second speech of those randomized against the first speech, which was a baseline setting speech. The PALISADE-2 study, among the three studies, we've had three, the two of them did not separate. One of them did. The one that did separate was the PALISADE-2 study. We have PALISADE-4 ongoing. I'll get to that in a minute. PALISADE-2, very importantly, we saw a statistically significant separation between the treatment group and the placebo group when they compared the second speech versus the speech on the Subjective Units of Distress Scale. We see this study as very important. We think it was the first ever positive phase III study using a public speaking challenge in a phase III setting for the acute treatment of social anxiety disorder. It was a very key milestone for us, and it anchors the PALISADE program at this point. We looked also at some secondary exploratory endpoints. We said, "How did the docs think subjects did second speech versus first?" Their STAT-sig as well. That was on the CGI-I. That's the clinician assessment of the subject's performance, second speech versus first. Most importantly, we looked at the patients. What did the patients say? How did they think they did second speech versus first on the PGIC? That's a scale, again, that's patient-rated. Very important to us because what you're trying to accomplish overall is to deliver back agency to people who are affected by this disorder. If they're able to have that agency and manage through a stressful event that historically has been problematic for them, now you're accomplishing something in a setting where you have a potential to change lives. What we've also been looking at very carefully, again, is how has what we've learned from all the other studies been able to impact the execution of PALISADE-4. PALISADE-4 is a replicate study to PALISADE-3, 2, and 1 in terms of study design and the endpoint. The big difference, though, is the more you do in development, as we all know, the more you learn. While its design is the same, it really isn't completely the same because we're able to take advantage of the learnings, operationally and even methodologically, analytically from the prior studies using AI and other emerging technologies as well as all of our best practices and human learnings from the execution of the trials. PALISADE-4, as guided, is a replicate in terms of the size, in terms of the endpoint and the design, and we expect that also To read out as previously guided by the end of the first half of 2026. If PALISADE-4 hits, then it complements PALISADE-2 in a conventional two-trial strategy, which we believe is one potential way to advance through the regulatory pathways, and there's some other ways we can talk about here in a minute. One of the important things we've seen when we look back across all the studies, a very constant treatment effect across the PALISADE studies. It's encouraging. You're always looking with studies to learn more. What is it that may give you confidence about drug effect? What is the potential for there to be placebo-related aspects that could be obscuring the drug effect? The fact that we see a treatment effect across the studies, which was similar, but that the variability has been associated with the placebo effect, obviously, that's been something that we've been very focused on. How do you mitigate the placebo effect, either operationally or potentially, methodologically or statistically? One important thing we constantly look at all the way back into prior studies, this is an open label study we did years ago. Nearly 500 subjects, over 30,000 doses, what we looked at here is: How is it working in the real world? When people are dealing with real-world situations, and they use our product candidate right up front of those situations, is it affecting the level of avoidance, the level of engagement, their overall fear and anxiety level? First and foremost, you look at safety. From a safety perspective, it's a stellar and a remarkable safety profile for a psychiatric drug. The only treatment-emergent adverse event that we see more prevalent than 5% in that study, nearly 500 subjects, was headache other than COVID. The fact that the drug is non-systemic, as we noted before, is very important to contribute, of course, to that, overall safety profile. Again, we also looked at how did on an exploratory basis, what do we see under the Liebowitz Social Anxiety Scale? That's a scale, standard scale in the space that looks over time, like a movie would, at the experiences that the social anxiety disorder patients have in real-life settings. Is there a basis to believe that the more people use it, the more they have success in real-world settings, the more confident they are, and the better their outcomes are. What we saw in this real briefly was patients continue to get better month over month over month against baseline as they continue to use it in real-world settings and typically upfront of the anxiety-provoking event. Looking at diaries and looking at really what were the experiences. This is what we're trying to do overall. This is how we improve patient lives. This is how we can actually be change-makers in this space is what's going on with people when they're using it, when they need it, as they need it to control the effects of the disorder. That was very important to see. I'm just gonna remark on this single trial, interesting new default option by the FDA, only because, again, there's always when you are advancing a program and you're building your program around how you think your drug works, you generate a comprehensive base of data, always with the totality of data, a weight of evidence, risk-benefit calculus kind of in mind. We have a very comprehensive data set that supports alternative, potentially alternative pathways. It's nice to see this. I think it was interesting to see that it was married up with bonuses to staff for speedy review. I thought that was kind of interesting. A lot of times you see things at the top from the agency that may not make their way down to the division level and the staffer level. This was seemingly a bit of a bottoms-up approach. That was encouraging to see. I'll just spend a minute 'cause I know we wanna save some time for Q&A. Refisolone, as I noted to you earlier, is our non-hormonal, non-systemic, rapid onset intranasal drug candidate for the lead focus for us is vasomotor symptoms or hot flashes that are due to menopause. As we continue to see suboptimal options in the women's