All right, thanks. Thanks very much, everybody. It's my pleasure to be moderating this panel with the Vistagen team. I'm going to have Shawn Singh, CEO, kick us off and give a background on the company and talk about the update with the pivotal program with fasedienol, and then we can do Q&A. So thanks so much.
Excellent. Well, thanks a lot, Paul. Appreciate being here. Thank you, everybody, for joining us today. We've made a tremendous amount of progress over the last year since we were here last year, and we are advancing a neuroscience pipeline that's unlike any in the industry. We've got multiple clinical stage programs, phase two, phase three, but with a completely new class of drug candidates, especially in the neuropsych arena, that we just haven't seen, and these are non-systemic, neurocircuitry-focused assets that just have an elegant way of
achieving therapeutic effects without systemic absorption, without binding onto neurons in the brain, but yet able to really see behaviorally exactly what we're trying to achieve in anxiety, social anxiety disorders, the lead asset in major depressive disorder. That's a second program, and also menopausal hot flashes. That's a very unique program that's neurocircuitry-focused, not only non-systemic, but also non-hormonal.
And so what we've been very busy doing, fortunately, we're in a solid cash position to fund through what we need to start this year to be able to complete next year, and then if successful, building on a success in phase three announced in 2023, to marry that up with one of the two phase threes that we're doing this year to generate what we think can be a substantial basis of support for submission of an NDA in the early part of 2026.
Yep. Okay. Great. So in the past year, you initiated PALISADE-3 and PALISADE-4. Do you want to just talk about how those studies are progressing with enrollment?
Yeah, we're very happy with the way they're progressing. With the clinical environment normal, as normal as we had seen it pre-COVID, it's a lot different. When you're with the PALISADE program, just to back up a step there, this is for the acute treatment of social anxiety disorder, for which there's no FDA-approved therapy, and what we have aligned with the FDA on is a study design, a public speaking challenge, and an endpoint for assessing the acute treatment called the subjective units of distress scale, and so over a four-week period, you have four visits versus screening.
And second visit, week two, you have a speech where subjects are after it's a single-blind enrichment gate, that they come in and they're told 15 minutes after they've received the placebo that they have three minutes to prepare for a five-minute speech to a group of strangers in a conference room setting. And if they're sufficiently stressed under that scale, it's a visual analog scale, 0 to 100, where 70 narratively correlates to more than a little uncomfortable. So in the study that was positive, we read out last year, again, a 70 for one
minute during that speech would enable them to be advanced to the next week, which is the randomization visit, double-blind, one-to-one drug to placebo. And the challenge is repeated. And so what we're measuring is the group-level difference between the second speech and the first.
And what we've seen in PALISADE-2 was no one has ever achieved the positive phase III study for the acute treatment of social anxiety disorder. We're the first to do that. And so we're replicating in PALISADE-3 and PALISADE-4, typical in neuroscience to build in some redundancy. One of those two we need to hit to complement the PALISADE-2 study, ideally both, at the same time generating sufficient open-label exposures. We're well over 800 exposures to date. So Palisade-3 and 4, we've initiated both of them this year. They will both read out next
year, early part of the second half of the year for PALISADE-3 and the end of the second half of next year for PALISADE-4. One of them has to hit to complement PALISADE-2. And we're hitting our expectations.
We got about 16 sites launched for PALISADE-3 and a dozen for PALISADE-4 .
Yep. Yep. Okay, and as it relates to the type of patients that you're selecting for in these studies, consistent with the prior trials for the most part?
Yeah. I mean, typically what you want to see and why you have these enrichment gates is you want participants who are severely affected by the disorder. That's why we have the 70 requirement for the visit two. They have to have one minute at least in the Palisade two study and now two minutes in Palisade three or four where they're more than a little uncomfortable. The benefit that we think we can assess with this, with fasedienol, that's the name of the fasedienol for the acute treatment of SAD, is we think enhanced if the subjects are severely
affected by the disorder, something that they've experienced for quite a while. Typically, the onset of SAD is in adolescence between about 10 and 17, and the mean duration is about two decades.
This is something where most of the subjects have been experiencing the disorder for quite a long time with very limited treatment options.
Yep. Yep. Okay. So maybe taking a step back, do you want to talk a little bit about the discordant results between PALISADE-2 , supportive PALISADE-1 failure, right? How you kind of make sense of all of that and what underlies your confidence going forward?
