A Novel Drug to Treat Social Anxiety Disorder. Talking Biotech Short Reads- Dr. Kevin Folta

I'm Kevin Folta. I've spent my life as an academic researcher with a commitment to student education. At home, we produce fruits, vegetables, and eggs for local markets. But I've always had a passion to share the stories of science and the exciting new technologies designed to help people and the planet. This is Talking Biotech Short Reads. Hi everybody, and welcome to Talking Biotech Short Reads. I'm Kevin Folta. And this week we're going to be exploring an entirely new class of drugs which are being used to treat mental illness. It's a completely new class of drugs, and the first one is aimed at curing, or at least giving some therapy to, social anxiety disorder. We're speaking with Sean Singh. He's the CEO of Vistagen. His original podcast, when I spoke with, uh, with Sean, is Talking Biotech Podcast number 386. So if you'd like the long-form explanation of what this technology is, that's where you'd go. It's originally aired on March 4th, 2023. So welcome back to Talking Biotech, Shawn.

Hey, Kevin, it's my pleasure to speak with you again. Thanks.

And this is a real breakthrough. I'm really excited that we had the ability to catch up on this. So remind me again of what is social anxiety disorder? How prevalent is it? And Is it something that we really need to worry about treating?

Well, thanks, Kevin. I'm really glad I have an opportunity to talk about this because it's a serious mental health condition. And as I'm sure you and your listeners know, we're in the midst of, unfortunately, a mental health epidemic. But it's not just shyness. It's a serious mental health condition that's characterized by debilitating emotional and physical symptoms that arise in really everyday, what most people consider everyday social and performance type of situations. So people have overwhelming fear of and surges of anxiety about being judged or embarrassed or humiliated in these types of circumstances. When you meet new people or have an interview with your, with your potential employer, go on a date, go to a sporting event, any situation where there's a social interaction component to it. And unfortunately, it's highly prevalent. It affects about 10% of the United States. And, and there really hasn't been anything as a new treatment option for folks dealing with this in their daily lives for a couple of decades.

Yeah, I have a friend who has this really bad. The guy is a guitar virtuoso, amazing guitar player, but he could never play on stage in front of an audience. And for a job, he works overnight at a library as a janitor because he can't interact with other people.

It's really— that's a great example of the opportunity cost in life that this disorder, which is a chronic disorder, the typical onset is often in adolescence between 8 and 17, but the mean duration of the disorder is decades, 20 years or so. So it's something that obviously you don't pursue your vocational aspirations as much as As you just noted, their social relationships are impaired. So it's a really challenging life. It's a self-imprisonment for many people that have to deal with the anxiety that surges in these everyday situations.

So are the treatments really just drugs, or is there also a counseling component to it?

Well, with every neuropsychiatric disorder or mental health disorder, there's always a critical need for a talk therapy component. So whatever the medication is, that's essential. But really what you're trying to achieve is a cognitive behavioral therapeutic effect. Over time, you're trying to build confidence and resilience, and you're trying to reduce avoidance of situations that are stressful. But the current medications, which really there has been no innovation for decades, they're inadequate. There's only 3 drugs approved. They're all what we would regard as old-school generic antidepressants. On an off-label basis, not approved, never been studied for social anxiety disorder, benzodiazepines are used with the real high abuse potential and misuse potential. Sometimes beta blockers are used. So overall, we've done a lot of market research across patient groups, physician groups, even payers, and really the dissatisfaction with the current therapies The problem is you have a high prevalence rate. A lot of people are affected, but very few people are actually wanting to be treated given the side effects and safety concerns and lack of rapid onset that is really not possible with the current medications. What people really want with this disorder and most anxiety disorders is a fast-acting anxiolytic or an anti-anxiety drug without abuse potential. That's what we see, the direction we're headed with our lead asset.

Well, as I recall, the drugs from Vistagen are administered through the nose as a nasal spray, and they actually are delivered to the neuron-rich region of the olfactory bulb, which really serves as a pipeline directly into the central nervous system where it can have effects on specific parts of the brain. So is that right? And then, uh, Tell me more about what happens specifically with the one for social anxiety disorder.