health arena, especially for this particular indication, our team is very excited about its potential. There's a very large need out there, even though we just saw the black box removed from hormone replacement therapies, which is another interesting thing where directive at the top seems to making its way down to the staff level. We think this has a significant fit because, again, not only is it non-hormonal, which is key, like, one of the most recently approved drugs, but it's also non-systemic. The kinds of worries, for example, perhaps about liver liabilities, they just don't seem to come into the, to the calculus for us with this, with this asset. The ability to use it on demand, PRN, again, provides an agency for women affected and how hot flashes affect them in their daily lives that gives them some control over that. This is a program we're excited about being able to by the end of this first half of the year, getting to a point where we've got some clearance from the agency on the ability to move forward in phase II. What we saw in phase II, and have already released is in a phase II exploratory study, we saw a reduction in both the number and the frequency, and some, and severity of hot flashes. That was important for everything that we saw in the ability to move this program forward on our own or with a collaborator in the women's health space. Itruvone for major depressive disorder will round out the discussion. Itruvone is another novel, rapid onset, non-systemic, pherine product candidate that we believe has transformative potential for the treatment of major depressive disorder. What we saw in studies, in the phase II study that was done, was very encouraging. Again, you've got the opportunity to deliver a drug at microgram level doses right on top of the receptor we need to activate to be able to project through the olfactory bulb neurons and then two regions of the brain associated with antidepressant effects. Here what we have with phase II was a very rapid onset effect that was sustained over time with a 6.4 microgram level dose. Again, we're not talking milligrams, so not 200 mg like in Advil. This is microgram levels and in a mode again where the safety profile was exquisite on the other side of the 8-week period for this study. This is a, an indication where we think the need is great. There's a lot of opportunities in motion of course, but what we see here is something significantly differentiated from everything ever moved forward. With a class of drugs now with a lot more robust understanding of the mechanism of action, the way that we think neural circuitry makes a difference to multiple different therapeutic indications and to do that with drug candidates that can be de-delivered safely and non-systemically, we think is a remarkable departure in any of the therapeutic areas that we're focused on: women's health, neuropsychiatry, cancer supportive care, and wherever else the platform might generate additional candidates as we look forward. With that, Stacy, I think I left a few minutes for Q&A. To the extent that you can you talk about early learnings as it relates to PALISADE-3 and what you might be applying to PALISADE-4? Obviously, it's something that's happening in real time. We won't pin you on it, but maybe also talk about whether or not you're getting a sense of who are the responders, what's the profile of a patient. Well, again, the learnings from PALISADE-1, 2, and 3 actually are at our disposal now as we try to not only assess whether there are adjustments operationally that can be achieved and accomplished logistically, site rationalization, recruiter rationalization, going back to sites for refreshed learning about placebo mitigation strategies, pretty standard stuff. Also on the methodological or analytical side, you know, using now what power is available to us through collaborators and their proprietary AI. The ability to look back across especially some of the vocal biomarkers that we're able because we harvested and collected audio recordings of the various speeches. Are there things that we're finding that could have a potential effect covariates that could have a potential effect on the ANCOVA, right? The analysis of the covariates that can be factored into not only the operating side, but for example, the potential to impact the statistical analysis plan, the SAP for PALISADE 4, before a database lock. We're looking at a lot of those things. Again, you take a pretty quick and deep look on PALISADE 3 'cause it's got the ability to generate the most data for us that could impact the PALISADE 4. We're also looking back meta-analytically as well. You know, are there things that, using, for example, you know, an automated neural network, are you looking for some non-specific patient contributors that may be obscuring a drug effect that we can tease out and we look through the AI and to have looked through machine learning to try to assess potential impact on that PALISADE -4, SAP? Okay. From what we recall, you have guided to telling the street when enrollment is completed for PALISADE -4. Maybe in broad strokes, talk about how enrollment is progressing for us. Yeah. The pace of play has been very much intact. The TLR that we project by the end of the first half is on track. There's been really no hold up there. We still expect to stay on that same pace. Okay. It relates to just a quick follow-up to your last comment to the SAP and maybe before database lock. What's the timing that you might expect? Is that basically Once enrollment is complete, you really need to then make a decision as to whether or not you need to make any changes from a statistical perspective. Yeah. Well, they run on separate tracks. I mean, the requirement is that if you have an adjustment to the SAP that's already been with the agency, then we have to give a little bit of time to socialize. AI may or may not generate anything. Machine learning may or may not generate anything that affects the SAP. As long as it's before the database lock with enough time for the agency to socialize around any adjustment to that, there's always, there's only so many covariates that you can really adjust. You don't wanna have too many in your SAP. Being mindful of that as well. We're looking at some things. Again, if they have a potential to impact the SAP, then it makes sense to get that in before database lock. We think we're with the traction and the timing that we're projecting for. Remember, enrollment here is a little different