Yeah, a lot of aspects to that. PALISADE -1 was conducted. It was the first time really this study design had been in the phase three setting. It was the first time the endpoint was also used. So again, there's no acute treatment approved for social anxiety disorder. So that part was new, plus the black swan of the pandemic caused a lot of things that when we look back at it, a number of excursions associated with what really is needed is very rigorous adherence to the protocol, especially if it's one that's new in the research community. So to some extent,
it was sort of death by a thousand cuts where we saw a lot of attrition in the CRO sector. We saw a lot of attrition also at the site level. The Great Resignation. We saw we didn't have the same ability as we now do.
And even in PALISADE-2, when things changed a little bit in the early part of 2022, people had to wear masks during the study. So that was not like it was in phase two. When you move from two to three, obviously what you're trying to do is control for variability. And we saw a lot more variability that came into play in the height of the pandemic, which is when PALISADE-1 was conducted. We also just several things that we've corrected for or tried to correct for as we move forward in three and four. For example, it's possible many of these are drugs that need to be administered in microgram levels right at the mid-septum. So if you inhale this intranasal formulation, it could go in your sinuses and your respiratory system. So if the subject were to inhale, again, not likely to get the benefit.
There were several things like that. The way these drugs work, why this new class is so remarkable is that at low microgram levels, 3.2 micrograms, a single dose within 350 milliseconds is activating receptors for peripheral neurons, chemosensory neurons that are only in the nasal passage. That's why they're all formulated as nasal sprays. What then happens is really there's a neurocircuitry projection forward to what's called the olfactory bulb at the base of the brain. That's sort of a relay station. From there, what we see are
relationships where neural circuits project to different areas of the brain depending on what we're trying to accomplish. For anxiety, obviously we're trying to drive activity to the amygdala, the main fear and anxiety center in the brain. For depression, we're trying to achieve an opposite effect. We're trying to stimulate that.
There's autonomic biomarkers that we've seen in the anxiety arena, for example, reduction in blood pressure, reduction in heart rate, reduction in skin conductance that also correlate to with some of the feedback we get at the behavioral end with the SUDS as the endpoint. To be able to not only administer it properly, we've got in PALISADE-3 and PALISADE-4, the investigators are administering the drug unlike in 2. We've increased surveillance remarkably. In PALISADE-1 and 2, you couldn't do an in-person investigator meeting. There were
significant limitations on in-person training. You would see sequence breaks, especially in PALISADE-1 when you were scheduling people to come back one week and the next week on a specific regimen. People were worried about getting COVID or they got COVID.
And again, the masks having to be part of the public speaking challenge, you can imagine how that could have affected things. So what we saw in the early part of PALISADE -2, the study that read out positively. Once the masks came down, once we were able to get into the clinical sites again, refresh training. Our main advisor is Dr. Michael Liebowitz, who's really the godfather of this indication out of Columbia. He interacts with the PIs, which is extremely helpful. And so now not only have we enhanced surveillance with our own owned assets, we don't have as an operating model. It's been important, not just us. I'm sure you've heard others where we've kind of debundled heavy reliance on CROs.
Right.
And having our own ambassadors and our own clinical site managers directly on site has made a tremendous difference in terms of the enriched eligibility assessments, the adherence to the protocol, the ability to intervene early even before a subject is randomized. Because if they don't make it past the first speech, they move into the open label study. If they are sufficiently stressed in the first speech, then they move forward. And that's the randomization body that gets included in the data set. So it's very important to make sure there's no interim chit chat. It's important to make sure people are trained up on the scale. It has a very specific script that you need to follow.
Because that's the one thing we aligned with the agency on early on was that people are afraid of talking to people and that you can, in a clinical setting, you can consistently provoke anxiety with the public speaking challenge.
Right. Right. Makes sense. So going back to the question of P1 versus P2, which is the more accurate depiction of the efficacy of the drug? There's an older study, right? That was the original proof of concept study that was done, I think, at two centers, Columbia and one in Mexico City. Is that right?
One in Maryland.
And one where else?
Maryland.
Maryland. Okay. So can you talk a little bit about that study? What's the history behind that study? Having a neuropsych center in Mexico City in a trial is like atypical. Not saying there's anything wrong with it, just hadn't heard of it before in a trial. So how much weight can we put on that study as a corroborator of P2?
I think a lot. I mean, PALISADE -2, of course, is what we looked to most recently because it's a US placebo-controlled study across 18 or so sites. So that's very important, and we see Palisade one is really the outlier. The response rate was about the same on the treatment side for both studies. It was the placebo rate that we really think got wonky as a result of a lot of the variability that we saw and we've learned about, so having Dr. Liebowitz be the main investigator in that phase two program, we did it two ways. First, we did the controlled setting where here and in other locations we had a public speaking challenge as well as a social interaction challenge.
