Episode Transcript
[00:00:00] Speaker A: I'm brutally pragmatic, you know what I mean? I want to figure out what is absolutely the cleanest and fastest path. The thing that they've heard repeatedly is kiss. Keep it simple, stupid.
[00:00:15] Speaker B: Well, Srini, thank you so much for taking the time to have this conversation. I've been looking forward to this for, for quite a while now. The audience at home. Srini is the co founder and now co CEO of Atied Life Sciences where he actually started as the chief scientific officer. But before me jumping in, I'd love for maybe you just give an interest in your career and how you ended up doing all this.
[00:00:35] Speaker A: Perfect. Well, Brandon, thank you so much for the opportunity. Really looking forward to it. My career has been kind of a. Has taken, you know, kind of a number of interesting twists and turns along the way. Grew up in a very small town in Kentucky called Weisburg. Went to the local high school, managed to get into Yale. That wouldn't happen at this point, but back then I was able to get at Yale and was actually going to go into physics as my major switched to computer engineering. Decided I really liked that application bit. And that's obviously going to come up a few times here. This can be salient later. Did a lot of work in digital signal processing. Did actually a master's in digital signal processing. But everything I'd done was really biomedically oriented. And so what became apparent during the undergrad and the masters was that there was a disconnect in the language people speak. So I had done the pre med. Anyway, so then I ended up applying for an MD PhD program. Got into the same one at Yale and did neuropharmacology there. So really focused on wiring in certain aspects of cognition. In fact, all the circuitry and some of the pharmacology that's relevant to one of our compounds is focused on cognitive impairment, schizophrenia. A lot of that actually was one of the reasons I was intrigued by that Communication as well as a compound was based on the work I'd done during my PhD thesis. Oh, wow.
[00:01:52] Speaker B: Yeah, I'm sure we're going to touch on that in a, in a second here. Before we get there, I'd love for you to just maybe tell us the story about how you ended up starting at tie and especially I know that you and Florian are halfway across the world.
[00:02:04] Speaker A: Yeah.
[00:02:05] Speaker B: How did this come to be?
[00:02:06] Speaker A: Yeah. So ATAI really started more as a fund initially it wasn't an operating company. So Christian Agarmeier has a number of these family offices and that's really what ATAI most closely resembled initially the initial investment was Encompass. The second investment was a company called Perception. And, and Perception, one of the co founders is a guy named Jay Kransler and he was my very first boss in the industry. So that's how. And he reached out to me to actually see if I would be interested in being CEO of Perception. Then when I met the team at atay, which was Lars Christian Florian, it just made more sense for me to join at the atelier level, particularly given the ambitions of turning a tie from a fund into an operating company. And that's obviously what I was very instrumental in.
[00:02:51] Speaker B: Yeah, and tell me about that. So it wasn't the initial vision for.
[00:02:53] Speaker A: It to be an operating company.
[00:02:55] Speaker B: What was that transition like?
[00:02:56] Speaker A: Yeah, I think some of that predated me to some degree. Right. So there have been a number. So again, this, this was around early 2018 or so, towards the end of 2019. There was definitely an ambition to invest in more companies.
[00:03:10] Speaker B: Right.
[00:03:10] Speaker A: Enhance perception.
But right around the beginning of 2019, I started talking to and working with Florian right around the beginning of 2019. And we talked about different models and different approaches and it just made more sense to kind of bring more people on. And so very quickly thereafter, I officially joined in April of 2019. But I was helping, I was working very closely with them before. And then there was other people that came on to, you know, chief medical officer and a few others to really make it an operating company.
[00:03:42] Speaker B: What, what made more sense about that?
[00:03:45] Speaker A: The ability to actually take a range of ideas that are early stage and actually do something with them, bring them to an inflection point yourself. So what we found was that there were a lot of companies like cures and other things that were really formed by academics that didn't have, that were very tiny, one or two people. They didn't have the breadth of expertise needed to take the drug into clinic. And it didn't make sense for a small company like that to have all those people. Right. I mean, this was a model by where, by which we could take these things and we could leave the folks that knew the company the asset the best within the ecosystem. But then we could drag and drop people into it with the requisite expertise, whether that's formulation or manufacturing the actual drug substance, or indeed prepping for clinical study.
