Excellent. Thanks, everyone, for listening in today. It's my pleasure to be moderating this panel with Shawn Singh, CEO of Vistagen Therapeutics, a company that has a big phase III readout this year for their lead product in social anxiety disorder. I'm going to ask Shawn to give a quick update and overview of the company, and then we will do Q&A. Shawn, take it away, and thank you for.
You bet. Thanks a lot, Paul. Always great to join you. I know it's just a bit of a speed date, so we certainly encourage folks to talk to us afterwards. Obviously, I'll be making forward-looking statements today to assess our 1934 Act filings as well. We're laser-focused on developing and commercializing an entirely new class of fast-acting, non-systemic intranasal drug candidates that we call pherines. That whole class, up and down multiple therapeutic indications, each with fairly stale standards of care, we're moving into a zone where we can harness the power of nose-to-brain neurocircuitry in ways that we just haven't seen before. Each of these assets that we are advancing has had at least one phase II positive study in the case of the lead program that we're in, a registration-directed program for the acute treatment of social anxiety disorder.
It's also had a positive phase III study. As you noted, it's an exciting year for us. We've got a couple of phase III readouts by the end of the year in the social anxiety program. We think we're able to move into a zone, if those are successful, where the first-ever approved acute treatment is on the horizon, possibly.
Yeah. Yep. Okay. Great. You know, I think when I talk to investors about your story, Shawn, it feels like the crux of the debate here is, you know, which trial should we index to? Should we index to PALISADE-2, or should we index to PALISADE-1? I'll leave that as an open-ended question, and would love your perspective.
The world's different, obviously, now than it was when we saw the effects of the Black Swan or the pandemic on a lot of work in the early days when PALISADE-1 was being executed mostly. Things changed, and PALISADE-2 is a reflection of that when the world changed and the masks came down, and in-site surveillance was a lot more possible, less turnover at sites with staff, CRO staff turnover. A lot of issues that others were affected by, especially in neuropsych studies. We see the world now a lot more like PALISADE-2 back end and phase II. We see PALISADE-1 more as an outlier in a lot of ways that impacted the placebo side of the ledger.
Things that we're doing now in PALISADE-3 and 4 are enhancements to the programs that allow execution just really in a much different way than even at the back end of PALISADE-2. It was a big deal when the masks came down. PALISADE-3 and 4 have no masks involved, but we're also able to train in person, surveil in person with our own team at sites, less reliance on CROs and CRAs from CROs. Some things that are, again, more like phase II with the IP being administered by the PI directly, like in phase II. We've got the audio recordings of the speeches to be able to make sure that there's rigorous adherence to the protocol, which is key.
The fact that in PALISADE-3 and 4, this isn't the first lap with this protocol and this endpoint in a phase III setting for the public speaking challenge. All those things, the confluence of things, being able to have a different degree of scrutiny upfront, pre-screening even is a whole different ballgame. We lean to the latter, of course, and that's what we're aiming to replicate, PALISADE-2 with 3 or 4.
Yeah. Do you want to give some color to folks on just the backstory around this public speaking design? You know, why was this leveraged? How standardized is it? You know, if you guys succeed and file for approval, it'll be new from a regulatory perspective. You know, what's your confidence that the agency is fully on board?
We aligned with the agency early on about what affects, again, this population. We're aiming, again, at the acute treatment of SAD, not the overall treatment like the long-onset antidepressants that were approved a couple of decades ago. That was a scale, the Liebowitz Social Anxiety Scale. It's more really a movie of their experience rather than a scale and a design that can assess minute-to-minute changes. With the acute treatment indication in mind, aligning with the agency that the people who suffer from this disorder, and it's a chronic disorder with a mean duration of about 20 years for the 30 million people that are affected by this in the adult population, that you can they fear talking to people, right? This is a fear of judgment, humiliation, embarrassment in many everyday social and performance situations.
