All right, we're going to get started with our next session. I'm Andrew Tsai, Senior Biotech Analyst at Jefferies. Thanks for tuning in, and it's my pleasure to have Shawn Singh, CEO of VistaGen, joining me today. Welcome, Shawn.
Thanks, Andrew. Great to see you again.
Great. So maybe a brief introduction about VistaGen, what you're working on, and what you're trying to achieve, and milestones over the next 6 to 12 months would be very helpful.
Great. Really exciting time for us. We are certainly at an exciting transition point, given that we've got one positive phase III study and an indication that no one's really ever got anything approved for, and no one's ever had a positive success for, as you know, the acute treatment of social anxiety disorder. We are advancing an extremely differentiated pipeline across a broad range of indications. Five assets. Each has achieved at least phase II, and in the one case, phase III positive data in the patient populations where we see significant need from social anxiety disorder through depression, several women's health disorders, cognitive impairment, and all the way down to cancer supportive care.
It's an exciting time where we are advancing what we hope could be a complement to replicate the positive phase III study that we've achieved already in an NDA-enabling program called the PALISADE phase III program.
Wonderful. Help us frame into context the market opportunity for fasedienol for social anxiety. How many patients in the U.S.? Should this be approved? Where would it be used?
The need is phenomenal. As we reported at a recent conference, we've seen an increasing prevalence of social anxiety across all demographics. Pre-COVID was certainly troubling. Post-COVID, more so. This is a disorder where the onset's typically in adolescence. The mean duration's about two decades. This is not something that goes away pretty quickly. What people stress and struggle with are their stressors in their everyday life, where they fear humiliation, embarrassment. As a result, they avoid a lot of things that could enrich their lives, and they don't engage to the level that would be optimal. We see over 30 million people in the U.S., 30 million adults affected by the disorder. If you look at the national health and wellness data that we see, that's about 10% of the population.
That prevalence is pretty similar globally if you bring in Japan, the EU, and other markets. We see, even if a modestly treated population currently treated maybe about 4-5 million people, that alone puts this as a product candidate with a $1 billion-$2 billion peak potential in the U.S. alone. Again, with the type of profile, what people seem to want when we get feedback from practitioners, from patients, is something that will work rapidly, something that does not have abuse liability potential. There is no requirement for this type of drug to have systemic absorption or to even chemically bind to receptors in the brain, especially abuse liability receptors, which we have seen is problematic for a lot of neuropsychiatric drugs over time, as you have seen. That is really the hallmark.
Mechanistically, we see sea change in the way that we're able to address this disorder in a tailored-to-fit manner. People want, with this disorder, something that they can use on demand because it's an episodic indication. It's not an all-day, every day, but there are stressors that are multiple times in certain days and other days none. Not having medications—you heard this probably last night from the Commissioner, the FDA—that having medicines on board in bodies that don't need them at the moment is something we'd really like to avoid.
Very good point. I see you've brought fasedienol or an example of it. What would be some real-world examples where you use this drug?
It's an incredible diversity of stressors. We look at patient diaries from an open-label context, for example. One of the things we're really encouraged in the PALISADE program and the ongoing studies is a really high throughput rate to the open label. That allows us to assess utilization. What we never have seen is any kind of a hockey stick inflection for utilization. That goes to the abuse liability question. We know with this disorder that we're seeing more engagement. Talk therapy is online, not in person, to have a drug that hopefully is ultimately not scheduled. When we went to the FDA, you might recall a couple of years ago, and the question was, do we have to do a human abuse liability study? The answer was no, not at this time.
We've since had tens of thousands of doses, and now all of our 1,100 subjects exposed. Every day you can think of a stressor. We've seen people afraid to eat alone in a food court, to go to a public restroom, go to their neighbors next door for a barbecue, sit in a classroom worried about getting called upon, presenting in a team context in a workplace, going on a date, talking to your boss, going on the job interview. I mean, it is a broad, broad range of stressors, unfortunately, in the day-to-day lives. It really depends on the lifestyle of the person. We see this sometimes in the open label as well, where you see maybe a drop of use on weekends when people are reading a book or going on a hike during the work week or school week.
