I'm Brian Abrahams, Senior Biotech Analyst at RBC Capital Markets. Thanks to everybody for sticking around till the end of the day, which I hope has been really productive for everyone. Our final presenting company of the day is Vistagen, represented by their CEO, Shawn Singh. Shawn, thanks for joining us. Hey, great to see you again. Likewise. Thanks for having us here. Always, a pleasure. Maybe if you could just start bigger picture with an overview of your pipeline and how you guys got into development of neuroactive Pherines like fasedienol. Yeah. Well, we have a real deep domain level of experience and expertise in, and that's based on the pioneering work of Dr. Louis Monti, who's our, he's the head of our translational neuroscience group. And what that's focused on really is the neural circuitry of the olfactory system and the brain, right? So the pioneering level of what we're doing in a neuroscience space, where historically you have all kinds of issues, right, with side effects and safety concerns and systemic medications, pretty much everything that's approved, right, systemic. We're focused on really using the nose, as a portal to administer, an entirely new class of drugs, that what we see from a mechanistic standpoint is to be able to do that with intranasal delivery, and tell you why about that in a second, but, of drugs that don't have to be systemically absorbed, they don't have to act directly on neurons in the brain. So relying on that sort of nose-to-brain neural connections, that ultimately, at the end of the day, what we're able to achieve with this new class of drugs we call Pherines, are different behavioral and different pharmacological, outcomes that involve different regions of the brain. There are similar sort of lock and key mechanistic approaches with the first two steps, which is nose, and then the olfactory bulb neurons, but then travels to different parts of the brain, depending on what we're trying to knock down. Hot flashes is one thing, one part of the brain. Anxiety, another one, as you know, different part of the brain. The pipeline consists right now of five Pherines. We've had five positive studies, either Phase 2 or Phase 3, across really five different conditions that we think are in the markets we look at, which are markets where the standard of care is stale or really doesn't exist. There's no guidance for social anxiety, for example, there's no guidelines for treatment- Yeah. ... of acute treatment of social anxiety. Major depressive disorder, vasomotor symptoms, which we all know, thanks to some commercials on TV with disease state marketing, are hot flashes, psychomotor impairment, appetite-related disorders. So a variety of different, large, highly prevalent indications where we just haven't seen anything move in a long time, and we know what patients are asking for. You hear it a lot with anxiety and depression, right? What is the clarion call? Rapid onset, no sexual side effects, no weight gain, no abuse liability. Right. And so with a class of drugs that we cannot detect the drug in the plasma, we don't see systemic exposure. We've radio labeled a couple of them, don't see that. We know we're not potentiating some of the worrisome things like GABA with benzos, no binding on abuse liability receptors. So there's a lot of distinguishing hallmarks that can really lead to compelling efficacy and really differentiated safety in an area where in neurological disorders and neuropsych, you know, there's a lot of room for improvement. Absolutely. Speaking of room for improvement, last year, you guys reported positive results from fasedienol in the PALISADE-2 phase 3 study. Can you elaborate on the key findings and what makes you most excited to move forward based on those data? What makes me most excited is we did something no one else has ever done. There's never been a positive phase 3 study in Social Anxiety Disorder for the acute treatment of Social Anxiety Disorder, and ours was the first. And it was under a study design that we were able to align with the agency on for as a public speaking challenge, and we used an endpoint that's helpful of measuring effect in an acute setting. The last time we saw a drug approved for social anxiety was 21 years ago, right? Mm-hmm. There's three old school antidepressant that are approved. Right. But for the overall treatment, longer term, longer onset, certainly have the common side effects and safety concerns, but nothing in the moment- Mm-hmm. where we can knock down, and in this case, it was a public speaking challenge with the single administration of the drug during a 5-minute speech, or 15 minutes or so before a 5-minute speech to a group of strangers, and what we assessed in that was how people did their second speech versus their first. So when they were double blindly randomized to drug or placebo, you're looking for group-to-group changes in the-- on the endpoint we use, which is the Subjective Units of Distress Scale. So in that study, we hit all the endpoints. The primary was a change in the SUDS, so a reduction in the Subjective Units of Distress score, which is sort of a, think about a thermometer, kinda 0 to 100. A 75 on that means you feel more than a little uncomfortable. Mm-hmm. Each minute during the speech, in a patient outcome reported way, which is something we all like, right? The patients told the rater how they felt at that particular moment- Right ... each minute during the speech. And so there was a first speech that established a baseline, and a second speech that was compared to the first one, and the double blind randomization to drug or placebo. The second allowed people to compare against the first speech. And we also looked at CGI-I. How did the clinicians who were involved in rating, they're basically the scribes, but what were their impressions on whether people improved in the treatment group versus the placebo group? Obviously, double blinded to make those assessments. We also, very importantly, looked at