Thanks for tuning in. I'm Andrew Tsai, Senior Biotech Analyst at Jefferies, and it's my pleasure to have Shawn Singh, CEO of Vistagen, joining me today. Welcome, Shawn.
Thanks. Pleasure. Always great to see you.
Same. Same.
A chance to talk about our story.
Okay, so for those in the audience who are less familiar with the Vistagen story, maybe talk about your pipeline, your, your lead program. What is it? Where, where are you in stage of development? What, what milestones can we expect?
Yeah, good. A lot of, lot of loaded opportunities there.
Mm-hmm.
We have a really exciting pipeline. It consists of six clinical stage assets, five of which are from a totally new class of neuropsych and neurological candidates called Pherines. The lead program, as well, I'm sure talk about a little bit more today, is with a drug called fasedienol. These are rapid onset clinical stage candidates that we don't see the need for systemic absorption. These are candidates that are achieving behavioral effects without having to get on top of neurons in the brain. So it's a really fundamentally differentiated mechanism of action up and down the Pherine pipeline, as well as really significantly differentiated safety, and we think the potential to set significant new standards of care in areas that have been stale for decades. Lead asset for social anxiety disorder.
We have a second asset called itruvone, focused on major depressive disorder, which we think for that, as with some other neuropsych disorders, we're seeing the ability to achieve benefits in a rapid onset way, without sexual side effects, without weight gain, without risk of abuse liability, given the way the mechanism plays out. Third asset focused on vasomotor symptoms or menopausal hot flashes. We've seen some significant reduction in the frequency and severity of hot flashes. Two other Pherines, one focused on psychomotor cognition, improvement for those impaired by mental fatigue. And then, a fifth one we haven't spent much time yet talking about, but associated with cachexia.
Mm
... appetite really. So different parts of the brain that we're able to impact without having to drop drugs on top of these receptors in the brain, usually associated with those, different indications.
Mm. And then milestones for...?
Well, the most important thing, we've just done something no one else has ever done, which is achieve a positive phase III study in the acute treatment of social anxiety disorder. So building on that, the most important thing we are focusing on is that registration-directed program, which would include two phase III studies, one of which we've already initiated.
Mm.
We think will read out mid-next year, and the second, in a, you know, typical redundancy-oriented way with neuropsych, that one will launch in the second half of this year. Both, and every other aspect of the registration-directed program, is intended to be launched this year and read out next year.
Okay. And the Pherine class seems to be pretty novel. So what kind of data have you generated to explain the mechanism?
Lots of data. You know, with pioneering neuroscience, it goes way back. So Dr. Louis Monti, he's been. He's our Senior VP of Translational Neuroscience. He's been working on this class of drugs for decades, and so a lot of different things. We know that these chemosensory neurons, the receptors for them, are uniquely located in the nasal passages. So all the Pherines are formulated as nasal sprays, strategically and necessarily because that's where we need to drop drug, right on top of the receptors that are activated within milliseconds. So you do a lot of things. We do tissue culture work in the lab. We take nasal mucosal cells, and we assess calcium flux. We've radio-labeled the drug with C-14 to assess tissue distribution. We've assessed whether the drug potentiates GABA.
The answer is no, not unlike a benzo. We've been able to do EEG and EMG studies, obviously assessing electrical currents. So a lot of different ways to... And of course, at the end of the day, it's the clinical data that prevail, and we've seen really remarkable behavioral changes and pharmacological changes with some of the ones that aren't neuropsych-oriented.
I see. So again, phase III underway, first one. Second one is start later this year, and then data next year. So should this be approved, what would be the market opportunity? What's the real-world use case?
It's a great question, and unfortunately, you know, it's a phenomenon that we see getting worse. It was already bad before the pandemic. It was about 10% of Americans affected by social anxiety, which for people that haven't heard much about that, that's a profound fear of being judged or humiliated or embarrassed in what most people consider ordinary, everyday social and performance situations. So it's a very significant stressor that debilitates, onsets typically in adolescence, chronic, chronically indicated, the mean duration's about 20 years. A lot of team orientation in the workplace or in academic settings, social media, of course, so a lot of stressors. And, you know, what we see is a population today that's just completely underserved. The 30 million people now, it's increased since we've had new data, it's-
30 million in the U.S.
