Right. Hey everyone, my name is Julian Harrison. I'm an associate on Paul's team, and I'll be moderating the discussion today for Vistagen Therapeutics. I'm joined today by CEO Shawn Singh and COO Josh Prince. Thank you both for joining the discussion today. We appreciate it.
Hey Julian, our pleasure. Great to see you.
Great. So just to get started, it would be awesome, Shawn, if maybe you could just provide a brief overview of Vistagen, just hitting on your key lead program, fasedienol, that you're developing in social anxiety disorder, as well as any maybe quick points on the pipeline and the status of your other programs too.
Sure, great. Well, appreciate the chance to talk to everybody today. We're pioneering an entirely new class of medicines called pherines, and the neuroscience underlying these drug candidates, it's really fascinating, the ability to essentially use the nose as a portal to be able to achieve behavioral and physiological effects without going through the body and without having to even get into and on top of neurons in the brain. So the pipeline consists, right now, of five pherines as well as a sixth asset that is an oral prodrug of an NMDA receptor antagonist, the glycine site.
But the main focus of the company is on our lead program, which we've recently been able to accomplish what we don't think anybody else has ever done, which is to have a positive phase III study in an anxiety program, with a drug that doesn't have to go through your whole body or even into your brain to achieve those benefits. So fasedienol is the lead asset for the acute treatment of anxiety in adults with social anxiety disorder, which is an indication that affects about 10% of the country, maybe a little bit more. The second program, and that's, again, that's in phase III development with one successful phase III study under our belts, and we're heading into two additional phase III studies to be initiated this year.
Second asset, itruvone, is also on the other side of a positive phase II study for the treatment as a monotherapy, for major depressive disorder. Third, PH80, in the women's health arena, two really interesting indications, positive studies in phase II for vasomotor symptoms or hot flashes associated with menopause and PMDD, or premenstrual dysphoric disorder. Two other assets, we should say a little bit more about them later in the year, for hopefully improvement of psychomotor or cognitive impairment, reaction time, and then another for enhancement of appetite in wasting syndrome or cachexia. So again, these pherines activate neural circuitry that is in the nasal passages, in the nasal mucosa of the peripheral cells that then broadcast forward to the olfactory bulb neurons, and then ultimately affect different regions of the brain associated with these indications that we've talked about.
Excellent. Yeah, it's definitely a super unique mechanism and pipeline as a whole. We'll definitely be spending probably the majority of our time talking about fasedienol today, but definitely wanna ask some more questions about the other programs as well. I guess just on fasedienol, definitely an interesting clinical development story. Can you just walk through it and highlight, you know, why you're confident in fasedienol's anxiolytic properties as you begin to initiate these phase III studies this year?
Well, certainly it helps when you have a positive phase III study under your belt, and that's on top of several positive phase II studies. You know, this is a drug class that's entirely new. The history after we acquired this class and then we acquired the company that had run the phase II studies, now wholly-owned subsidiary Pherin Pharmaceuticals. So back in about 2018, we started on the path to develop this lead asset as an acute treatment. There's no FDA-approved acute treatment for adults that are affected by social anxiety disorder, so it's a wide open lane. And we aligned with the FDA on the study design for an acute treatment, and that was the public speaking challenge. We also aligned on the endpoint back in 2020. And then we began down a path where we've initiated phase III studies.
First one was negative, and likely pandemic-impacted variability was a key factor there. We can probably unpack that later today. Then the second one was positive. So, with one phase III completed, the pathway now forward is to initiate additional phase III studies to complement that so that ultimately we get to a potential NDA submission at the front end of 2026. So the goals this year are to initiate all the potential NDA-enabling studies necessary to read out next year to support that NDA submission.
Excellent. Yeah, totally makes sense. And, you know, as you pointed out, definitely some mixed phase III data with respect to your past studies and PALISADE-1 and PALISADE-2. I guess with respect to PALISADE-1, that failed, what were some of the key driving factors that you believe behind that failure? I know you mentioned, you know, certainly impacted by COVID. Any additional color there would be great, and any details as to why you, you know, you're more confident moving forward now, as you initiate this program this year.
Yeah, sure. Josh will unpack some of the enhancements that we've made to even PALISADE-2 based on a lot of lessons learned, and also just the fact that we're in a clinical development environment now, which is a lot more what we're all used to. We've been in this industry for several decades, and a lot more like what we saw in the timeframe when PALISADE-2, the vast majority of the subjects in PALISADE-2 were randomized versus PALISADE-1.