an indicator we really like, which is the PGIC, the patients saying how they felt they did the first speech versus the second speech, obviously comparing those on drug versus those on placebo in the one-to-one. So hitting that endpoint with more than 2x, the number of subjects on drug responded as being either very much less anxious or much less anxious over the group that was on placebo. Then the final was the percentage of responders with a greater than 20-point drop in the SUDS. So every one of those endpoints hitting is what really generated a lot of excitement for us and brings us and some of that study was even done during the acute phase of the pandemic. Mm. What we really are happy about is the vast majority of the subjects in that study were at a time when we started to see some changes in clinical research, the ability to surveil- Right. - the ability to- Yeah. The masks came off and things- Yeah ... that were different. So, that, that gave us obviously a lot of confidence moving to where we are now, because it was better in PALISADE-2 than I. Yeah. It's certainly better in III and IV- Yeah - that we launched III just recently. And I wanted to talk about that a little bit more because, you know, that first study, which was run during the peak of COVID- Yeah ... you saw, I think, a 17-point SUDS reduction for the placebo arm, so it didn't end up showing separation versus the drug. Yeah. The placebo effect you saw was much less in PALISADE-2. What were some of the key factors resulting in these different outcomes? And I guess, what gives you the most confidence that PALISADE-2 reflects the true treatment effect here? Yeah. Well, I certainly, we certainly think PALISADE-1 is sort of an outlier. Yeah. It was, as you said, when sort of the wonkiness of the black swan of the pandemic was laid out on the clinical research community. We had, you know, no in-person investigators meeting, really a different level of surveillance potential. You would have a higher probability of protocol excursions. You'd see a lot of turnover, attrition at the sites, attrition at the CROs. So things that we normally, in an industry, rely on as part of the tradecraft to really limit variability, right? When you go from Phase 2 to 3, you're trying to control variability. And there was just a lot of variability that from the COVID, from the pandemic, we think that impacted the way that study was done. PALISADE-2, on the other hand, just even, for example, the masks coming down. Yeah. Like, fundamentally different- Yeah - to make it more aligned with how phase II was run. And so when we look at how you can do things to effectively try to limit variability, one of the things we all like, I think in the agency as well, is that you can provoke anxiety in a controlled setting consistently across sites with the public speaking challenge. Mm-hmm. And it makes sense to use an acute endpoint, the SUDS, to be able to assess the benefit you can possibly achieve with your drug. But it also means now we move into III and IV, where, like I just noted, II is better than I environmentally. III and IV this year, phenomenally differently than it was before. Yeah. So you're able to have an in-person investigators meeting. We're able to get back and retrain. In PALISADE-II, when the masks started coming off, there was a lot more of an opportunity to get right back in the faces of the investigators and the coordinators. In PALISADE-I, that was really also the first lap with this study design in a long time. Right. In a phase III setting, we don't think there ever was. And so there had to be some, really some understanding of how to train up the sites and how to make them embrace it. Now, PALISADE-2, a lot more ability to interact with the sites. 3, 4, it's to a completely different level of the ability to surveil. Yeah. We've changed our operating model, like others, probably you've had on this stage. We rely a lot more on our own direct internal clinical trial strategist, direct communication to the sites- Mm-hmm. Not relying so much on CROs. We've unbundled a lot of services from CROs. We've got some other aspects within the protocol to make sure that someone who, let's say, they can't pass a smell test for some reason- Right ...... COVID has messed up their nasal cells for a few weeks. You can't have had a nasal swab up front about a month. So there's different things where we've learned a lot of best practices- Mm ... even more so than we knew before- Mm ... from, from PALISADE-1 and 2. Now, going back to people, especially veteran sites that we have a lot of experience with now, this protocol isn't a mystery. This endpoint isn't a mystery. Yeah. What's really important is to be able to surveil rigorous adherence to that protocol. If the recipe's followed, you know, it's a good shot of everything working out well, right? It's making sure that verbatim instructions are given, and the whole public speaking challenge is executed according to form. How validated is the regulatory path for social anxiety disorder, and how validated is the SUDS endpoint? Like, what were the discussions with the FDA like as you were in the process recently of the phase III planning? Yeah. Uh, previously. That happened many years ago. Yeah, sorry, in previously as well. Back in 2020, in the early innings of 2020, it was important to be able to say, "Look, we know there's only three drugs approved. Yeah. They're all old school, long onset antidepressants. They're not acute treatment. This is a completely different mechanism and a completely different drug. And oh, by the way, it's not a benzo. So how do we show you that? Yeah. Well, no potentiation of GABA. Oh, by the way, it's non-systemic. How do we show you that? Well, we radiolabel the drug, and we show the results from that study, no tissue distribution. But mostly and it's also not a fixed dose situation. One of the things that we really do like, and which the agency agreed with us on, is this study design for acute treatment