Secondly, that you can provoke anxiety consistently across sites with the public speaking challenge. That means there's one trigger and one stressor that's being assessed across the participants in the study and across the sites. With that in mind, what's the appropriate endpoint? We aligned that the appropriate endpoint for measuring minute-to-minute benefit potential of a drug is the SUDS, the Subjective Units of Distress Scale . Each minute during the public speaking challenge, the subject reports how they feel on that scale, 0 to 100, with a 75 being more than a little uncomfortable each minute.
That's helpful not only for us to make sure we can enrich the population with the appropriate subjects that can be affected by the disorder in a beneficial way, but it really provides a standardized paradigm, really, for assessing a provocation that's commonly experienced by folks.
Yeah. As it relates to the FDA, you know, any thoughts there on the agency's comfort with it would be helpful. I guess maybe even just bridging on that, right? Like, how well do we understand what a clinically significant effect size is on this scale, and how might that come into also the regulatory prospects of fasedienol if you do hit a P-value?
Yeah. There are standard assumptions, I think, around effect size, you know, somewhere around a 0.4 in neuropsych studies has been pretty commonly embraced, as you've seen.
You mean like you mean a Cohen's D of 0.4?
Cohen's D of 0.4, yeah. You know, the key for us, again, from very early on, was making sure that we could align with the agency on the study design. Others behind us also have had input from the agency about using the SUDS in the public speaking challenge for acute treatment. Those were some oral systemic drugs, a couple of different companies you probably know about. You know, we've seen it. We've seen guidance from the agency, not just to us, but to other sponsors, about the appropriateness of the study design and the endpoint associated with that design. Of course, the Liebowitz Scale, which is really the only other scale to anchor approvals, those were for totally different types of drugs and a totally different indication for the long-onset, you know, no old-school antidepressants going to give the acute treatment benefit.
Yeah. Okay. Makes sense. From a regulatory perspective, how important is it to also show maintenance of benefit? Considering that this is an acute treatment, you also, I think, would like people to be able to use it as much as they would like. How do you satisfy the agency on showing that, you know, repeat dosing over time still works, repeat dosing over time is safe? What's going on there at Vistagen?
We did align with the agency on a repeat dose study, mostly for safety-oriented reasons and sort of a common sense thought, perhaps, that people might think more is better, and to try to assess whether or not using a couple of doses within a short period of time within a 10-minute window has any potential effect on safety. If it is the case that the dosing in the redose scenario, it may inform labeling. It may be a guide to the fact that a second dose administered within 10 minutes is safe, as we anticipate it will be based on everything we've seen. Again, the acute treatment dynamic, though, and the acute treatment indication is grounded in the public speaking challenge and the SUDS. Full stop.
We have wonderfully seen in the open label study that we already talked about, about 30,000 doses in about 500 patients, 481 patients, that people using the LSAS, again, it's open label, so it's a little different scenario than placebo-controlled, but we think people do get better the more they use it. The confidence that builds from knocking down acutely the symptoms that are associated with them being judged or humiliated, embarrassed, and you get that over and over again. The Liebowitz Scale can capture that. We had seen that in the placebo-controlled crossover where there was stat-sig on reduction in avoidance. The Liebowitz Scale captures whether people are engaging in their stressors more or less and whether their fear and anxiety levels are decreasing or sustaining.
I think what we like out of this is especially the PGIC, which is a secondary endpoint in PALISADE-3 and PALISADE-4, where the patients are saying how they thought they did second speech after first, combined with the CGI, which is the clinicians also assessing whether they thought the subjects were less stressed, less anxious, second speech versus first. This is in a double-blind setting, so nobody knows who's on what. What we saw from PALISADE-2, contextualizing even the group-level change on the SUDS, you get to a very clinically meaningful conclusion for this particular disorder. That's done with one dose in a highly provocative challenge, so.