[00:04:33] Speaker B: Now one of the things that kind of came up in my kind of background research here is how much your engineering background has influenced the way you think about drug development, company building, building a biotech. I'd love to hear from you how that influence has kind of manifested?
[00:04:47] Speaker A: Well, it goes back to what I said. You know, initially I started with engineering, but then I did the PhD that I realized I really didn't like the sort of, you know, the nebulousness of a pure academic research. Right. I did my internship, realized that clinical medicine was really not for me. So that was like kind of the nadir. I wasn't really sure where I wanted to go at that point and, and got introduced to that person, Jake Ransler, through an alumni connection. He was also Yale MD, PhD, but about 10 years earlier. And it really got in gel because this was application. Right. That is what engineering is about. Right. There's science that's been put together from different sources. But then how do you solve a real world problem? And the real world problem here is all these worldly indications. How do you get something to a patient, how do you get this compound to the doctor, how do you actually treat people? So it was a wonderful way of pulling it all together for me.
[00:05:44] Speaker B: And how do you think that maybe changes the way that you approach this relative to maybe like some of your contemporaries?
[00:05:50] Speaker A: I think the team's probably bored of hearing it, but I'm brutally pragmatic, you know what I mean? I don't really care about the proof. I want to figure out what is absolutely the cleanest and fastest path. The thing that they've heard repeatedly is kiss keep it simple. Stupid. Of course, you know, and there's just a lot of kind of learnings from engineering how to keep things simple, how to keep things scalable. Right. Like that's why we did what we did with our DMT asset, for example, way back when. It's like, how do you get something that patients are going to deal with? Well, right. The doctors are going to deal with. Well, that are, that is easy to manufacture kind of schlep around. That's where we went with the oral transfusal belt. Yeah, we could have gone with needles, we could have gone with a lot of other. But it's like we're trying to optimize for uptake, we're trying to optimize for scalability. Originally we had digital therapeutics as part of that as well. We have down prioritized that a little bit just based on where the field has gone. But it was always about how we can make this scalable, how can we make this an actual product that people will take, the doctors can work with.
[00:06:57] Speaker B: Now we're jumping around a little bit, but I'm too curious not to go There. When you think about your DMT asset, surely there must be some trade offs in pursuing this right of administration.
[00:07:07] Speaker A: How did you think about those trade offs? Well, the biggest trade off is that it's very difficult. Difficult to work with. Right. I mean to manufacture, I mean to actually design it and then make it in a scalable fashion is not easy. I mean to make something that is injected is trivial in the grand scheme of things. And if the drug is only bioavailable, there's lots of expertise with that. But these oral fin films as they're known are, you know, much more niche and there's a group of, there's not that many companies that really do that. So we went after it knowing that it was going to be hard. We had a good group of people that were working on it and frankly the results that we got recently exceeded expectations by a pretty significant margin. It turned out to be much better at delivering drug than we anticipated. So yeah, I mean that's always a challenge. Right. So depending on the moiety itself it might work, but it might not get there, might not get enough into the body. Yeah. And we were, we kidnapped. Yeah, it's really good.
[00:08:04] Speaker B: Tell me about that a little bit more. So you went in with a set of hypotheses. How have those updated?
[00:08:12] Speaker A: Well, I mean some of the core hypotheses have actually been borne out. So the core hypothesis was that we want something that fits into an existing paradigm, mainly Spervato.
[00:08:23] Speaker B: Gotcha.
[00:08:24] Speaker A: So that was the pragmatic element that we talked about. Right. There's already a company called JJ that's got lots of dollars behind it. If anybody can do the heavy lifting in terms of establishing a commercial infrastructure, it's them. So let's make something that can more or less get dragged and dropped into the infrastructure that they've created, that they will create. Now this was a couple years ago but. And it was doing okay, but not quite there. But of course now Spravano is doing very well.