dynamic is really the most appropriate one. We had in phase 2 also a social interaction challenge, where it was sort of a meet and greet, and that also works. We didn't; neither did the agency really wanna confound the public speaking challenge or the social interaction challenge, so that one stressor didn't affect another. But we aligned on everybody with this disorder. Basically, social anxiety, for those who don't know, it's a profound fear of being judged or humiliated or embarrassed in a lot of what we all consider ordinary daily life, social and performance situations. So you can provoke that type of anxiety with the public speaking challenge. We aligned with the agency on that. There's been a lot of work done in phase 2 with this challenge in an acute setting. And then the SUDS, the Subjective Units of Distress, really is the only endpoint. The old school drugs were approved on the basis of the Liebowitz Social Anxiety Scale- Mm-hmm. -the LSAS. Mm-hmm. It's more like a movie of experience over time. Right. Whereas the SUDS in the public speaking challenge is, it's more like a Polaroid. It's one single administration to see if you can, within a 15-minute window, knock down, but typically, causes a lot of opportunity costs in people's lives. Yeah. Once we aligned on yes, most people fear talking to people, and two, in a very controlled setting, we can consistently provoke with the same stressor across sites, the logic fell into place. Okay. And then we're able to educate that this is not a benzo, it's not a fixed-dose antidepressant, it is something where the patient can control their use. People like that because with social anxiety, if your stressors aren't on you, you're asymptomatic. If- Right. You also have days where you have multiple different stressors in a particular day. People here, this conference may have the same stressor throughout the course of a day, right? But most importantly, you need the patient to be able to say, "I need this now. I need this today." Our studies so far have been able to support up to four times a day. Mm-hmm. Especially in the days where there are distinctly different stressors. When we read the diaries and what causes people to have issues, it's all over the place. Yeah. I mean, it's really a remarkable diversity of situations. Mm. It's important to have something that you can take it out of your pocket or your purse- Right ... and have it available to knock it down. We see the onset of activating the neurons that we have to put into play, the chemosensory neurons in the nose. It's in milliseconds. Hmm. And then you see projection to the olfactory bulbs at the base of the brain, and then go to different regions of the brain. So it's, it's really important to see a rapid onset and the duration of the effects about an hour. How are preparations going for the initiation of PALISADE-3 and PALISADE-4? Well, three, we're all over it. We just did that at the end of March. Okay. So that study is on its way. It's a replicate of PALISADE-2. That's the most fundamental point, same study design, same endpoint, with some of the enhancements that we've talked about. PALISADE-4, we've guided to second half, so we're on track for that as well. Our goal this year, really, and fortunately, we're well funded to be able to accomplish that, is initiating everything this year that remains in our registration-directed PALISADE phase 3 program for Fasedienol, the lead drug for the acute treatment of social anxiety disorder. So the idea is, and the plan would be everything's initiated this year, and they all read out next year with an objective of filing, submitting an NDA sometime in the first quarter, first, at least the first half, if not first quarter of 2026. Got it. Can you- We need one of the two studies to hit. Okay. Ideally two, right? That's redundancy is not uncommon in neuropsych, as you've stated many times. We also will be able to gather a lot more open-label safety data so that we can see chronic use. Even those manifest acutely, the mean duration of this disorder is about 20 years- Hmm ... and the onset is typically in adolescence. Mm. So we're seeing a lot post-COVID, just like pre-COVID, team orientation in the workplace, in school, people, social media pressures- Yeah ... for sure, skyrocketing. As people are reengaging, we're starting to see it get back to normal. Yeah. So along those lines, can you frame the social anxiety disorder market for us? I mean, it seems like a very large unmet need on paper, right? But how do you think about the addressable population? Like, which are the docs who would prescribe a drug in that setting? What's the patient willingness to go on to therapy, and how much could the market expand beyond sort of the beta blockers or- Yeah ... whatnot, that are used today? Radically- Yeah ... radical expansion, to take- Yeah ... the last part first. The first part is we've been able to estimate, based on data that are out there, especially back in 2021, it's about 25 million Americans- Mm ... adults that are affected, so about 10% of the population. Wow! The treated population, we see somewhere around 5.5 million, but that's a lot of that's comorbidity with depression, probably other... See a lot of comorbidity with SAD- Yeah ... Parkinson's, cancer. I mean, a lot of times, it's not just depression. We saw a lot of people come into the treatment universe during COVID, for various reasons. The problem is, there aren't really good go-to options. And so we see a lot of people come in, and they're since the silver linings of the pandemic, right? It's okay to not be okay. People are talking about it more. That's helpful. Yeah. Telehealth increased, majorly important for what we wanna do down the road as well as now. People are becoming a lot more aware. So the total addressable market is really... It's remarkable, and it really has the potential. We were talking about this the other day. It really has the potential to be one of the most attractive consumer-oriented products