because it's only the randomized subjects who make it into the second speech that are included in the dataset. We do have the first speech serves as a bit of an enrichment gate. In case they're not sufficiently stressed, they don't get randomized 1- to- 1. We're trying to make sure we budget the time properly to not only get the as comprehensive as we can analytical look at things, as well as leaving time to socialize that with the agency all before a database lock. Okay. Would you expect that's gonna be a key component, when it comes to managing the placebo response, or is there any other factors? It has a potential to. It does have a potential if you can adjust for what covariate might have a fixed effect on the ANCOVA. If it seems like there's the potential for that to occur, that would make sense to then try to address that with the SAP and the agency. In addition, you have to do, and we already are doing the operational logistical adjustments relating to some sites, relating to one of the recruiters, relating to getting back into various sites and refreshing training around the kinds of necessities to drive rigorous adherence to the protocol and make sure the training on the SUDS of the subjects is right on spot as it needs to be and that there's people are following the recipe, you know. As it relates to the open label extension trial that's ongoing, to the extent you can comment, how is that progressing? When it comes to some of the other, let's say, endpoints that we consider for versus SUDS such as the Liebowitz Social Anxiety Scale, how do you, how are you kind of thinking about the totality of endpoints there, especially... Yeah. The open label that we reported on before was very important for us. It again, it told us what's going on in the real world, how we think the drug would be used downstream in life if we're successful in achieving regulatory approval, right? That's important. That's why we had the open label extensions to both PALISADE-3 and PALISADE-4. Safety-wise, again, I wouldn't expect anything that's remarkably distinct and different from what we've seen across all the completed studies. It's very remarkable in terms of the prevalence associated with treatment-emergent adverse events. The exploratory endpoints, just to remind folks, you know, the Liebowitz Social Anxiety Scale or LSAS is sort of like a movie of experiences patients have over time, as you know well. Whereas the SUDS is more like a Polaroid or a selfie, right, during the course of a 5-minute speech. Both of them have important contributions to why we think the drug has potential to change lives. The LSAS, as an exploratory efficacy endpoint, is built into the open label studies PALISADE-3 and 4, similar to the standalone open label study we do with about 500 subjects and 30,000 doses. What you're looking for there against their baseline, and we've had very successful throughput from all the studies into the open label. That's important to know. A very high percentage of subjects want to go into the open label. We're getting a nice body of subjects into each of the studies. What we're looking for there is, over time, as they're assessed, are we seeing a reduction on that scale? Specifically, you're looking at avoidance, and you're looking at are people avoiding their daily stressors or their real-world situations that are problematic for them with this disorder. Are they avoiding them less? Are they engaging in them more? Is their fear and anxiety going down over time? It's a very meaningful endpoint. It's valid and reliable. It's been anchoring the three old school antidepressants, as you know, that have been approved. Yeah, we'll be looking at that. I hope we can have some visibility into the exploratory efficacy side, maybe even before PALISADE-4 reads out. We'll see. We've gotta wrap the full body of patients through several months before we wanna say something about that. Okay. As we await the PALISADE-4 outcomes in the first half of this year, just help us understand the different paths forward. Obviously, in success, what's the regulatory path forward there, and what kind of decision-making is going on behind the scenes, for, in case PALISADE-4 does not hit? Yeah. From the very beginning of this program back in 2020, we built and will continue to build a very comprehensive base of data across both controlled and open label studies. First, the very conventional strategy, if PALISADE-4 is successful, combining with PALISADE-2 in a conventional two pivotal trial, adequate and well-controlled trials to anchor with additional broader and data. No question. Broader knowledge comes into play as well, even with two adequate and well-controlled studies. That's one track. Another track is what we just saw recently last week vocalized again. It's not entirely new, but it's nice to hear from a commissioner speaking exactly what we had heard months ago about a single trial with commitments and compelling evidence potentially anchoring an NDA. That'd be a second lane there using PALISADE-2, phase II, open label, some EGNR studies, some of the other publications that we've got associated with mechanisms of action. The agency here, this division, we believe this division is familiar with mental health and studies where there's often gray. If you have a demonstrable alternative pathway to demonstrate efficacy that can be validated with data, that's something that we would advance. That's second lane would be advancing on a single pivotal trial strategy to anchor an NDA. Third is there's always room for another study design that could be like could be a Liebowitz-based study, again, to complement the public speaking challenge study. We know this division has seen two different types of studies before to approve a drug. That becomes another alternative to be able to complement what we've seen overall from phase II forward with Fasedienol and social anxiety disorder. Okay. In the last few moments, as we think about PH80, maybe, when we should expect a next update, so timing for the next catalyst? For Refisolone PH80. I think what we're working on there is to be able to get to a position where we can facilitate further U.S. development for that asset. For that, we need to get, we need to get an IND in the other side of that submission with the agency's blessing to proceed forward. That's something we hope to be able to accomplish by the end of the first half of this year. Okay. Wonderful. Well, thank you so much for the time today. You bet. Thanks, Stacy.