Blockbuster this year based on run rate and they've got 4,500 clinics set up and it was a heavy lift because even they stumbled out of the gate and they had to learn a lot and they were able to do it. But a smaller company would have faulted in that process. But now we can ride their coattails. So that two hour window was absolutely critical. That is something that we went after and I'm very happy that we did that. Obviously looked for short acting compounds. We went with DMT versus 5 methoxy DMT because there was more data around it. There was one additional study that was conducted with DMT that actually did show good efficacy. So least that has been borne out as well. So, so far so good. I think for the most part.
[00:09:32] Speaker B: You know, one of the things that also came up as I was doing the research was how it sounds like you. You're always taking kind of like the. The commercial, to use your terms, kind of like pragmatic lens. Like, how does this actually bear out.
[00:09:43] Speaker A: In the real world? Are you concerned at all about how.
[00:09:46] Speaker B: Maybe some of your contemporaries are approaching this and in the way that you've designed it relative to others in terms.
[00:09:51] Speaker A: Of the key players? I think there are. Yeah, there's different approaches and different views. I mean, clearly, obviously we know Beckley very well. We've taken a stake in them. We definitely appreciated their approach to things. Yeah. Which is why we decided to take that stake. Others are looking at, you know, multiple inhalations and things of that nature. I was just aware of the FDA's reticence around things going into one's lungs. I had experience by proxy, essentially. We had a. At a previous company, we had a collaboration with a company called Alexa that actually did inhale product signal administration in your lifetime, most likely. Right. It's called. It was a. I don't remember the trade name, but it was essentially inhaled lox, it bean locks, beans and atypical. So when someone comes into the emergency room and they're agitated, you could use this instead of injecting them or something. So basically kind of breathe it in. FDA made them jump to so many rooms. Right. So many drugs. That's why I did not want anything that went in. So that was kind of a pragmatic consideration. I know about in general having very rapid rate of rise, you know, very rapid PK for a compound that is getting into the brain can be problematic. It can result in tolerability issues. It can result in a lot of different, you know, a lot of things that can be concerning. Including like with 5 methoxymt, sometimes a PTSD like syndrome can occur. So I didn't want that. So I kind of had an idea around the sort of PK that I wanted. But again, VLS01 does hit that BPLO 3. The Beckley asset also seems to have that. It's just some of it is kind of having some experience with CNS drugs previously, but also having experience with inhaled also just kind of understanding, being a physician, been in on that side of it. Have a pretty good sense of what's going to work. Fortunately at previous jobs had a lot of commercial experience as well. So I can kind of fold that in. Sure. That view. Yeah.
[00:11:41] Speaker B: I can see how all these kind of viewpoints are coming together to form a perspective.
[00:11:45] Speaker A: Yeah.
[00:11:46] Speaker B: You know, one of the things that, you know, maybe a, an outside in viewer might look at it, they might say, well, you've got this beckley steak. Developing 5mvo DMT. You're developing your own DMT, both for treatment resistant depression. Competitive in the portfolio. Not competitive.
[00:12:00] Speaker A: How do you think about that? Pharmacologically the two compounds are very different. Both obviously classical psychedelics. But there's a strong activity of the so called 5ht1a1a receptor with 5methosy5dmt that isn't there. With DMT, subjectively and anecdotally people do say that there's differences in the experience of those two molecules. There's compounds there that we can talk about. The reality is that it's a, unfortunately a very big space. There's lots of patients with treatment resistant depression and everybody, you know, you could sort of say all SSRIs are the same, but of course they're not and the standards of care is kind of rotate through and people will respond to one and not the other. The reason for that is that the pharmacology of each of these SSRs psoriasis is actually different. They all hit so called SIRT, that's what we call it makes them serotonin reuptake individual. They hit other receptors and that may be playing a role. Now we don't know that to be clear, but we don't know if you'll pick up different subsets of patients with DMT versus 5 Oxy DMT. But I do know that that fundamental premise of possibly rotating. Right. Is going to be. Is absolutely going to be key. I think that's going to be pretty important. Now the other way to think about it again going back to the size of this population is right now it's on the order of 50,000 patients I believe that are treated on a regular basis with spraviol. Right. That's giving you a $1 billion run rate. Yeah. And there are several million.