You know, when the fasedienol MOA and the pherine MOA entirely across the entire pipeline, while it's the same kind of lock-and-key approach with the nasal chemosensory neurons that we activate within milliseconds of these pherines that then project forward to the olfactory bulb and then different regions of the brain, it's got groundbreaking potential to be the first approved acute treatment, but at the same time, a lot of the clinical research community, especially in phase III development, hadn't been familiar with the study design associated with the public speaking challenge. We hadn't seen ever a phase III study using the public speaking challenge or using the SUDS as the primary outcome measure to assess efficacy in acute treatment.
The Leibowitz Social Anxiety Scale was used for the three antidepressants, those are the only three drugs approved, for social anxiety disorder, but over a long period of time, over a 12-week period. So that's a scale that's not relevant to the acute treatment dynamic that we're approaching here. And again, back to the pandemic, I mean, a lot of the things we all take advantage, and just sort of assume are part of clinical development, the normal course of clinical development, just weren't as possible back then during the black swan of the pandemic. At least during the acute phase. And most of the PALISADE-1 was conducted in the acute phase. And so things like shelter in place and mask wearing, a much higher level of anxiety among the patients based on psychosocial stressors that we've seen from the folks in PALISADE-1 versus PALISADE-2.
We saw a lot of site and CRO turnover, things that were associated with attrition rates during the pandemic. Mask wearing, of course, was a huge piece of the puzzle that wasn't as impacted in 2022 when most of PALISADE-2 was conducted. So things like that that not only were even in a normal course of events, it would have been a challenge to control variability given the newness of the study design and the endpoint. Add on to that, the pandemic effect on the ecosystem needed to execute, having in-person investigator meetings weren't possible, on-site training wasn't as frequent, surveillance was a lot more impacted, out-of-window visits, things that you really wanna control variability as much as possible, obviously, when you're scaling up. And the acute phase of the pandemic sort of affected that pretty specifically.
A lot of the things that we see going into PALISADE-3 and 4 building on PALISADE-2, are associated with ways to enhance not only the eligibility upfront, making sure there's a rigorous assessment before someone even signs an ICF, but also throughout the course of the study to ensure rigorous adherence to the protocol. Josh, maybe you could just unpack some of the enhancements we've built into PALISADE-3 and 4 on top of two, that we've run by the agency.
Sure, yeah, definitely. Thanks, Shawn. I think it's important to just remind everybody too that the core, the key elements of PALISADE - and PALISADE-2 are identical for PALISADE-3 and PALISADE-4, right, in terms of four visits, study design, two public speaking challenges, randomization at the second. And it's really those tweaks that we're making to ensure that we have the right subjects, and that we're reducing variability across the study that are the key changes for PALISADE-3 and 4. So, you know, a key one, at the outset is just implementing some new eligibility review processes to make sure that subjects are appropriate for the study.
So, additional levels of screening through both pre-screening questionnaires and through checks against national database to make sure that we're not getting professional subjects, some of the some things like that we're putting in place. But really, most importantly, is between the first visit where they're screened and the second visit where they do the first public speaking challenge: having a third-party eligibility review. Again, just making sure that every inclusion and exclusion criteria is perfectly met so we get the right subjects in the study. Another key thing that we're putting in place that we're really excited about is we've actually implemented a new model of oversight.
So, you know, not just relying on the CRO for everything, but really working as a partner with the CRO with our own site managers who are site-facing, will be at sites, you know, in conjunction with the CRO site monitors, just making sure that we really have a pulse for what's happening at sites. So, you know, that, like, that was one of the key things through the pandemic, not being able to do that, just really excited about having that visibility into sites and the ability to kind of quickly correct, to add training, to answer questions, you know, all of those things. Along that line, you know, having an in-person investigator meeting, same thing, right?
I feel like you're starting four steps ahead of where we were able to start with PALISADE-1 and PALISADE-2 because you have those in-person discussions, answering of questions, you know, all those things, which is great to get the study started.
Excellent.
And then.
Super, super help. I'll go, sorry, go ahead.
No, I was just gonna say the last thing, really, really important is just the audio recording of those public speaking challenges to make sure that we're on top of, again, consistency across, you know, all of the sites, and making sure that things are being run appropriately.
Excellent. That's super helpful. And I guess just to quickly follow up and clarify on the public speaking challenge design, I guess for folks that aren't familiar, you know, it definitely sounds, you know, it's a little bit of a unique design for anxiety. And as you described, you touched upon briefly, Shawn, you know, this hasn't really been used, you know, previously, and there's been like different endpoints. So I guess can you just talk about how, you know, you landed on this study design, and whether there's precedent and then, you know, how you landed on like the SUDS, for example, over the LSAS, which is, you know, another established anxiety endpoint?