Right. Right. Okay. Very good. I think the other questions you and I have talked about, Shawn, relate, again, on the regulatory side, assuming that you are successful with one of these two studies. The two, let's ask the most important one first, and that's really, you know, let's say, look, anxiety is really hard, right? I think good drugs and anxiety can fail in half their clinical trials. So, let's say you split the difference in PALISADE-3 and PALISADE-4. Again, do you feel like you have a viable package, and do you feel comfortable that PALISADE-2, in the context of stopping enrollment early, would count as a pivotal trial?
The answer is yes on both of those. Look, we were able to accomplish with PALISADE-2 in probably a more statistically challenging scenario than what's currently in play for three and four, stat-sig and a clinically meaningful difference on the SUDS with a safety profile that's remarkably distinct from any anxiolytic that we've ever seen. To guide through our advisors, former FDA folks, and counsel, and everybody that we look to for guidance, one of the two has to hit to complement it. We're not yet in this disorder where it's the case where one would probably carry the day.
Part of the reason we have the redundancy built in with three and four is to be able to capture in the open label extensions some additional exposures that top off to the ICH guidelines at 1,500 total exposures and 100 at 12 months, 300 at 6 months. Yeah, we believe that if PALISADE-3 or 4, ideally, we're driving for both, are positive studies that they complement what we're able to deliver on PALISADE-2. Assuming we hit the safety database numbers, and even I think there's an advocacy argument, even if we're not quite at the full complement of the guidance given what we've seen so far. Remember, we went to the agency a while back and asked if we had to do a human abuse liability study based on everything that we tendered.
The answer to that was no at this time, and nothing since has driven that, in our opinion, has driven it off that initial assessment from the agency. It is just the typical remaining components. We have a couple of non-clinical studies that are to roll, the CARC and the reprotox, and then the Reg batches, which are already on their way.
Yeah. Yep. Okay. Makes sense, Shawn. The other regulatory question here that I bugged you guys about a lot when I was first doing work on Vistagen just goes back to this question of dose selection, right? The FDA, I think, wanted you guys to do this other sort of repeat dose study. And the beauty of fasedienol, right, is that the systemic exposure is almost nonexistent. The side effect profile looks very benign. The challenge that that might raise, right, is how do you actually know you're in the efficacious dose range? Can you actually elucidate a biological effect? You can't look at receptor occupancy. I guess from just even a repeat exposure perspective, you can't detect the drug. Like, how do you validate the device is behaving reliably and as planned?
What are you guys doing to prepare to tackle all of those inevitable questions from a regulatory perspective?
A lot of things, as you can imagine. It's busy. I mean, remember, this fasedienol offers a completely new MOA that's not really amenable to typical bioavailability data requirements, right? Unlike the typical CNS products, fasedienol is acting as an agonist on receptors directly. It doesn't follow the typical pathway to absorption and circulation and receptor activation. You know, our work has not we haven't been able to detect, you know, this drug systemically, even at very low levels of detection. You know it's metabolized in the nose. We developed an FDA-agreed-on assay that showed it's not absorbed and can't be detected in plasma at, you know, one nanogram per mL. It's not detectable in the brain in our C14 radio-labeled studies.
We've got to the point where we're also using a metered- dose spray device that's been already certified to ensure consistent spray delivery. Provided that the device is inserted properly in the nasal passage in the direction of the septum, you know, the spray plume predictably contacts the nasal receptors. We target all these variants the same way. As to dose, again, we arrived at the dose through a series of informative studies that include, right from the beginning, tissue culture studies with human nasal cells that show cellular response to the drug by imaging, increased calcium channel signaling. We then moved to these, we've talked about these electrogram of nasal receptors, these EGNR studies that we do in healthy volunteers that generate dose response curves that show variable receptor responses at increasing doses.