So treatment resistant depression, it's about depending on the estimates on 3 million or so. I mean, you know, it's a huge patient population. There's lots of room for different approaches. Yeah. Again, more pragmatically, some people will not like inhale, some people may not like the thing in the mouth because who knows Right. They may have different subjective effects that they don't like one of the others. So we'll see.
[00:13:56] Speaker B: Regardless, you're taking a bet on the shorter duration?
[00:13:58] Speaker A: 100%.
[00:13:59] Speaker B: Yeah.
Diversifying there.
[00:14:02] Speaker A: Yeah. For depression, I think we think that that's really a good approach because of change.
[00:14:09] Speaker B: So specifically for depression, you're taking this bet?
[00:14:11] Speaker A: Yes.
[00:14:11] Speaker B: You're not taking this bet elsewhere?
[00:14:12] Speaker A: We are not. So we are developing RMDMA in the form of EMP01. We recently announced that we're pursuing social anxiety disorder with that. Right. Exciting. Yeah, not very exciting. And we are also developing ibogaine. Ibogaine is for substance use disorders in general. We're developing for opioid use disorder. So those both have much longer effects. I think when all is said and done, RDMA will be more or less like a psilocybin. But I think in terms of duration. Right. Duration, ibogaine is longer. There's no doubt about that. It is, but it's a different environment. It's a different environment where, you know where it's going to be delivered. It's inpatient detox facilities. So just, you know, a different endpoint there. Sure.
[00:14:57] Speaker B: Now, before we dive into social anxiety disorder, one of the things I had to ask Jaz Singh, from your product, you wanted me to kind of follow up and ask, how do you think about long term effect maintenance? It sounds like you're envisioning a world where folks may be cycling on and off. How do you see that?
[00:15:13] Speaker A: Generally the idea is to get the person into remission. That's what that initial sequence is all about. And then use it on a PRN basis, on an as needed basis after that. Because depression, all of these indications are chronic disorder. Certainly they're all chronic. I don't view any of these. This is a cure. There'll be some subset of individuals which will get take the initial sequence and be functionally cured. They want a depression again. That is undoubtedly going to be the minority because, you know, the patient has a life, they have their stressors and that's going to likely precipitate another round of depression or what have you. So the idea is exactly that they get them into remission and then as things deteriorate, when they deteriorate, either go back to that, you know, go back to a single dose, go back to a couple of doses, get them back in remission, let them stay there. Yeah, that's how I envision it. That is more or less what has happened with Srivata. Yeah.
[00:16:13] Speaker B: Do you have any early Inklings on development of chicken resistance or any like.
[00:16:19] Speaker A: This in this category. Yeah, unfortunately we don't. There's just. It's so nascent. Right. I mean really we have one good trial and that is Compass. Yeah, that is our one good trial. I mean we obviously had a 12 week data from that, but that was really it. The phase three program that Compass has ongoing now is going to be very involved. So their first phase three will be reading out soon. The six week endpoint is going to be what it is. I mean, I'm really interested in seeing what happens after that. Right, yeah. Right. What percentage of people get the redose? How does it look on the redose? Their second phase three trial is also going to be very interesting because there they do actually do two doses.
[00:16:59] Speaker B: Right.
[00:16:59] Speaker A: So it's two doses, three weeks apart and then primary, it's six weeks. That's going to be really intriguing. I am curious to see what the incremental benefit is and what that means for, you know, time to relapse. I think it's going to be incredible.
[00:17:12] Speaker B: Yeah. It seems like there's a lot of magic happening in the six to nine month window there. Other people are waiting to see.
[00:17:17] Speaker A: We're all, we're all waiting to see that. It's just, it's just early days.
[00:17:20] Speaker B: Yeah. The second part hitting question for you. Spoke to, spoke to Glenn before this as well.
And Glenn wanted to know your opinion on whether the kind of magic is happening in the subjective experience or potentially isolating the neuroplastic effects. I know the two of you debated this on it.
