Everyone, thank you for joining us for the final session that we have for today. My name is Nevin Varghese. I'm one of the biotech analysts here at RBC Capital Markets, and I'm joined on stage by the CEO of VistaGen Therapeutics, Shawn Singh. Shawn, thank you so much for joining us.
Hey, Nevin, it's a pleasure. It's especially a pleasure to talk to you, given your experience with brain trauma.
Yeah.
The effect of neural circuitry.
You did your research on me as well.
Totally relevant to what we do. Before we start, just as always, I'll be making forward-looking statements. Encourage people to take a look at the risks described in our SEC filing, especially our most recent Q and K.
All right. Let's jump right into it. I guess before we get into some of the specifics, can you provide us an overview of your platform and some of the learnings from the studies that you've conducted with fasedienol, both around the drug's properties and also optimizing study conduct, just in regards to social anxiety disorder and some of the learnings that you've taken away?
Sure. I could take up our whole time, but I'll try to be brief. We are developing an entirely new class of intranasal neuroscience product candidates called pherines. fasedienol is the lead asset at the top of that class, or the head of that class. The hallmarks of the class really are remarkable and differentiated from just about anything you've seen previously in many of the indications that we're dealing with, if not all of them. These are reliant on nose to brain neurocircuitry that we activate with microgram level doses dropped directly, and sprayed directly onto the receptors of the neurons that we need to activate to achieve the behavioral and the autonomic outcomes that we're targeting with the indications. Such as the amygdala in for anxiety disorders, SAD, or the hypothalamus in the case of menopausal hot flashes.
Doing that, but without requiring systemic absorption or direct activity on neurons of the brain, has not only allowed us to achieve very rapid onset effects in what we've observed over time, especially in SAD with fasedienol, but also, really a very favorable tolerability profile so far that we have observed in hundreds and hundreds of subjects now that have been exposed to the drug. fasedienol is for the acute treatment of social anxiety disorder, which is a chronic disorder that manifests acutely but affects about 30 million adults in the U.S. This is a fear of, and anxiety about being judged or humiliated or embarrassed in everyday social and performance situations in daily life. We're trying to do with fasedienol, what we observed is its ability to knock down those symptoms upfront and even during the stressful events that people encounter in their daily lives.
That's in an open label setting. We've seen that repeatedly. In the controlled setting, we have public speaking challenge studies where with a single dose, we're trying to, again, under an endpoint called Subjective Units of Distress Scale, measure minute to minute effect with a single dose in a controlled clinical setting, to knock down those symptoms that are associated with the fear and anxiety related to Social Anxiety Disorder.
Got it. I know we had somewhat recently seen the top line from PALISADE-3. Although there wasn't any meaningful separation from the fasedienol group and placebo, I know that you've since gone back and looked at the data in more depth. Can you walk us a little bit through what those analyses are? I know specifically you've mentioned utilizing some AI and machine learning, as well to take a look at this. Then how you are intending on using this analysis and specifically what modifications you have made to the PALISADE-4, which we'll see data from in the near term.
Sure. All right. Let me see if I can remember each of those parts. I may have to get back to you. Bottom line is with any program from the very beginning, you build a body of evidence, a totality of data approach. From the very beginning of this PALISADE program, which consists of four phase III studies, PALISADE-1, PALISADE-2, PALISADE-3, and PALISADE-4. PALISADE-1 and PALISADE-3 did not statistically separate. PALISADE-2 did. PALISADE-4, as you noted, will be reading out by the end of this quarter. Looking at the totality of data in PALISADE-1, PALISADE-2, and PALISADE-3 data sets from the randomized portion of the studies, it's been very important to see fairly constant treatment effect across the studies.
What's been variable has been the placebo response, and you unfortunately often see that even with identical protocols in mental health studies, you see variable outcomes. The totality of data is really important, not only in the controlled setting, but also in the open label setting to provide context for really is there a treatment effect that's clinically meaningful, that's durable over time? That's what we've been observing. From some of the work that we've done since the PALISADE-3 readout, was really to go back to PALISADE-4 execution and make sure that it's as rigorous as possible, make sure that we refresh on placebo mitigation strategies, made some adjustments to rationalize some of the recruitment capabilities, as well as some of the statistical measures that are associated with covariates. In particular, pre-IP dosing and pre-IP SUDS. What's the anxiety level?