Yeah, excellent memory. So using the nose really as a portal to achieve activity, physiological activity and psychological activity, behavioral changes, is the novel innovation here. So we have a drug class that's administered as nasal sprays. They're called pheromones. These are neuroactive nasal sprays that when they are administered to the only place in the body, the mid-septum of the nasal cavity, there are certain neurons called chemosensory neurons there that when they're activated, it's really sort of a relay situation through one interneuron, as you noted, the olfactory bulb neuron, to parts of the brain that are associated with different behavioral or pharmacological effects that we're trying to achieve. So the amygdala is really the main fear and anxiety center of the brain. When we spray a very low amount, microgram doses, and this only works as a nasal spray, you couldn't drink it. These receptors and these neurons are only in your nasal cavity. What ends up happening is there's really a sequence of neural circuits that are kicked into gear, and ultimately that part of your brain that is your fight or flight, your fear and anxiety center, there's inhibitory activity that in a rapid onset manner, you're going about 3 inches from the nose to the part of the brain associated with that fear and anxiety center. We see inhibition of these fear-off neurons that are in the brain. So it's a totally different approach because the current medications, all oral, have to go through your whole body, broken down in your liver, through your blood, up to your blood-brain barrier. So again, we're trying to achieve a rapid onset effect. Through the nose as a portal to the different parts of the brain that are associated with different conditions. In this case, anxiety. We have another drug that stimulates parts of the brain in an antidepressant manner. That's a drug for major depressive disorder. So you can achieve that, the effects, without having the drug go through your blood, without having to have a drug go into your brain and act directly on neurons in the brain. What you're doing instead is triggering neural circuitry that results in the effects that we're trying to achieve, anti-anxiety or antidepressant, or we have a drug for menopausal hot flashes that affects temperature regulation. So it's across a wide range of different disorders depending upon the specific type of pharyngeal that we are developing. We have 5.

Tell me more about the speed and time course of this particular drug, because if you're spraying it directly into the nose, it goes right into the— right towards the brain versus something that you would take orally, which— or intravenously or whatever, which may have to become systemic and accumulate to a specific level before you start seeing therapeutic effect. So, tell me a little bit more about that.

It works really that same way that we just described. And, we just saw a very successful, I believe the first that we've seen in the space for a decade and a half, Phase 3 study of this drug in social anxiety disorder. Very simply, a small amount is sprayed right at the mid-septum of the nose. That then kicks into gear interneurons that then broadcast forward to the part of the brain where we really— we're not trying to completely put you to sleep. But when you have an overactive amygdala, when you have a— you need some anxiety, of course, to energized, to be focused, but you don't need excessive anxiety to deal with your daily life. So this drug gets to circuits in the amygdala and then inhibits that fear-on activity. It inhibits the GABAergic activity in the amygdala to achieve a rapid onset within about 15 minutes, and the duration is about 30 minutes. So the best of this, the best aspect of this drug is it works quickly. It's of short duration of effect. You can take it multiple times throughout the course of the day, is what we've seen in studies so far. And the safety profile has been consistently favorable in all studies to date. We had an open-label study earlier this year. We announced results— over 30,000 doses administered. The adverse event prevalence for everything other than headache, which was only about 17%, in 481 subjects. There's COVID at about 11%, which doesn't relate to the drug, but every other adverse event was less than 5% prevalent. And that's remarkable for a neuropsychiatric drug. We just haven't seen it. It's a once-in-a-generation type of approach for a disorder that has inadequate therapies and hasn't seen anything new, anything at all innovative for decades.

Well, with this very short term therapeutic window where it actually works. Is the goal really to try to wean people off of the drugs to kind of buffer them through the first stages of an anxiety moment so that with time those become, you know, less imposing and maybe allow them to not use a drug at all?