[00:17:36] Speaker A: We have, we have. I mean the way I think about it is again, pragmatically simple minded. Right, right. It's just there are two phenomena that are occurring. One is neuroplasticity, which we all talk about, but there's also network disruption. That network disruption is manifesting as the psychedelic experience.
But it is alteration in how the networks in your brain are functioning for that period of time. In the context of profound neuroplasticity. That's probably right. Now that's what I view as the key, the interplay. Yes. Because I can envision a scenario where there's lots of network disruption that doesn't result in the absence of neuroplasticity, that then just kind of goes away.
[00:18:19] Speaker B: No change.
[00:18:20] Speaker A: Right. So I can drive. So cannabinoids are a good example because cannabidoids cause all sorts of network disruption and those hallucinatory type behaviors can occur there. But there isn't thought to be this marked Release of growth factors and you don't get persistent beneficial effects. And the converse is interesting, Right. I mean I can. And this one is more of a thought experiment, but I can certainly see that I give you something that is profoundly neuroplastic and in the context of therapy that could be great. Right. So you get, you know, you take something, gives you an hour of neuroplasticity, you go in and actually do some exhaustive therapy. Right. Interpersonal. Yeah, I could see that being beneficial. Conversely, I can see someone taking that, going out, driving a car, having a car accident and that having a profoundly adverse impact. Right, right. Because for the same reason you. And those are two extremes. There's the intermediate one that gives me pause and that is you're depressed, you have ruminative thoughts that are negative. I give you this compound and now you set those ruminant thoughts into even more. You really firm those up in your brain. Not great.
So I mean, these are thought experiments, right.
And we don't know the answer. And I guess we'll, we'll start getting some of those data. I know the. Their Deluxe is a company that's working on the non psychedelic, non hallucinatory compounds. I think they're read out, they have a phase two, but it's, I want to say a year from now or something somewhere in that ballpark. So we'll see. And I. And there was some conjecture that those drugs do have subjective effects. And the question is, is that truly psychedelic? Is it hallucinatory? I have idea. Yeah.
[00:20:08] Speaker B: And do they interplay enough in order to.
[00:20:10] Speaker A: Exactly, yeah, exactly. Fascinating. Yeah.
[00:20:13] Speaker B: Well, now you're on the record.
[00:20:14] Speaker A: But so there's more data. I'm going to stick with that.
[00:20:16] Speaker B: Yeah, of course. You started to touch on your social anxiety disorder program. Maybe just start with how did you start looking at this as an indication? Because I know that there isn't been a tremendous amount of work.
[00:20:27] Speaker A: Yes.
[00:20:28] Speaker B: Done in sad.
[00:20:29] Speaker A: Well, that's one of the reasons we started looking at it. Fair enough.
Social anxiety disorder is very prevalent and it is quite impactful for the patients to have it. It wasn't really front and center until Covid. And Covid had a marked influence on social anxiety, even in adults, but particularly in younger individuals. I mean, I can speak to this personally. I had three kids that were. Yeah, they were all in high school when that started, when they got hit with COVID And it was really tough on them, you know, because they lost these important windows of socialization and you know, they're still recovering quite frankly. So it. It has moved into more prominence because of COVID but it's still where depression was maybe 10 years ago. So there's old stuff that was approved. Right. Two SSRIs and SNRI that were approved 20 years ago. That's it. Therapy works great. Everybody says that therapy works great for trd, but it's difficult to implement. So that doesn't. That's not all that helpful. So that's what. One of the reasons we got intrigued by the indication. Now there was a little bit of data around social anxiety disorder. It is a prominent symptom in autism. Right. It's not quite the same as it is in endurotypical, but there are, there's certainly overlap. And there was a small study that was conducted with mdma. Right. So that was kind of intriguing, robustly positive results. But the results that we got with our MDMA is where we started. We're so. I mean, it was so differentiated and so unexpected compared to MDMA that that's what kind of got us thinking, where else can we take it? And there are a couple of things that were notable. First, we, we were looking at something called the Emotional Breakthrough Inventory.