Is there a differential at baseline between subjects on drug and on placebo that we can analyze for that covariate in the stats plan, the statistical analysis plan for PALISADE-4? That's aligned with published FDA guidance on trying to balance covariate potential in randomized studies. We followed pretty rigorous statistical guidelines, had good and solid statistical advisors. The ML and AI also helps contribute into some of the patient profile dynamics and some of the things that we want to know going forward and into PALISADE-4.
Got it. Can you talk to us about what you're seeing in terms of population differences or similarities between the PALISADE-2, which did work, and then whether you see any of those similarities within PALISADE-4, if that's something that you may not have disclosed yet?
It's not something we could even assess yet because the PALISADE -4 data's blinded. The key is to make sure you try to level the playing field for the statistical analysis if you've identified the covariate that might have a fixed effect on the ANCOVA.
Got it.
Right. Going back and looking at the prior data sets from PALISADE-1, 2, and 3, it became clear to us that was a change in refinement to the SAP for PALISADE -4 that we wanted to make well before database lock, which is what you have to do, and make sure that that was something we submit to the FDA.
Got it. Now with that, we're going to see the top-line results from PAL-4 any day now, I think before the end of June.
Right.
Can you help us understand what you would consider clinically meaningful there, just given that PALISADE-2 was successful as well? Are you looking for similar effects in PALISADE -4, or do you think that some of the modifications that you've made could potentially improve that delta versus placebo?
We looked at when we modeled PALISADE -2, it was based on phase II, and so PALISADE -3 modeling based on really the vast majority of subjects in PALISADE-2 were randomized once the pandemic was over.
That really gave us a better take and a more recent take on how we wanted to power PALISADE -3 and 4. Again, that's you typically power, obviously for a 90% power to achieve what you would think would be a clinically meaningful effect. It doesn't mean it necessarily has to be the same as PALISADE-2, because you learn from your most recent studies, but similar ballpark.
Okay. Then what's your rationale for exploring repeat dosing?
It's more in line with discussions with the agency about a desire to see, from a safety perspective, what may occur in real life if the drug's successfully developed and approved, which is that some people might think more is better and might dose within a more frequent period of time than is studied in the randomized studies or in open label. This one, the repeat dose exploratory study, focused on a second dose within 10 minutes of the first, and then of two other arms where the placebo's integrated with one dose, and then another arm with two placebo doses. Really from the perspective of the mechanism and the MOA, fairly unlikely that additional dose is going to do much in terms of-
Okay
any additional safety risk. Once you occupy the receptors, they get into gear pretty quickly within milliseconds.
Got it. Okay.
We go from nose to amygdala in less than a second. Based on EP studies we've done with electrogram and nasal receptors and olfactory bulb EEG studies that we've done. That now we can sense and assess the depolarization at each of those levels very rapidly.
Okay. How have those conversations with regulators been in recent days? I guess we're seeing a little bit of flux of the FDA to say the least. They've talked at one point about potentially a single trial being sufficient, although we haven't seen much guidance on that. How are you thinking about this moving forward, just given that PALISADE-2 was successful? How are you thinking about the totality of the data package and potentially that serving as enough for an NDA filing?
Whether something is or isn't sufficient for a potential NDA submission, I think we're going to have to give more guidance on that after further discussions with the agency which you'd expect after program-
Yep
completes. It's always been a solid base of confidence for us on the totality of data, going all the way back to the very beginning and even some of the non-clinical studies that we've done to assess this drug's potential effect. Again, looking at just the clinical side, phase II forward, that confidence still stays. With the open label, what we've seen, and again, cautionary there, it's open label, we don't want to go too overwhelmingly reliant on open label data, but it does help assess utilization patterns. It does help us understand how people apply the potential that fasedienol gives to regain agency in an acute use need that they have in the real-world setting. Again, for 20+ years, there's been nothing approved for social anxiety disorder and certainly never anything for the acute treatment.