30 million Americans, 12% of the country now, that's up from 10% in recent data that we got from the National Health and Wellness Survey. So the treatment population's also gone up. A lot of that treatment population's associated with comorbidity with depression.
Mm.
So you tend to see a match set, unfortunately, anxiety to depression, sometimes suicidality. Part of the reason why, you know, when we got Fast Track designation, it's a serious and life-threatening disorder, and it doesn't just go away in a minute. And so one of the benefits we see with the, the way that fasedienol has been de-risked in the clinic is that the more often that it's used, the more confident people get, the less often they avoid their stressors, more often they're engaging. So back to the market, I mean, it's... It's just big. And right now, there isn't anything. There's not a single drug approved for the acute treatment of social anxiety disorder. The three drugs that were approved were approved over 20 years ago, three old-school antidepressants, two SSRIs, one SNRI.
So in this space, certainly you'd see sometimes off-label use of some of the other, anxiolytics. Benzos are there. They're obviously not a great go-to these days, especially with the FDA's upgraded warning about abuse liability. Sometimes you see a beta blocker used, sometimes a Lyrica, sometimes a, you know, gabapentin, but mostly really you've got an unsatisfied population just simply saying: "Look, I don't like the alternatives.
Mm-hmm.
We see ultimately this to be very consumer oriented, right? Just like you hear discussions often about weight all over the place with the GLP-1s, it's a similar thing with anxiety. So to be able to meet the consumer where they are, to educate the medical community so there's awareness of the disorder and the options, those are all part of getting to meet the patients where they are. It also helps, telehealth will make a big difference. In mental health, it's not the same telehealth as in with hospital systems and, you know, infrastructure investments that they want procedures. Mental health's a different ballgame, especially if we have a drug without abuse liability potential and scheduling, that we can get recurring scripts, online, subjects can see psychiatrists and docs online. The conversation about anxiety is now in primary care visits.
So the landscape has changed a lot, and the silver linings from COVID, I guess, is it's okay to not be okay, especially in a workplace setting. You have dialogues like you and I talked about recently.
Right.
There's a lot more conversation about that, and then the ability to access mental health care has become just a lot more institutionalized. So we think it has a multi-billion dollar peak potential. It's pretty easy math to do, even at a modest price point that would be under prior auth and a utilization that's maybe somewhere around six fills a year would be kind of what we're modeling at this point.
I see. And did you happen to bring fasedienol with you today?
I didn't.
No.
I can't bring my active with me. I do have a placebo.
All right.
It's a standard vial. It's a standard Aptar pump as well, so nothing unusual there. It is drug device combo, but luckily there's a lot of precedent to be able to cross-refer into.
Yeah.
Yeah, I carry the placebo. It's a microgram dose, right? So it's a real fine plume. We're talking 3.2 micrograms, and we can do that, again, because you're applying the drug directly onto the receptors in the nasal passage. So a small amount within milliseconds activates the MOA that we see is so novel, which we can unpack the MOA-
Right.
-time permits.
And so again, the real-world use case is 15 minutes before you anticipate having an anxiety episode, you spray this one time in your nose, and it should curb your anxiety.
It's what we saw in phase III. So that was a public speaking challenge in a clinical setting, and we've aligned with FDA on people with this disorder fear talking to people, right? Whether socially or in performance situations, so that you can provoke anxiety consistently in a clinical setting with the public speaking challenge. So for assessing acute benefits, the Subjective Units of Distress Scale and the public speaking challenge are exactly what we need to be... And that's the lane we need to be in to get the label that we're seeking for this asset. So, it's
Mm-hmm.