And both of these are published where people had to do a bit of a meet and greet in the same sort of dynamic two weeks in a row. And because Dr. Liebowitz was involved and his history with this disorder, with a lot of confidence in the phase two and that once we were able to control for a lot of the things, it's always hard moving from three sites up to 15, 18, especially when you have less ability than conventionally is possible to control variability. So what we look at really is three positive studies and one that wasn't. And even in the real world
setting, we had a phase two study where people were told outside the clinical setting, take the drug, expose yourself to stressors, then rate yourself on the SUDS as well as a scale called the Liebowitz Social Anxiety Scale, which Dr.
Liebowitz created. That's more like a movie, whereas the SUDS is sort of a Polaroid, and on both of those cases, what we saw is the people who got the drug first, even when they crossed over to the placebo, we saw a carryover effect. Because what you're trying to do ultimately, it's almost like having a little therapist on your shoulder where, like in cognitive behavioral therapy, it's sort of see you got through that last event, and social anxiety disorder, about 30 million adults in the U.S. are affected by it, and when they're not exposed to
stressors, individuals affected by the disorder, they're asymptomatic, but when they are predictably having to deal with a stressor, it could be any number of things, something like this. It could be going to your neighbors for a barbecue.
It could be going to a ball game, going on a date, sitting in a class. They need an ability to take something out of their pocket or their backpack or their purse and use it on demand and tailor it to fit the way that the disorder affects their life. Many days they'll have multiple different stressors, distinct stressors within a particular day, morning, noon, night. Other days they'll have none, and so what they don't want is a medication in their body that is affecting them, whether or not they're affected by the main disorder. They don't want antidepressants that are generating weight gain or sexual side effects, the types of things that are associated with off-label therapies as well, like benzos. There's a tremendous risk there of addiction and misuse and overuse.
So what we're approaching here is the ability for somebody over time to, with successes in an acute setting, to be able to build confidence and build resilience and engage in the things that typically are costing them significant opportunities in their life. And when we measure the use over time, controlled study or open label, we see that the more people use it, the more confident they get, the more they engage, the less they avoid. And that's exactly what we're trying to achieve. Even in the PALISADE-2 study, one of the endpoints, an exploratory endpoint was asking the patient after the second speech, how do you think you feel? How do you think you did the second speech versus the first? That's called the PGIC.
That patient reported outcome on top of the SUDS as a patient reported outcome was like 2X the benefit of drug over placebo, which is exactly what we're trying to achieve, make people feel more comfortable and more confident engaging in things that they typically have avoided throughout their life.
Yep. Yep. Okay. Makes sense. So maybe let's talk about a couple of other angles here. So as it relates to fasedienol, the drug, the mechanism, you alluded to one of the atypical things about this drug, which is that it's not actually detectable in blood or plasma, right? So how do you actually go about selecting the doses here? And how do you go about satisfying regulators that you accurately selected the doses here?
You work backwards from the clinical effects, but upfront, there's a lot of things that you can do. These neurons, these receptors that are in our nasal cavity are human species-specific. So some of the things that you would typically want to see in a non-clinical setting in an animal model-based, you don't see on the efficacy side. But what we do have, many things that we do out in our labs out in South San Francisco, we will harvest nasal mucosa and we will assess calcium flux, for example. We will also do ePhys studies. Ultimately, you're always looking at the psychometric endpoints at the end of the day, right? SUDS and CGI and PGI. But what we look at early on is we're trying to assess whether it's through FMRI, whether it's through some of the autonomic markers.
But we also do what are called EGNR studies, the electrogram nasal receptors. And these studies assess for us with subjects who come in. We put electrodes in their nose and up here by the base of their brain at the olfactory bulb. And after establishing a baseline, we'll administer a microgram level of the drug candidate. And what we will look for there are depolarization, electrical charges that give us some sense that we're like an EKG. You're reading out activity from the drug. So we do that. We have another set that we focus on the olfactory bulb called EGB studies. So there are ways around it. I'm thinking I'm missing on.
I think you captured it.
So there are ways to really get to confidence level. Of course, at the end of the day, you got to have the behavioral effect.
Of course.
but when you get back to it, and there's an artisanal way that you come up with the candidates in the very beginning, of course, to even figure out what you're going to test, but these are some pretty efficient ways that we're able to know whether we want to put something even on the track, let alone advance it down to deep clinical.