You see a lot more utilization as it goes through different stressors associated with daily life. Because again, ultimately, what drives this disorder and over such a long duration is the fear of being judged or humiliated or embarrassed when you're with other people. Even that fear sets in when you're not even with other people. That's what's challenging because that brings a large group of people in that simply don't want to use alcohol. They don't want to use benzos. They don't want to use opportunities that are out there today. There really is no good available treatment for the acute treatment of SAD, social anxiety disorder. We would certainly have as our primary goal to be the first company ever to get an approved treatment for the acute treatment of SAD.
Wonderful. Like you said earlier, you succeeded in one study. All you need is one out of two in the upcoming studies. When do those studies read out, to be clear? Secondly, why will those studies look different or similar to the study that succeeded?
I'll take it in reverse order. Our whole goal has been to replicate the historic success we had with the PALISADE II study. Everything that we've done in the PALISADE III and IV studies right now is with the objective of replicating that outcome. For PALISADE III, our guidance is Q4 of this year. For PALISADE IV, it's the first half of next year.
Okay. What are you doing differently this time to ensure success?
You always want to do whatever you can do to control variability, right, when you try to scale across a large number of sites. A few things. There's been a lot more rigor and a lot of additional scrutiny in the pre-screening mode, right? Making sure that subjects that we think have the potential to respond to the drug, better potential than not, to respond to the drug, are the ones that are ultimately randomized. There's a lot of scrutiny and a lot of rigor between lead generation and that visit, one, that first visit. Some stricter criteria associated with comorbid psychiatric disorders, for example, THC levels that a subject might have, lab testing associated with that. The ability to make sure everywhere we can, we're enriching the population to improve the probability of success.
There's no guarantee ever, obviously, as you know. What we have learned, we really have the most experience in a phase III setting with the public speaking challenge design and this endpoint. A lot of subjects now that we have run through this in a lot of sites and a lot of PIs. The ability to execute in an environment right now where the masks are no longer part of the program, we're able to surveil to a greater degree during the course of the study whether people are rigorously following the protocol. Most of the enhancement has been associated with, once that lead is generated from a centralized recruitment campaign, making sure that the right subjects who should be eligible to be randomized in the study are the ones that are making it through Vista II and through Vista I.
Since once it is at VistaGen, the rates we've seen on throughput have been pretty similar to what we saw in PALISADE II.
I see. Is it fair to say that you're placing a lot of confidence in these investigators to make sure the trials do right? Are there checks and balances going on just to make sure they're truly disqualifying patients if they don't qualify for Vista I, Vista II?
Yeah, there's a lot of safety checks and toll gates in the whole process from the top of the funnel all the way through the randomization point. As you know, in the study design, the first speech is intended to ensure that they're sufficiently provoked with the public speaking challenge. The reason we use that design is because you can provoke anxiety consistently with that challenge. It's the same stressor that you're measuring the acute benefit of the drug in that context, right? That's the endpoint we're striving for here, just to make people with only one dose in a treatment context show that we can drive down their symptoms very rapidly. Yeah, the answer is we've got an expanded internal team that surveils not only eligibility, but also rigorous training, rigorous adherence to the protocol. That is intense.
It's all day, every day, and across all sites. Fortunately, we have a lot of sites that have been involved already, so the learning curve was not very steep. The quality, given the aggregate lessons learned through all experiences all the way from phase II till now, really puts us at the leading edge of expertise on how to execute this trial design.
Can you give us a sense of how screen failure rates are trending relative to the prior two studies?
We are definitely seeing, in terms of subject selection, the intention, again, was to ensure that we have a high-quality patient population that gets through Vista I, right? Always emphasizing quality over speed. I think the impact of the enhancements that are associated with that subject selection, specificity and rigor, that's caused there to be fewer subjects through the phase I or to the phase I. Once they're through the phase I, again, like we said, the throughput to the end of the study has been pretty consistent with what we've seen historically.
I see. Any discontinuation rates so far?
If you're talking about once people are from VistaGen through, no, nothing appreciable, nor have we seen that really in any of the studies. Again, it's a four-week study paradigm. What's helpful now, as opposed to prior times when you might have seen out of scope in terms of with the pandemic and other times where you'd see site turnover or you'd see patients coming in possibly broader periods of time than in the rigorous one week, that's just not the case. It hasn't been what we've seen since PALISADE II has been exactly what we saw in phase II and what we're seeing also now in PALISADE III and IV. Having a normalized clinical study environment has been really helpful.