There's a lot to learn from the totality of data. One important milestone I think we expect to hit by the end of the quarter is eclipsing the minimum safety requirements for ICH guidelines. Not only the aggregate, but also the six and 12-month numbers. That's also a key piece of your advocacy when you're talking about any registrational pathway. Whether or not the single trial anchors in the way that the former commissioner noted in The Wall Street Journal, I think we wait to see that.
Yeah.
Richard Pazdur's commentary yesterday, I think, was pretty appropriate.
What applied in oncology and rare disease may not apply in psychiatry or pain or addiction. I do think there's a flexibility that's possible when you look at a risk-benefit calculus, especially given the safety profile that we have been able to develop over lots of subjects now. It's an encouraging risk-benefit calculus at the end of the day when you look at totality data, regardless of where PALISADE -4 goes.
Yeah.
We couldn't even consider the PALISADE-2 alone single trial earlier than achieving the aggregate safety database that's necessary, because this is a chronic disorder. It manifests over about a 20-year mean duration and onset's typically in adolescence. You want to be able to use the drug acutely in an ideal setting. That's the TPP that we see, where patients have control to tailor it to fit how their stressors impact their daily lives. They're not going to go away in a minute. What you hope to achieve is that over time, confidence builds with each successful. It's almost like cognitive behavioral therapy amplified when you have successes in the real-world setting. What we see when we look at the Liebowitz Social Anxiety Scale, which measures over time reduction in fear or anxiety, we see reduction in avoidance, increase in engagement.
Those are exactly the kinds of things that you're trying to look for when you talk about clinically meaningful outcomes. That's key. That's very important to us in addition to what's achieved in the randomized studies for the acute label.
Okay. Yeah, talk to me a little bit more about what you've seen in the open label extension data and some of the supportive data that you've seen there that potentially suggests that at least in the real world, patients might be potentially using this differently, or maybe that some of that confidence is improving over time.
Yeah
what their use patterns tend to be in the open label, how that's changing over time.
Yeah. It's really people with this disorder go through seasons and different seasons in their journey. What affects them in high school, maybe with social media, when onset occurs or team orientation in the classroom changes as they move to college or become a young professional or a parent. As different social and performance situations come on subjects in patients with SAD in their lives, they need to be able to fit how they want medication to help with that. With the current antidepressants, for example, you don't have this disorder all day, every day.
It's episodic. In some days, what we've noticed is people have multiple different scenarios. In the morning, there's a meeting. In the afternoon, there's a lunch. At night, there's a date, or you meet your in-laws. You have these stressors that are across a broad range of experiences at different times in people's lives. With the open label, you can gather that information from a broad diversity of demographics as well as a broad diversity of types of situations, and the utilization may vary. If you're in Central Park reading a book on a Saturday, no need for the drug. You don't even want an antidepressant in your body.
Right
You know the side effects are there. There's other days, again, where you have multiple different stressors, and you want that at hand. What we do see in the Liebowitz scale assesses like a movie experiences over time. The SUDS is more like a snapshot, a Polaroid of a short-term acute experience. With the Liebowitz scale, what you're able to see is over time, are people engaging in things they avoided frequently before, and does that increase their confidence to reengage? The wins that occur acutely definitely impact the future behavior and how people make decisions to try to control the anxiety and the fear that comes upon them in their different situations. It helps us also to understand utilizations. Like I said, some days it's multiple days. This drug can be taken up to six times a day, and other days, none.
That helps us to understand downstream what we expect possible utilization would be if we successfully approve and commercialize the drug.
Okay. I know you're also doing a long-term safety repeat dose study as well. Mentioned earlier. When do you expect that data to be available? When might data lock be for that?
Next quarter.
Next quarter.
Third quarter, yeah.
Okay. Got it. Switching gears to itruvone as well in MDD. You've reported some positive Phase IIa data for that. You've shown symptom reduction as early as after a single week, and tolerability looks fairly good there as well. Can you walk us through how you're planning to design a Phase IIb program and what the primary endpoint might be, patient population, study duration?