I suppose one other point, Shawn, is through the course of those clinical studies that you mentioned, we tested various doses and we landed on the higher end of those doses for the future studies and for the future label. So kind of because of the safety profile that we have, the ability to go to the higher end of the dose range gives us comfort that that'll be good for the FDA.
Right. Okay. One of the good things about these drugs is these cells are turning over every three weeks, right? And you're also not having direct binding onto the kinds of neurons that have typically been associated with, say, abuse liability, right? So we've got a lot of good things going for us in the beginning because we're relying on that neurocircuitry. And there's a very powerful neurocircuit projection from the OBN. I actually got that from one of the investors today earlier. It's nice to hear it when the community is starting to hear it.
That's interesting.
I heard that fed back to me. That was great.
Yeah. Yeah, yeah, yeah. Okay. Okay. Very good. What else is Vistagen doing to satisfy the other natural regulatory questions here related to redosing both over the long term and also like in the immediate term, right? You have that specific study, right? But I can just imagine a situation where someone is panicking, they take a dose, they do it, they panic, they do it again, right? I mean, these are the natural FDA questions. Where are you guys?
Yeah, I'm glad you said panic because while we're focused on social anxiety disorder, we think the drug has application across a whole range of acute anxiety scenarios, panic being one of them, so you get into a mode where you obviously know what you have to submit for the NDA downstream, and so as I noted earlier, everything that we think we need to have completed next year, if we have a positive PALISADE three or four to support an NDA submission in 2026, has to be started already or will be started before the end of the year. That's a couple of
non-clinical studies that are still there, reprotox. We've got a small human factor study. This is a standard amber vial and a standard actuator, so the drug-device combo, it will be relying on the DMF from each of the two manufacturers of those components.
But we will do the repeat dose study you alluded to, most likely for safety-oriented reasons, not sure, maybe the FDA thinks more might be better. It doesn't really matter. But that repeat dose study will be three arms, small study, drug-drug within 10 minutes, drug-placebo within 10 minutes, and placebo-placebo within 10 minutes. If there is an enhanced effect, then that would certainly be something to be effective in labeling. It won't change the course of what we have been doing in phase 3 with the Palisade studies. But we also don't think there'll be a safety issue. More is typically not an issue either.
Right. Yeah.
Once you occupy these receptors, again, within milliseconds, over-occupancy doesn't really seem to make much difference one way or the other. As long as you kick them into gear early on, you get the downstream effects that we're seeking.
Yep. Do you want to talk about the OLE data you've generated and what have you learned on safety and the presence or lack of tolerance?
Yeah. Well, early on, when we first met, the question was, well, this is a drug going in the nose and Spravato, the drug from J&J, which is a nasal ketamine, had gone out. So people were like, well, isn't it possible that you're going to see abuse potential?
Yeah.
So in addition to saying, look, we have not seen binding to the abuse liability receptors, we also have seen through the course of large open label studies, we had one, about 500 subjects over 30,000 doses anywhere between four and 10 months. And the most prevalent treatment-emergent adverse event was headache at 8.7% and nothing else over 5% except COVID, which wasn't part of it. So what we've continually seen across the whole class, and largely obviously because of the fact we're not dealing with systemic types of risk factors.
We're not seeing liver liabilities, kidney. We're not seeing the kind of off-target liabilities that we see with a lot of the neuropsych drugs. So we've seen a consistently distinguishable safety profile across every other drug that we've ever seen in neuropsych or even outside in neuroendocrine, for example, with the hot flashes.
We think that pattern will hold. We asked the FDA if we had to do a human abuse liability study. The answer at that time was no. All that's happened since then is that large open label study, and in PALISADE-2 , there was no N1, there was no TEA. It was very placebo, nothing over 2% except placebo with paresthesia for one subject. We're not worried really. We don't think the drug will be scheduled. It's amenable very nicely to what we see a lot of, which is telehealth and mental health, not having a drug that's scheduled, especially when we're seeing most of the engagement right now in psychiatry is online. That would be conducive to the type of commercial aspects that we see here. A lot has changed since COVID on the commercial side.
A lot of the reach is very similar to the narrative around GLP-1 drugs where patients and consumers and advocacy groups are doing a lot, and most of that's done digitally.
Yep. Yep. Okay. Makes sense. Anything else to add, or do you want to move on to itruvone?
You're game to go anywhere you want.
Okay. All right. Trying to think if I've exhausted every fasedienol question. So maybe just to tie that up, so timing of data?