Sure. Just one final thing on what Josh had. Clinical measures, sorry. There's no masks involved in PALISADE-3 and PALISADE-4. So, that was a big factor, we think, in the conduct of one and two that is simply not part of the process. We landed back in 2020, we aligned with the FDA on a couple of things related to the development of this program in phase III. And one is that people with social anxiety disorder, remember what this is, is a pronounced fear and anxiety about being judged or humiliated or embarrassed in what most people consider common, everyday social and performance situations. And so what we aligned with is that people who have disorder are afraid of talking to people. And they're anxious about that.
That the other thing is we can, while there's a remarkably diverse set of triggers that are associated with people who are affected by this disorder, like you can imagine, the different stressors, the public speaking challenge is a design or is a way to provoke anxiety in a clinical setting in a consistent way across sites. So the public speaking challenge for an acute treatment was landed on as a long-used study design, not one that supports an approval, because there just has never been controlled studies in phase III for an acute treatment opportunity. A lot of that's because the MOAs of the historical drugs in this neuropsych space. So because we could then implement the same challenge across sites, using an endpoint that's associated with that design was the next question.
The Subjective Units of Distress Scale is really the only way of assessing efficacy in an acute setting, at least in our opinion. In the context of this public speaking challenge, it can also be used in a social interaction challenge. In phase II, we had highly static data in a social interaction where people had a bit of a meet and greet. But we wanted and the FDA agreed that it was best to just have the one challenge, so there was no sequence effect, and that we would implement that consistently across the various sites in the study. The Leibowitz scale is the Leibowitz Social Anxiety Scale, or the LSAS. Historically, was used to approve back in the late 1990s, and the latest was 2003, so over 20 years ago, the three antidepressants that are approved for the overall treatment of social anxiety disorder.
So think about the LSAS, which you're assessing there is reduction in fear and anxiety and hopefully reduction in avoidance or increase in engagement in stressful situations through the course of that 24-question endpoint. But it's more like a movie of experience over time. Fortunately, we have LSAS data that gives us confidence in placebo-controlled studies and in our open label that shows when this drug's used acutely, as we believe it will be used if we can get it approved, but used also over time, people build confidence with those acute wins. Every time they knock down their stress and their stressor in an acute setting, they build confidence, they build resilience, they build the ability to enhance or increase engagement in the stressors that bother them.
But think of the LSAS as a movie and think of the SUDS more as a, a Polaroid, a snapshot of a five-minute window because for those that haven't seen much on the design, it's a four-visit study design. First is associated with screening for eligibility. Second visit, subjects are single-blinded to a placebo. And 15 minutes later, they're told they have three minutes to get ready for a five-minute speech to a group of strangers. And each minute during that speech, they're giving the subject or the rater a score. So a patient-reported outcome is a very important part of this process. The, it's not a subjective assessment by the rater. They're simply recording a score on a scale that's 0- 100, with say 75 meaning more than a little uncomfortable at that point in time.
If someone has a 75 at least one minute in PALISADE-2, we'll move that to two times in PALISADE-3 and PALISADE-4. Then they're offered, then they're randomized to come back a week later, repeat the challenge. And what you're looking at at the end of the day, when they're double-blind randomized to drug or placebo for the second speech, is whether or not they did better in the second speech when on drug versus their baseline established at visit two, which is the first speech. Fourth visit is simply safety.
Excellent. That's super helpful. And I guess just one follow-up to a couple of questions. So, assuming you are seeking a broad social anxiety disorder label, I guess what gives you confidence that, you know, testing in this sort of public speaking challenge design will sort of result in a label that's broader for situations outside of that? And then I guess secondly, for something that's gonna be used sort of as needed and perhaps chronically, you know, what does that change from a regulatory perspective and what are you doing to sort of get the FDA comfortable there?
Well, you have to do for long-term dosing, look, this the mean duration of this, disorder is about 20 years. The onset's typically in adolescence, 13-17. Social media, team orientation in the workplace, in the academic settings, these are stressors that, induce social anxiety largely in the first place. And we've been seeing the rates continue to grow, grow like crazy. We believe that the public speaking challenge and the acute treatment challenge that's associated with the public speaking challenge design is, is giving us the ability to treat acute anxiety in adults with social anxiety disorder, full stop, whether it's socially driven, performance-related. We don't think that there's a distinction in, in the way that we'll be able to, to promote the acute treatment use across all different triggers and stressors. And you can imagine, again, there's a big mix of social and performance-related stressors.
And then in terms of chronic dosing, well, we have to follow the same typical guidelines to enable that long-term dosing with an integrated safety database that includes 100 folks at a year and 300 at six months.