ever. GLP-1, like, there's always a dialogue about weight, there's always a dialogue about anxiety. And we have now digital marketing, obviously, capabilities that are completely different. And our commercial model is actually a lot different in terms of headcount and resources pre-pandemic versus now. Yeah. We've been able to trim that back about a third because there's just so much more efficiency- Yeah ... especially a drug that's not scheduled and isn't over prior auth levels for- Yeah ... for pricing. What kind of a sales infrastructure do you think it would take to market, fasedienol, and is this something you would potentially do independently or- We certainly can. We certainly have that intention, no question about it. When you look at the psychiatrist out there, you'd ask about that, maybe 15,000 or so, we call them psych-like primary care physicians or psych-like PCPs. These are primary care nurse practitioners, doctors who will be willing to prescribe anxiety and depression drugs. They don't often go a little beyond that. Right. They won't go to schizophrenia. Yeah, yeah. But, you know, those, especially now, when you have the American Association of Psychiatrists, right? They're talking about anxiety in primary care visits. So it's a reasonable population to be able to address. We think our challenge is going to be more making sure that the patients don't know more than the doctors. There'll be a lot of chatter about, you know, the potential benefits of a drug like this if it fits the target product profile. But having medical education, a lot of disease state marketing upfront- Mm-hmm. -where we're allowed to do that within FDA guardrails, to what is social anxiety? Mm-hmm. We know we've seen, even with the awareness that's already been generated with some of the advocacy groups we work with, it's skyrocketing. It's, that's not a great thing, obviously, because you see a match set typically with anxiety and depression, and we're seeing more suicidal ideation. Mm. We're seeing... you know, those are the bad end consequences of this. So hopefully, you know, we get to a point where what we see with this drug, when it has been used over time in daily life, is these acute wins in settings where it's almost like having an invisible therapist next to you saying: "Look, what happened? You didn't get embarrassed when you had that interview with your boss, or when you went on that date." And doing that over and over again. Mm. With these acute treatment wins, builds the confidence, it builds the resilience, it builds the ability to reduce your avoidance of the Right. things that are opportunity. It's self-fulfilling in a positive way. Yeah. Yeah. So the alignment with cognitive behavioral therapy is really nice. Mm. Because, again, it amplifies the ability for that loop to circle back and say, "Okay, it wasn't so bad. It wasn't so bad. Yeah. You just need that over time. What are your expectations for what the pricing and reimbursement landscape for a drug like this could look like? And have you had any initial payer discussions or feedback? Yeah, we actually have. We've done a lot of pressure testing- Yeah ... not just on how we think payers, providers will be willing, to some of this is on our website, to prescribe because it fits the TPP they're talking about, right? Fast onset, no abuse liability, non-systemic, right? A lot of the issues that cause people to not wanna prescribe. But, the conversation there first was, "Well, what do you think about step edits?" And answer: there is no approved- Right ... acute treatment, right? So we don't see a step edit verdict here. The other side of it is, too, as long as it doesn't get to a point where we think we can price this effectively and have multi-billion dollar peak sales opportunities and still stay under prior off levels. So that's a key part of the strategy, especially when we're dealing with telehealth. And as long as we're able to achieve what we've heard from the FDA already, was, do we need to do human abuse liability study? Answer to that at the time was no. Again, we're not hitting opiate, nicotine, dopamine, we're not hitting the receptors that are usually in that abuse liability cascade. So if it's not scheduled, and we can effectively do a lot of what we're talking about with the digital footprint, we can get out there even before the drug gets to the market. There's a lot of efficiencies that we can achieve, especially if it's at a reasonable price, and it can be renewed, you know- Okay ... easily online, and a lot of SAD patients would rather have their consultations online anyway. Got it. Maybe just a couple last really quick ones. On the safety profile, it sounds like you're not seeing systemic exposure. Are there any- No ... safety issues or adverse events that you're looking out for, based on what you've seen so far? We always look out for anything that bothers us, that makes it line up with whatever people had before. But what we've so for example, we did a study where we've had over 750 exposures at this point, and many for many months, 85 for over six months so far. The study we did, where it was open label, for multiple months, about 30,000 doses, a little more than that. Mm ... in that study, about 500 patients- Right ... 481. The most prevalent, treatment-emergent adverse event was headache- Okay ... 8.7%. No other TEAE over 5% prevalence, which is just remarkable, obviously, for a neuropsych drug. So that's very exciting. We may see a little bit of nasal irritation- Sure ... transient, most likely. These cells turn over pretty quickly. Yeah. Right? So tachyphylaxis, tolerance- Right ... those kinds of things, and are not hitting the abuse liability screen. Good. Pretty confident and comfortable. We've not seen anything change in any clinical study, and really on any of the pherines, not just this one. Good. Well, we're out of time, but Shawn, thank you so much for the update. Absolutely. Great to catch up. My pleasure. Appreciate it. Thanks.