It's not necessarily 15 minutes. That's the study design. The duration of the effect's about an hour. Like I said, the activation of the. Again, our focus is around olfactory system neural circuitry and brain neural circuitry. So what we're trying to do is create a, a neural circuitry, a pathway, nose to brain neural circuit pathway, that once we activate the chemosensory neurons, they then project to the olfactory bulb neurons at the base of the brain, which then project to different parts of the brain. That's what we're able to assess with EEG and others. So that for anxiety, the target is the amygdala, trying to generate GABAergic activity there, but without potentiating GABA like a benzo. For vasomotor symptoms, hot flashes, targets the hypothalamus to regulate body temperature.
So that's what's so unique about these distinct synthetic chemicals that are able, based on different subsets of the chemosensory neurons in the nose and different subsets in the olfactory bulb, those connections have unique ultimate landing spots in the brain to deal with and address the different indications that require different brain signaling. It's not exactly the same as when you smell sewage, you know, your brain says, "Ugh.
Mm-hmm.
When you smell fresh bread, it's like, "Okay, great." But think about the fact that your olfactory system can generate different, different brain-related consequences.
I see. And so one Phase III was positive, one was not, however. What happened? Why do you think that was the case, and how have you designed these next two Phase IIIs to succeed and look more similar to the one that worked?
Yeah, well, one thing to note upfront is we were really the first to pioneer entering the phase III universe with this protocol and with this endpoint. Like I said, there hadn't been anything approved ever for acute treatment, let alone anything even for overall SAD. So clinical research community hadn't really had a full embrace on a scale-up. But then you bring the black swan of the pandemic in, and that confounded what was, you know, the kind of normal tradecraft you want to be able to apply in a clinical trial. And so that, we saw a lot more excursions associated with just scheduling differences, rater changes. We had the masks going on most of PALISADE-I, the first study, almost all of PALISADE-I timeframe that we were-...
able to surveil, and then here comes PALISADE II at a time where predominantly the subjects in that study randomized were at a time when things changed in 2022, when masks came off. We're able to get into sites and retrain, and refresh, and surveil. There was less turnover at the CRO level, at the site level. There was less, you know, the great resignation. So there was just the things you try to do to control variability when you're scaling up-
Right.
There was just a lot less opportunity to control that during the first study, because what we saw was a placebo rate that was higher than we typically had seen in any other prior work. Then PALISADE II came along, and we saw a lot more rigorous adherence to the protocol, fewer excursions, the ability to get into people. We didn't have an investigators meeting in either of the two studies, but moving into the environment now in PALISADE III and IV, 2024 versus 2022-
Right
... let alone 2021, radically different.
I see.
Not only that, it's the same protocol, design, or same study design, public speaking challenge, same endpoint, but there's been some significant enhancements that are intended to leverage lessons learned, but also improve the kind of things that really help when you're executing a study.
Mm-hmm.
Surveillance is key, so there's less reliance. We unbundled a lot of reliance on CROs. Our own people go to sites and train up. We had a great investigators meeting before PALISADE-III recently, another one coming up for PALISADE-IV. The masks are not involved at all in PALISADE-III and PALISADE-IV. We're able to surveil with audio recordings whether or not the sites are rigorously adhering to a very specific script-
Wow
... during the public speaking challenge, and even training up the subjects on the SUDS. So many things that are associated with enriching the population and also with ensuring that you're able to execute with rigorous surveillance, because that's what's key with this. I mean, running this, it's not that complicated of a study design, but there's things that if they don't go exactly right.
Mm-hmm
... or even close to right, you know, they do cause some variability you don't wanna see. We think 2024, 2025, executing PALISADE III and IV is just a much, much better-
Right
... clinical. It's not just us, everybody's affected by that in our industry.
Right, especially-
Plus, this is now the third lap and will be the fourth lap with this study design and this protocol. So the research community alone, plus the read-through from PALISADE II, has a positive impact on the ability to make sites understand and execute the protocol properly.