Speaking of the clinical trial design, this was previously blessed by the FDA a few years ago. Given FDA changes recently, have you spoken to the FDA recently to just make sure one more time maybe that they're on board in a sense?
You can rely on the FDA making agreements with you early on. We have been aligned with them on this study design since early 2020. That is important because that is how you have predictable investment in studies and why you want to be able to hit the end based on the beginning you agree to. We are always in an ongoing conversation with the agency across all real aspects, even in the context of NDA prep now, whether it is CMC, non-clinical, clinical. We aligned early on that people with this disorder are afraid of talking to people fundamentally, and that we can, as a study design, consistently provoke anxiety with the public speaking challenge, right? You can apply that across sites. You are not having to assess a broad diversity of stressors as you would maybe say in a real-world study.
Although, as you know, we had positive real-world data in phase II. It just made it, when you think about scaling a study across sites in a phase III context, you want to do what you can do to control variability, always. Having the same stressor as the provocation in a clinical setting with a very rigorous recipe that you give to each site of how to execute it, that's been very helpful. We haven't seen a departure from that at all.
Okay. For your studies to be stat-sig, will they fundamentally be clinically meaningful? Can you describe what kind of change in SUDS would be clinically meaningful?
You can take a look at PALISADE II, right? We're replicating PALISADE II, which we think is not only stat-sig but clinically meaningful. That has really been the objective. You have a situation, again, where unfortunately, there's nothing else out there that, in a benzoepidemic-laden society that we have right now, is problematic. We see tremendous safety benefits again, which separate from the pack. It's not just that you have to achieve efficacy and stat-sig separation on your endpoint. The safety card comes into the mix as well, considerably into the mix. We constantly hear from practitioners and patients, they want something that works quickly, that they can, again, tailor to fit on demand for their lifestyle, that has no abuse liability potential, has no weight gain potential, has no sedation potential and cognitive impairment, no sexual side effects.
We see that up and down the pipeline with this mechanism that in each of these distinct variants that we're advancing, again, hallmarks have been associated with time to onset and then what we've seen in completed studies to date in terms of safety, especially as to weight gain, sedation, sexual side effects.
Right. Efficacy is only one part of the equation here. Okay. So we've been mentioning the successful PALISADE II study. When can we expect a publication on that to maybe help propel awareness of fasedienol within the doctor community?
You mean beyond what you write?
Yes.
Yeah. Later this year, I think, is what we're targeting for that, for the publication. We'll see. Again, the potential when you're running studies too that are similar to what you'll be publishing on, there's some strategic components associated with that. Again, especially with this particular study design,
Yup
there's strategic reasons to do some of the things in terms of the timing.
In the meantime, you're running peripheral studies, maybe one of them, the redosing study. Are there any other studies you need to run at this juncture before you file?
We'd run a small human factor study based on use of this device, pretty similar to what people have done before, that the pre-products that use the same vial and the same actuator. We'd have a small repro tox study. We'll finish up our CARC study, even though the drug doesn't systemically absorb and you can't detect it in plasma. We're still doing check the box. That's basically about it. The small human factor, repro, and finish the CARC.
I see. And so once the data reads out in Q4, fingers crossed, it's positive, when could you file?
We think we could file in the first half of 2026, right? And so we'd go to the FDA for a pre-NDA meeting, clearly show where we are at that point, especially as where we are with respect to safety. We could certainly provide additional safety on the other side of the submission. But that would be the timeframe we first have in 2026.
If unfortunately the first one doesn't read out positively, you're still committed to finishing the PALISADE IV?
Oh, yeah. Sure. Absolutely. It was always a sort of a safety net study, but at the same time, we want the safety bodies from that. Yeah, absolutely, that was, we definitely will.
To file in first half 2026, do you need enough, do you have enough one-year open label follow-up data to help meet ICH guidelines, if that's even relevant?