And not surprisingly, it's a measure of emotional breakthroughs when you feel like you kind of overcome an internal hurdle. What we found is an incredible dose response across the dose range. We testify different doses. So that's always. That's when I get excited, probably say, yeah. I mean, in a phase one, you have small N. You're looking at a bunch of different things. They're all exploratory. When you see beautiful dose responses, that's when things get really intriguing. So we saw that emotional breakthroughs have been correlated with efficacy, particularly with psilocybin and depression, but also in other affective disorders, including anxiety. So that was the first thing that got us intrigued. Then there was a measure we did this measure of self compassion. And self compassion has adversely impacted a number of mental health conditions.
This internal harsh critic can be problematic and depression, but it seems to play a very prominent role in social anxiety. I mean, this harsh internal critic is one of the reasons you feel socially inadequate in the subset of patients. I don't want to over generalize. Yeah. Certainly in subset of patients that. That can play a role. So that was intriguing. Yeah. And then beyond that, this compound just. We looked at these, this measure called the 5 DAC, which is the nature and the intensity of psychedelic experience. And this compound looked a lot like a psychedelic on this measure and not like mdma, which was intriguing. It was a much more inwardly focused thing. But in the details it was different than a normal psychedelic. I mean, like, you know, there is this, there's a, there's a sub scale around visual restructuring and normally that refers to the hallucinations that one sees. But in the case of this compound, patients are saying, or subjects, in this case, or healthy volunteers are saying that they were able to view their life differently. That's a whole, that's a whole different level. Right. You know, a person's just seeing this stuff on the wall differently, you know what I mean? So it's a really intriguing compound. And you know, we could still pursue PTSD with this we had talked about initially. But sad is such a prominent issue and there's no one else pursuing it. Yeah, there's one of the companies looking at a compound for acute administration where you're going in a situation where you know you're going to be anxious. But this could be more rebound. Yeah.
[00:24:32] Speaker B: For the audience, mdma, rmdma, what's the difference? How should they be thinking about that?
[00:24:38] Speaker A: Yeah, so that's a great question. So there's multiple compounds that, or drugs on the market that are actually that consist of two different molecules. And these molecules are like your hands. Okay. Or mirror images of each other. They don't superimpose.
[00:24:51] Speaker B: Okay.
[00:24:52] Speaker A: And just, you know, it's not so easy to stick your right hand into your left glove. It's the same thing with molecules and their receptors. And they're so taking the right handed equivalent molecule, it's going to fit into its right handed receptor. Sure. Yeah. But not so much in the other side. So there's different pharmacology.
[00:25:10] Speaker B: Okay.
[00:25:10] Speaker A: Now many times one of the enantiomers just doesn't have any activity, but in some cases, in many cases they actually do and they're very different. And in the case of mdma, the acid enantiomer is actually much more like a stimulant. So it causes dopamine release, norepinephrine release, it really amps you up. And the other enhancement, rmdma, is much more serinergic. And so the initial conjecture was that by getting rid of the amphetamine like properties we could maybe get all of the benefits which are thought to be serinergic, all of the so called entactogenic properties in a compound with much better safety and tolerability. Wow. So that was the initial hypothesis because if you look at mdma, there are problems with it causes pretty much blood pressure increases. It's the element that pharmacology is associated with some kind of abuse potential. There's purely serene energy, typically is not interesting. So that was another element. You do see other phenomena. You see hyperthermia. It's basically you get a fever in many situations when you take mdma. And that can be dangerous.
[00:26:16] Speaker B: Right.
[00:26:16] Speaker A: And then there's bruxism, which, you know, it's basically grinding your teeth. Wasn't, you know, there were some data suggested that that could be from the dopamine as well and the Norton effort as well. So these are all the reasons that we decided to go after that one. But then when we actually tested it, as I mentioned, the results were fascinating.
[00:26:33] Speaker B: Now, I know that classic MDMA may not be categorized as a classic psychedelic, but you suggested that RMDMA may also have a little bit of this subjective experience. How do you think about that?