In following the positive data readout, which came second, you know, as COVID was subsiding too, does it make sense to seek a breakthrough designation? Because this does seem the first of its kind, and where are you at with that?
Yeah, well, as I noted, we have Fast Track, so that means obviously this is a serious and life-threatening indication, right? So you're also looking at, is there an approved therapy? Answer, no. This would be the first approved. Are there available therapies? Is there a set of guidelines for a standard of care? Because you also have to look for available therapies, right? Is there approved or available? And, you know, with what we were able to accomplish with PALISADE-2, we check a lot of boxes. So there's really solid advocacy points. With the agency, you know, it's never, nothing's ever a sure thing. But what you look at, do you have solid points to advocate for any particular position, let alone, you know, in this case, moving from Fast Track to breakthrough?
So, like I said, I think we check a lot of solid boxes, and it's a prudent move to assess-
Okay
... and move on.
When can we expect the publication, journal publication of these Phase III studies?
We've been out, quite a bit. I mean, we've been able to do, presentations at, ADAA, ASCP, NEI, the CNS Summit. So we've been able really to have excellent uptake by KOLs and, in the psychiatry, in the neuroscience universe, which has been terrific. The feedback's been fabulous, and a lot of excitement coming from the read-through from PALISADE II. In terms of journal publications, we have a draft manuscript that we expect to submit pretty soon, very soon, to the kinds of publications that you think, pay attention to something that hasn't happened before in a certain indication that affects a heck of a lot of people.
Okay.
So we'll see, but you know, it's a solid manuscript.
Right. Okay, very good. And so two phase III's starting up, just one actually needs to succeed. That's correct, right?
We think so, yeah, absolutely.
Yeah.
To complement, you need two, that's the standard with the FDA-
Yeah
... in most cases. Yeah, so to complement PALISADE II, we have initiated PALISADE III already. PALISADE IV is in the second half of the year horizon. Every aspect of what we believe is a registration-directed program to achieve the first approval for the acute treatment of social anxiety disorder, if the PALISADE phase III program is successful, will be initiated in 2024, all completed in 2025, with a target submission, if successful, in the first half of 2026.
I see. And are there any peripheral studies or that you need to accumulate or generate, or open label data, follow-up data you need to generate before?
Yeah, both. The last lap, you typically, we'll see a couple of preclinical studies that we need to finish up. We also have... There's a repeat dose study. The FDA wants to see what happens if someone takes it twice within 10 minutes.
Mm-hmm
... which again, we think nothing that we would expect worrisome from that, because once you occupy these receptors, over-occupying really doesn't do much. You may see some nasal drip, but the nose can only hold so much.
Mm.
The PALISADE study. So, you know, those main studies, we fortunately, as we've gone to the agency before and assessed, well, do we need to do human abuse liability studies? You and I have talked about this. We showed an enormous amount of data. We saw in our largest open label study that with about 30,000+ doses, about 500 subjects, the most prevalent treatment-emergent adverse event was headache-
Mm-hmm.
at 8.7%. Nothing else over 5%. So for a neuropsych drug, it's remarkable, and it makes sense, the differentiated safety, if you don't see systemic uptake, and you don't have to get into the brain and, you know, have a pinball game with the different-
Right
... abuse liability receptors. So that part, as of all our current interactions with the agency and things that have ensued since they told us that we didn't have to do a human abuse potential study back in 2021, we think we're still in line with that.
Right.
Mostly, it's wrapping up a little bit of preclinical and then the two clinicals.
And then maybe one more question on this program. You did mention the repeat dose study. I think data could come later this year, and maybe, talk to us what positive data would be, because my understanding is there's three arms, drug, drug within 10 minutes, drug placebo within 10 minutes, and placebo, placebo within 10 minutes.
Right. Three-arm small study. We'll initiate that this year, but it won't read out this year. It'll read out next year as well. And again, what you're trying to see there, there's some sense maybe initially a pretense about what was it, a safety concern.
Mm.