Yeah, we should by that time have what we need on the 100 for the 12 months, 300 for the six months, not quite sure. Again, we are always allowed to supplement with safety from all the other studies as well as from PALISADE III. We already have a few notches on our belt already on the 12-month, and same thing with the six-month, a decent population moving forward. By the time we've fully randomized 236 in PALISADE III, and not even if it's the full complement in PALISADE IV by that time, there's a really substantial safety database already created and in process. That'll just keep building strength on strength.
I see. You're working on a redosing study. What's the purpose of that? Could that data set read out before PALISADE III?
Not before PALISADE III. The purpose of that study, which we started just at the beginning of this year, it's a small study, exploratory study. FDA wanted really primarily to focus on safety, right? People's human nature saying, well, if one's good, maybe two's better. Within a short period of time, the way that study is designed in the repeat dose-oriented arm, it's two doses within 10 minutes. We know fasedienol activates the chemosensory neurons in about 25 milliseconds. That's with a 3.2 microgram dose. The reason is we're dropping it directly on the receptors to the neurons that we want to activate. It's about 300 milliseconds to get to the olfactory bulb neurons. Activating further, activating more receptors in the nose to achieve what we know we've already achieved with one likely may not change the outcome from an efficacy perspective.
At the end of the day, safety-wise, there's no concern either.
I see. I see. It'd be interesting to see because I think there's three arms: drug, drug plus drug, drug plus placebo, or maybe vice versa.
Placebo, placebo, drug, placebo, drug, drug.
Right.
Three arms, 20 each.
Basically, like you said, it's more of a safety check-the-box kind of thing. Drug plus drug, your point is we might not see an improved benefit on.
Oh, no. I mean, it's a small study. It's really designed more from the safety perspective. It could inform labeling if that's better, that there's not a worry to practitioners if people do do that. Again, it's a pretty small study with 20 subjects per arm. We're not really powered for the kind of outcome we're looking to see in the registrational trials.
Right. And that data set would come after PALISADE III, but still this year, or could it be early 2026?
It'd be right around with PALISADE IV in the first half of 2026.
Okay. Okay. Very clear. Years ago, you did partner with AFAMED, a Chinese partner, to develop this in China. How has that relationship been? There is a plan to do a global study. Where are we there?
I think it's mostly in a wait-and-see mode from their perspective to see how we roll out the PALISADE program so that they can leverage the U.S. NDA with the PMDA. At this point, they're sort of in that wait-and-see mode, which is fine for us. We think the strength of our NDA is going to be leverageable in a lot of different markets, not just China. We, as our strategy, is the ex-U.S. partner as well in other markets. We'll see how that goes.
What is your current thinking about commercialization? How many sales reps do you need once this is approved to maximize the sales growth?
Yeah, it's really interesting the way that's developed. I think the answer is that's still in flux, right? Because what we're seeing, especially, and we're not even trying with the centralized campaigns, is we see the interest from folks hitting the website. It's a substantial number without even targeting patients as you would in the digital ramp in a commercial mode. There's a unique benefit there, especially because what we see is the interaction with the practitioners is online. Practitioners don't really want these days psychiatrists to see subjects in person. They don't. Also, the patients with SAD typically won't want to see. We've heard from several academic centers that 10 out of their last 10 have been all online, and compliance is increasing in the follow-up visits.
The digital impact, especially across the socials and things that we've seen as we've been in this recruitment campaign for PALISADE III and IV, in the environment we're in right now, we see a lot of the narrative, sort of like with the GLP-1 drugs, that there's a conversation out there from consumers and influencers about anxiety similar to about weight. Pre-COVID, post-COVID, we've substantially reduced the headcount that we think is needed from a commercialization perspective, given the leverage now that exists from the digital side. It's still not going to be zero, but somewhere in a couple hundred level with the sales reps, leadership, 50 or so. We do that. That builds also on a kind of a toll-gated basis, right?
A little bit now, more on the other side of the next pivotal study to complement PALISADE II as we move to a launch environment where it's also the case too. Just think about the commercials, right? This is a case where the direct-to-consumer advertising, it's a completely different commercial where you're not spending 30 seconds talking about all of the worrisome side effects, safety concerns, risk of stroke, coma, all the things that take a lot of that buy-up. The cost and the impact of what we're able to deliver based on this target product profile, there's a lot of economies there. It is very doable, especially in social anxiety disorders. We're maintaining that optionality, of course, and we'll see how things go.