So again, what we see with this drug, and we do believe it needs to be used, over time, but in an acute way, because each time that there is an acute success, it really does somewhat rebuild the hard drive of the brain to look almost like cognitive behavioral therapy, where the confidence can build on itself, almost like you have a psychotherapist right next to you every time you're okay eating alone in a food court or raising your hand in class or working in a team project or going on a date, to say, look, you didn't get embarrassed, you didn't get humiliated, you didn't get judged. And next time that stressor comes upon them, same sort of benefit.
We see that because we've seen LSAS-related benefits not only in a placebo-controlled phase II study, but similarly in the open label study, the more people used it, the better their scores were on the LSAS, including avoidance of those stressors, so more engagement. That's the way we really want to see this. One of the things interesting from PALISADE-2 was the PGIC or the patients reporting how they thought they did, those on drug versus on placebo, in the second speech compared to the first speech. And especially there was more than 2x's, as you've seen, benefit in that patient-reported side. That's what we were hoping for, to improve the lives of people that are affected by this disorder with huge opportunity costs in their life because of it.
Excellent. And then in the same vein of sort of this, you know, sort of chronic dosing, you mentioned before that you're gonna be running, perhaps, a repeat dose study. I guess could you just talk about, you know, the rationale behind that and, you know, what you believe that sort of will support with respect to either its real-world use or supporting a submission package?
Well, a lot of times, you know, it's advocacy with FDA. That's an art. So, you do listen to the FDA and you do things even sometimes if they don't totally make scientific sense, like a CAR-T study for a drug that isn't detectable in the plasma, but you do these things. In this case, the FDA wanted, and it's realistic to expect that people will dose more frequently than maybe what we've seen in the duration of effect associated with the studies. We think it's about an hour, the duration of effect of the drug, and the onset, of course, is rapid. But the repeat dose studies intended to assess if a second dose is administered within 10 minutes of the first.
On the one hand, it's important to note that the activation of the neurocircuitry that we thinks critical to achieve the behavioral changes is within milliseconds. And there's also only so much capacity the nasal passage can accept. So we will certainly take a look at what the FDA's ask us to do. We think it's gonna be placebo and then within 10 minutes, placebo in one arm. Dose within 10 minutes, again, placebo second arm, and then dose, and then another dose within 10 minutes of the first in the third arm. And we'll do that in a public speaking challenge context. Certainly it's a safety takeaway no matter what. We don't think there's any incremental safety concern. Again, remember this drug's not going through your whole body. It's not binding to abuse liability receptors in the brain. It's not systemically absorbed.
Again, so we don't think there's any safety-related concern, but again, it's something we want to make sure we're aligned with the agency on.
Got it. Totally makes sense. I guess just as we're sort of close to coming up on time here, anything you want to say with respect to the rest of the pipeline, any specific program that you're particularly, you know, excited about, in moving forward?
Well, we have late-stage data and two other assets. So phase II data with itruvone for major depressive disorder as a monotherapy, again, with rapid onset, totally different safety profile, no sexual side effects, no weight gain expected, no abuse liability potential. So really remarkably distinct from other approaches right now in major depressive disorder. And then the third asset, PH80, for vasomotor symptoms or menopausal hot flashes. I'm starting to see commercials for a new NK3 receptor antagonist that Astellas got approved. It's nice to see that because, well, we've got, again, with a consistent safety profile across this platform is, and this is in a case where there's objective measurement, right, a reduction in the severity and number of hot flashes of what we saw in phase II with PH80.
Again, nonsystemically delivered, patient-tailored use, similar to how we see it in, in SAD, to, to enter a space that hasn't seen anything new for decades. And this is a, we think, a very exciting program that will be advancing into phase IIb, hopefully within about a year.
Super exciting. Thanks so much. This has been super informative and really helpful. I guess just to take things home, do you mind just reminding folks of your cash runway?
Cash position? Yes. We raised about $140 million last year, reported $126 million at the end of December. We think that takes us through everything we need associated with the studies to start in 2024, all three out in 2025, and if successful, to support an NDA submission in the first part of 2026. So we think it takes us to 2026, and that includes additional development across the pipeline, some of the programs we've talked about. So cash position's strong. It's a very de-risked phase III program at this point with one positive study and funding to drive us through some of the key studies we think we need to get done to complement the positive PALISADE-2 study we reported late last year.
Excellent. Super exciting. Well, thank you so much for joining us, Shawn and Josh, and for the excellent presentation. Appreciate you all for listening in, tuning in for the next presentation. Really appreciate it. Thanks all.
All right. Thanks .