I think the thought is, FDA's right, you know, people might say, "Well, once is good enough, then maybe twice in a short period of time is better." So, we may inform labeling. It may allow, instead of saying, you know, once every hour, up to four-six times a day is where we're landing with this. Because the key again is with social anxiety, if you don't have your stressors on you, you're asymptomatic, and so people don't want drugs in their body all day when they're not needing them, especially antidepressants, with all the predictable side effects. They also, you know, don't wanna have cognitive impairment. So, you know, we'll see. It's
Yeah
... it's something that we're expecting to maybe have a potential additional narrative in a label to say it's okay if you end up using it within a 10-minute period.
Right.
Whether or not it's a better than one dose, we'll see. I mean, obviously, we hope both are better than placebo.
Right.
It's a small study. It's a public speaking challenge. It's the same thing, same design. It's just not similarly powered.
Understood. And importantly, you do or do not have the cash to- ... see these studies through?
Cash is always critical. I mean, the point of doing an offering, fortunately, worked with, with your team on the other side of the house last year-
Mm
... with a really solid book and really, what we believe are long bias, healthcare-focused investors. We raised the capital to complete in full this registration-directed program, for PALISADE, for the fasedienol and SAD. So cash is, we last reported $126 million at the end of our third quarter. We're reporting on Tuesday, but we still think we have adequate runway to cover everything we need to get done to get this program completed with potential for an NDA submission in 2026.
Great. So, as you're prioritizing this program, are you also working on other programs in the pipeline, or are they kind of on pause? Maybe walk us through, like, for instance, the next later stage program would be PH10 or itruvone for MDD. What's the next?
Yeah. Never a good idea to pause movement on really awesome and promising candidates. But fortunately, each of them doesn't really have a major burn component at this point, and we'll stage some of the activity to be consistent with what we need to do. So for example, PH80, we need to—we wanna do the next phase II study in the US, and so we're getting a US IND enabled with some reasonably low spend associated with that IND-enabling program. Same thing would ultimately be the case with PH15 and PH284 at the bottom end of the pipeline. Or with itruvone, we wanna make sure that we have really solid consensus with KOLs-
Mm
... and with the agency on the protocol for a phase II- B study, which would be US. You know, one-to-one, two-arm study. What we saw in that study in phase II- A, which is encouraging us moving to phase II- B, is rapid onset, again, without the issues people worry about, sexual side effects, weight gain, sustained over an eight-week period, with the 6.4 microgram dose, dosed twice a day. So that's the study protocol. We're really in the kind of, not quite the last lap on that, but close to making sure we have rock-solid consensus within the research community as well as with the FDA.
And then one question on the hot flashes. Astellas has a drug in the market right now. I think unfortunately, sales have been a little bit slow. Why is that, and why doesn't that shake your confidence?
It always goes to the product profile, right? I mean, that's, it's an NK3 receptor antagonist. It's a new, asset into a space that 80% of women, 45-65, are affected by. Hormonal therapy is really not a liked, likable go-to.
Mm.
What we've seen in here, you know, you have to take a blood test up front, you have to monitor liver function each month for three months with blood tests. So because it's systemically absorbed, you still gotta deal with the same issues with liver and kidney. And what we have distinct from that, again, is the ability for a patient to control the use, when what we've seen was a reduction in severity and number over four weeks in hot flashes. But it's always bringing it back to the patient to be able to control the use of the medication, like in SAD, on an as needed basis, to be able to deal with the problem. And to do that without having to run through the liver and the kidney and, you know, it's just a whole different approach.
Right.
Which is why with Fuji Pharma, you know, we have this... As you know, they gave us $1.5 million to make sure we didn't talk to anybody else about Japan as we're doing this IND-enabling program. So could be some potential ex U.S. partnering. Well, we intend to partner all assets outside the U.S. and keep them all in the U.S.
Great. I think that's all the time we had, but thank you, Shawn, for this discussion.
Great.
Very informative, and thanks for sharing the progress, and thanks everyone for listening in.
Absolutely. My pleasure. Thanks.