Right. Ultimately, your sales reps would be targeting not only psychiatrists, but PCPs moving all the way to the front ends.
Yeah. The specialists as well as primary care physicians, nurse practitioners. There's folks all in the ecosystem that are very motivated to see something different. We hear this from PIs at our sites in the study. We hear this from people on the open label. There's a dramatic interest in having a paradigm shift in the kind of medication support to complement talk therapy in today's world, right, with the number of stressors and the way that people are affected by them and how they want to be able to tailor to fit support.
With this drug, what we see, and we've seen in one of the open label studies that we commented on, we think the more people use it, the more success they have in an acute setting, the more frequently that success is repeated, confidence is built, resilience is built, avoidance goes down, engagement goes up, things that really are enriching lives in kind of game-changing ways that the patients and practitioners and advocacy groups have not seen, and are not seeing other than what we think we're bringing to the table in SAD for the acute treatment of SAD.
I see. I see. You mentioned going back in one of the peripheral studies, a human factor study. What is that design like?
Pretty simple. Just to make sure people know how to take it out of the package, unscrew it, put it together, have it, and that they know how to use it. It is pretty simple, straightforward. Not a lot of risk factor there. A couple dozen subjects.
Got it. Speaking of disruptive therapies like what fasedienol could become, totally understood, it could differentiate over current treatments. There are other drugs in the pipeline. When we think about competition, maybe even psychedelics come into play for social anxiety. What are your thoughts on competition and why that's irrelevant to fasedienol?
Competition is not irrelevant in any way. But as you and I have talked about for a long time, I mean, our perspective as a company has been we're rooting for everybody. There is no one-size-fits-all. There's plenty of room. Perhaps the impact of psychedelics may be more so in depression than in the acute treatment of anxiety disorders, especially given where we see differentiation, obviously, is the fact that we don't require systemic absorption or we don't require chemical activation of receptors in the brain, right? We're not seeing psychotomimetic side effects. We're not seeing any of those things that typically have been associated with a lot of neuropsych drugs. From a competitive standpoint, the target product profile we've got for fasedienol is very differentiated in all ways. The numbers are enormous, right?
Again, even if we're talking about a 10% penetration rate on the currently treated population, let alone the folks who will come into play when they say, "Look, I know I didn't want to take alcohol. I know I didn't want to engage in marijuana smoking. I know I didn't want to take a benzo. Now this, and I only have SAD.
Why do I need to take an antidepressant for my SAD?" There are reasons to believe, a lot of reasons, especially from what we are seeing at the top of the funnel in recruitment, to believe that the patient universe is expanding, as awareness is expanding, and what is needed is an approved acute treatment that does not cause them to say, "Wait a second, I am not sure of the cost-benefit here with the risk of abuse liability or weight gain or sexual side effects or whatever it is or all of those that cause compliance to really be problematic with existing meds." Even with existing meds, if they are taken as they should be, you have a decent opportunity to complement talk therapy. Obviously, when they are not taking them, it is not getting better, especially if they are taking something worse that causes another problem like alcohol.
Right, right. Today we talked a lot about, or all about fasedienol, but you do have a fasedienol portfolio. Is it safe to assume you're putting all your resources to ensuring phase III success, or are you making progress with other fasedienols as well?
We certainly optimize capital allocation to fasedienol and the PALISADE program. No question about that. That said, we're making considerable progress up and down the pipeline. We now, as you know, have five assets in clinical stage with positive phase IIa or later data. That's a tremendous pipeline with a broad diversity of potential indications. We're staging the PH80 program for U.S. IND in the fourth quarter. Hopefully, with that, we can progress forward with vasomotor symptoms, hot flashes. There is a tremendous interest and need for a new drug for dysmenorrhea, for PMDD in the women's health arena. We've got the depression program ready to go, capital-enabled. We would move that forward. A lot of excitement up and down, even with some of the earlier stage assets that we haven't talked much about yet.
Great. I think that's all the time we had. Thanks for the update and best of luck in your phase III data.
Thank you. Appreciate the interest. Thanks for having me.