Like we've started everything already that's on the two core studies. And so it takes time once you get LPO to do the queries and the like. But I think second half for both, but at the very front end of the second half is where we're aiming for PALISADE-3 and PALISADE-4 back end just because we've staggered the starts of those two.
You guys are well capitalized through that?
Yeah.
Okay. Okay. Yeah. Yeah. Maybe talk a little bit more about your pipeline, other mechanisms you're pursuing.
The other two assets that we would identify right now is lead programs. PH10, that's where we're working very closely with the team at Harvard around the protocol for that. This is for major depressive disorder. Again, the major change here is that it's a non-systemic approach that we see with a safety profile that fits what we're hearing. Patients seem to want rapid onset. They do not want weight gain, and they do not want sexual side effects, right? And sedation, some do, some don't, but most don't. They want to be able to function. And this is a different approach. This is probably twice a week over a six-week period is what we're aiming at. And as a standalone therapy, not adjunctive. So basically what we saw in phase 2A with two different doses, we'll go forward with the 6.4 microgram dose.
It's a little bit higher, still micrograms, and we'll look like we did in phase two at HAM-D 17, so tremendously excited about this program because, again, what we hear, the clarion call, people just need something different. They need to know sooner than later whether they have a potential, and along the way, they don't want to deal with what affects their life incredibly, especially on the weight gain side, so we think we're fitting on that one. We've got a real solid team that we work with in terms of KOLs and internally. The other program that
we're tremendously excited about is the menopausal hot flashes. The market is massive. The alternatives are extremely limited, and there isn't anything that's a non-hormonal approach.
And so what we saw in the phase 2 study, again, was the ability, like with SAD, to tailor to fit that kind of an as-needed option for women that are experiencing hot flashes, menopausal hot flashes, who don't want to go to a hormonal option. They don't want an NK-3 because of potential liver liabilities. And so we're providing what we think is a case where, as with SAD, it's a used when needed, as-needed option, but one without the kinds of liabilities that we think have hindered that market for decades now. So that's an IND enabling program that we
should be able to get. One phase 2 is completed. We want to get back into phase 2 in the U.S. sometime. That IND would be around the middle of next year. The phase 2B program for major depressive disorder is staged. We've got an open IND.
We want to finalize the protocol then by the end of the year, maybe early January, to try to get back into the clinic for that with phase 2B.
Yeah. Okay. Okay. Great.
Any questions?
Yeah. I mean, my only other just broader regulatory question, again, not to harp on the whole pharmacokinetic thing, but you know what? I'm going to harp on it because I'm a biotech person. I always worry about device stuff. Like on the device side of the FDA, how do you validate the reliability of your device if you can't actually measure its output?
Yeah, you establish a lot in the human factor study, no question about that.
Right. But like you can't measure like the exposure is consistent, right? Like does that matter?
We don't think it matters.
Okay. Can you tell us why not?
You're actually going directly on the receptors in the nose, right? And with the plume that has to go right into the mid-septum. So you really actually are over-occupying with the spray plume where you really need to land and penetrate in order to get to the chemosensory neuron receptors. So there's just sort of common sense as well, which is if you're putting it in there and you see the plume and all those things you measure out for sure, you're covering what you need to occupy in order to trigger what we see the rest of the thesis build out on, which is the neurocircuitry cascade that we're putting into place. We're not inhibiting too much. We're not exciting too much. It's sort of this Goldilocks zone. Anything to add on that?
Yeah. I would just say it's a completely different approach than other traditional PK-type things. So it has to be different types of data and kind of the culmination of different types of data?
From a device standpoint, we have all the specs in terms of the plume geometries, the velocity of the plume as it comes out, the droplet size, like all of those things measured and quantified and shown to be consistent over time, the stability of the data showing that over time you still have the same amount of active drug and solution that you're delivering. All
those types of things that are showing that the device is consistently doing what it needs to do. And then as Shawn said, you're blanketing those receptors. And then we have eGNR studies, as Shawn mentioned, that show dose response based on activating those receptors.
So it's kind of the combination of all of those things that get us to confidence that there's not going to be an issue there.
There's no chapter in your PK textbook for the pherines.
No.
We'll be writing a new chapter for sure. But again, it is the combination of those ways to get at exactly what they're trying to achieve by knowing those things.
Yeah. Yep. Okay. All right. Makes sense. Well, best of luck, guys. Appreciate it. Look forward to the data next year.
Appreciate the time.
Bye.