That's absolutely the goal. You improve lives, we think, one mind at a time, and really Hopefully, at the end of the day, our treatment model prevails if we're successful in remaining in phase 3 development, where people have an opportunity like they would use a rescue inhaler for asthma, right? On-demand, patient-tailored use in the midst of a particular stressful situation. But then using that over time, having the ability to generate more confidence, more resilience about engaging in those events, very much like cognitive behavioral therapy, right? There's success after success after success because you're able to deal with the situations coming out of each one saying, wow, I went in that interview and I wasn't embarrassed or humiliated or judged. Same thing when I went to my neighbor's for a barbecue or went on a date. So it is a combination of being able to have something at the ready. That's what this latest phase 3 study that we had showed. It was rapid, active in a speech, public speaking challenge. But then what we also saw in a recent open-label study with several hundred subjects was that the more people used it, the better they got. And that's consistent with what we think is the optimal paradigm for treatment of this disorder. And ultimately, sure, you want to get off every medicine. Every human can get off every medicine. That's a wonderful objective. We hope to be able to help that. And psychotherapy continues to also be a component of that, no question about it. There's no— there's never one size fits all of any medication. So a patient being able to have control of when they need their medicine, because if there isn't a stressful situation, social anxiety isn't affecting their life, and they don't want medicines in their body like an antidepressant with side effects when they don't have the stressors upon them. So the ability to use it on demand without safety and abuse liability concerns is, is a huge movement forward from where the And tell me about fasadiol.

This is the new drug and just went through a phase 3 trial. And so what were some of the results?

Well, what we just announced, it's PALISADE-2 is the name of our phase 3 study. So hopefully this is at least an anchor in what ultimately could be a new drug application for this drug for the treatment of adults with social anxiety disorder. Then ultimately, paediatric studies would follow downstream, because again, the prevalence among youth, especially post-pandemic, is alarming. But the PALISADE-2 study hit on every single endpoint. The primary endpoint, which was in the context of a public speaking challenge, the drug was used and compared to placebo, highly statistically significantly better than placebo. Secondary endpoint was clinicians rated how they thought subjects did from the first treatment or the first challenge to the second challenge. Statistically significant. Very importantly, what we call the patient-reported outcome was that patients thought they were much improved or very much improved in a statistically significant manner on the other side of treatment. So, and then safety, of course, as I noted, was there was really no adverse event more prevalent than 2%. in this trial. So again, consistently safe, rapid onset effect that we see consistent with their Phase 2 development. And I'll tell you, it's a tremendously exciting feeling for a company whose mission is to make a major difference in the lives of people suffering from this and many other mental health disorders.

And that's really great. And with all the focus on mental health disorders and ways to potentially treat them, this kind of therapy is fantastic. And so what kind of timeline are we looking at and what comes next?

Well, you still have to walk the process, as we know, in our country. Fortunately, you have to have at least 2 adequate and well-controlled studies. We think we have one completely done now. So halfway to that goal. You also have to have your drug exposed to about 1,500 patients at least before you can submit that application. So the target right now would be If we could submit, finish up Phase 3 development by the end of '25, submit a New Drug Application sometime in that last quarter of '25, maybe early '26, and then ideally by the end of 2026, make our way through the process. That all requires one more adequate and well-controlled study. Regardless of how many we run, that's the requirement. FDA just needs 2. So our opinion is we're We're certainly on the way. Yeah, great question. There are 5 total fairings right now in the pipeline that we've announced, others that are earlier-stage development. But again, the key with these is they selectively directly modulate different brain areas that are involved with different disorders, right? So while we have fasadienol for social anxiety disorder, we have a drug called Itruvone that's staged for Phase 2B development in major depressive disorder. We announced recently a drug that's called PH-80 that had successful Phase 2A in menopausal hot flashes, a disorder that desperately needs new medications without safety issues. And We have 2 others. One's for wasting syndrome cancer patients, and the other is for a condition that we think is associated with cognitive impairment.

Yeah, can't come fast enough. So if people want to learn more about Vistagen, where should they look?

Our website, absolutely, uh, vistagen.com.

So yeah, thank you very much, Sean. I really appreciate talking to you again.

Always a pleasure, Kevin. Have a great summer.

And thank you for watching Talking Biotech Short Reads. Subscribe, tell a friend, share with others, because taking innovation to application requires our communication, especially in social media, because the acceptance and deployment of new therapies requires all of us to be sharing the beautiful solutions that science gives us. I'm Kevin Folta, and thank you for watching Talking Biotech Short Reads.