The EGNR has been a really important tool because your typical, you know, many of the chapters in your typical PK textbook, they just do not apply in this with this platform of drugs. Previous clinical studies also informed. Some of the early studies, the phase II studies, the PALISADE-2 study even with 1.6 and 3.2 micrograms that induced efficacy better than placebo. It is kind of a little bit of an end-around way compared to your conventional small molecule that is systemically absorbed and has to hit directly on receptors in the brain. A key piece of this puzzle is that there is no direct chemical activity on neurons in the brain, including the abuse liability receptor. That is the case for all these, the variants up and down the pipeline.
Yeah. Yep. Okay. All right. Maybe let's take a step back and get out of the weeds and more just on the practical element of timelines. Where are you with PALISADE-3 and 4? What's the updated timeline on top line? And what can you say about where you are with enrollment?
Yeah. We guide to we're guiding to both of these studies reading out this year, and we'll stick to that. We will certainly announce when we get to the last patient out, meaning the last patient that's randomized in each of the studies. Typically, there's one more visit after that, which is a safety assessment. Only the subjects who are randomized get included in the dataset, as we've discussed. We'll guide on that. You know, we're comfortable with our projections and our guidance. The fact that you've got a lot more efficiencies built into what we're able to do on the execution side, it allows really the right amount of time to make sure we're focused on quality enrollment, which is key with this disorder and any neuropsych disorder, and the fact that we have a couple of enrichment gates that are very important.
The audio taping of each of the speech has been a very significant factor in making sure we get the adherence to the protocol that is necessary for the study to be executed efficiently. Having our own people that we rely on, I have a lot of confidence in our own team to be able to be in sites and dealing directly with those that have to execute the study at the sites.
Yeah. Okay. Great. We look forward to that. Maybe to wrap things up, do you want to look, I think it goes without saying, right, that anxiety is a huge market. Maybe the only sort of nuanced commercial questions here are it's an acute treatment that someone might use chronically. What does that mean for how you might think about pricing something like this? You know, I guess, are there any good analogs for a drug like this in psychiatry?
In psychiatry, interesting. I mean, there's certainly no analog for the acute treatment of SAD. And in psychiatry and anxiety, I mean, you know the other players. Just watch an episode of White Lotus, you'll get a sense of the impact of the benzos. But the answer is, you know, we have to really understand the fact that the market has changed. When you talk to psychiatrists just down the street from you there at Massachusetts General Hospital, you know, most of the interactions right now, if not all of them, is online with that group. And so, the ability for the marriage of telehealth and mental health to be as tight as it is and sustain as tight as it is is really important, especially if we have a drug that we would not expect to be scheduled based on everything so far.
The ability now for these engagements to be online and with recurring scripts that could come online, not like trying to get Ativan or, you know, another benzo. It's a key piece of the overall make sure the consumer helps us and at the same time making sure we educate the market, the practitioners about it. Keeping it under prior authorization annually, we see maybe about six files a year. It's not an all-day, every-day type of disorder. It's very episodic. Weekends, you see a decline in use in the open label. Depends on the life of the person, whether what their job is, if they're in school, socially what they do as to the use during the course of the week.
Tracking utilization and tracking the kinds of things that drive your commercial assumptions, I think, especially some of the work that we've done with Payors, there's no step added expected because there's no approval for an acute treatment. It's not like we got to step over old-school antidepressants. It's informed us quite a bit on how we can put this in a zone where we kind of strike the right balance between pretty heavy consumer-driven demand based on the way we can access people digitally as well as the concerns or possible concerns of the Payors.
Yeah. Okay. And then cash runway, Shawn?
Runway, we had $88 million at the in our last Q we announced at the end of December. That runs us through Q1 of 2026.
Okay.
If either of these is a positive study or ideally both, that first half of 2026 will be the target to drop down the NDA.
Okay. Okay. Great. We covered a lot. Thank you very much for taking the time and excellent for listening. Yeah, best of luck. We'll talk soon.
All right. Thanks again, Paul. Appreciate it.
All right. Thank you.