Yeah. itruvone's unlike any approved antidepressant or anything that we see in development today. Like all the pherines, they're rapid onset, non-systemic, and in this case, with itruvone, highly differentiated, we expect, related to a lack of weight gain, a lack of sexual side effects, a lack of sedation, some of the things that really are the clarion calls of folks that are affected by MDD. As you noted with itruvone, as the other pherines, three of them beyond itruvone, we've seen positive exploratory data in phase II-A setting. Those studies were done outside the U.S. We want to bring them back into the U.S. For the next phase II study in itruvone, we'd see it more like a six-week study and with "high dose," which is 6.4 µg BID.3.2 BID. That would be using HAM-D17, just like in phase II.
We see those with a greater propensity to have anxiety to be impacted favorably by itruvone, more so than anhedonia, which is why we would go to HAM-D over MADRS.
Okay.
Looking at that over various points of time, but again, the key there is to assess it in what we see at day 42, but also take some looks earlier on.
Okay, got it. Would that also involve other kind of secondary exploratory?
Yeah
endpoints as well, like SHAPS.
Several. All the standard battery.
Okay, got it. When do you expect to initiate that trial? I know you have an FDA fast track designation as well. Does that influence how quickly that could initiate?
It doesn't really impact initiation. What impacts initiation is capital.
Okay.
Same thing with refisolone for the hot flashes program. We've been disciplined in our capital allocation, driving it towards the fasedienol program, given its significant lead in development and the fact that it's anchored on one positive phase III study. See where that goes. The plan is still continues, work with a lot of the KOLs you know to set up the protocol that's well beyond that point and assess sites and hopefully the ideal scenario, we'd be able to initiate that sometime in early 2027.
On the refisolone program as well for hot flashes, is there any more that you might be able to share about the phase II-A data that you observed? What magnitude of reduction in hot flashes you saw at the end of treatment and durability beyond just the four-week window?
Yeah, we don't have data beyond the four weeks, but the four-week data are really incredibly exciting to us.
Okay.
What we saw was a reduction in the number and the severity of hot flashes across that four-week period. That was with probably a lower number of opportunities for subjects to use the drug, we'd like to increase that in the next study, possibly up to 10x a day, given the average number of hot flashes that we see women experience. Again, the safety profile we expect to be remarkably different from what you see with the NK3s and the labels that each of those drugs has. Again, it's a fundamentally differentiated mechanism that is intended, similar to SAD, to allow women to really control their use when they need it, as they need it, and up to hopefully up to 10x a day over a period of years. What we see out there right now, there's nothing like it.
It's a very interesting indication for us because there is a lot more overlap now between mental health and women's health. Especially in menopause. We like that fit. We've always known that fit, and so if we can try to do anything we can to reduce and provide new treatment alternatives that are on demand as needed and give women agency over controlling how their menopausal hot flashes affect their daily lives, that's the ultimate goal.
Okay. Then can you remind us about what the IP for all these compounds look like?
It's a mixed bag, really. On some of them, we've got patent protection, others we don't. We'll rely initially with downstream strategies that are pretty customary in our space relating to formulation, relating to device, that provide some extended commercial exclusivity.
Okay, great. Lastly, can you tell us about what the cash runway looks like and some of the prioritization of the programs that you have in the pipeline?
The capital allocation, all the resources have been really prioritized towards the programs that have reached the stages they're at with refisolone and itruvone. Those are extensive IND-enabling programs, otherwise towards fasedienol and the phase III program and the repeat dose study and some pre-commercial activities that are stage-gated to enable that. Cash runway at the moment runs us into 2027, we'll see how that goes on the other side of data.
Okay, sounds good. I guess lastly, what are your latest thoughts on looking to potentially partner this or take this forward alone?
Yeah. It's key for every company in our space really to allow for strategic optionality, and that's as it relates to financing, as it relates to commercializing, it relates to development partnering. All of those are within our scope, and we constantly move them in parallel paths, and remain opportunistic. There are certainly potential fits in each of those areas to give some efficiency and allow capital to be utilized really rationally across the opportunities that we've got.
Excellent. Cool. Thank you so much, Shawn. Appreciate the time and appreciate everybody in the audience as well. Thank you.
You bet. My pleasure.