[00:26:45] Speaker A: Yeah, I mean, it does definitely. Well, I should say the phase one subject to replication. Phase one, it certainly behaved very much like a psychedelic with some differences, as I mentioned. Right. So there were. It was somewhat in between, I think, from the perspective of safety, et cetera. It was a very inward focused experience. So one of the challenges. Well, the potential benefit, but also the challenge with MDMA is it's externally focused. That's why it's a drug abuse. Right. In the sense that why do people take it when going to a rave? Right. That's why. So we had therapists that actually were familiar with mtv. They had. Yeah. Been therapist in the context of MDMA as well. And they said this was very different. The subjects were internal, they were doing their own thing, they were quiet as opposed to talking and trying to externalize.
[00:27:32] Speaker B: I mean, a big part of what.
[00:27:33] Speaker A: The therapist is doing when someone's on MDMA is saying, go back inside.
Right, Go back. Yeah, yeah. That was not an issue here. Wow.
[00:27:42] Speaker B: And is that hinting at maybe like a little bit of trial design, I guess, benefit of not needing psychotherapy as an assist.
[00:27:50] Speaker A: In all of the classical psychedelic instances, there's really no true space for therapy while the patient is on the compound itself. Now, one can debate how much therapy is actually needed or useful when a subject is on MDMA as well. Other than redirecting, we've never anticipated anything. It's really much more about safety, etc, which is actually no different in some sense than esketamine or ketamine. Right. Because there are perceptual distortions that occur with those compounds. The patient may very much feel out of sorts. Right. That's their kind of psychedelic light in many ways. So you do need someone to keep an eye on to make sure things aren't going sideways. They can have reactions that are very anxiogenic, right? Yeah. And they're kind of. They need to be settled down. That can happen with all of these components. So there needs to be someone monitoring the patients. But we never anticipated therapy occurring. Now, we do view the importance. There is an importance to the prep work. This is a very unusual experience to somebody that's uninitiated.
We're prepping for the real world. We're prepping for where most people haven't taken these compounds as opposed to more trouble weavers, etc. It's a very unusual experience and you need to prep the patient for. Then you need to give them some skills in case things become challenging, because they can. So that's what we want to do in the prep work. And then afterwards, I want to make sure that there's psychological safety stuff may have come up. Sorry, we know that that can happen. Things that haven't been repressed, any number of things can come up. And you want to make sure that the patient is adequately taken care of. Some people will require it, many people won't, and that's fine. But you want to make sure the patient is psychologically stable. It's kind of like something if the patient comes back the next day and says, you know what, I had a little bit of chest pain when we were doing this.
You got to refer them out.
You're going to do an ecg, you're probably going to get a cardiology.
Same thing. That's medical stability. This is psychological stability.
[00:29:49] Speaker B: What does great pre work and post work look like at this context?
[00:29:54] Speaker A: Well, I think a big part of it is as I outlined. I mean, really making sure the subject understands what they're getting into. Yeah, right. And there is, this is more conjecture. So, you know, just let me label it as such. But there is a notion of suggestibility with these experiences. Right. So if you go in being very scared and thinking about other things that may very well come up during the experience. May not be, but it may. Right.
Again, going back to thought experiments, I probably wouldn't want to give this cop out if you on the way over to the doctor's office, had a car accident or you just broke up with.
[00:30:32] Speaker B: Your got some bad news or something.
[00:30:34] Speaker A: Significant other, whatever you're, you know, whatever. Right. You probably don't want to do it then because that may actually make for a much more challenging experience and not necessarily in a good way. Right. So I think Making sure that the subject is. Understands what they're getting into is focusing on what they want to get out of it. That is definitely more anecdotal this one, but I could sort of see how that might be good. If you have the things that you want to work on at a front of mind. There's a possibility that that may be beneficial. That needs to be confirmed for what.
[00:31:06] Speaker B: It'S worth now are the clinical staff meeting the patients and going well, like how bad was your day?
[00:31:12] Speaker A: Well, I mean, generally speaking, yes. What is their mental. Where are they? If they are really looking pretty rattled, maybe you want to not do this. So yeah, I mean, in a general sense, absolutely. And then finally some of the things I was telling you about, stuff may come up that is challenging during the experience. Just learning how to breathe. Yeah, right. I mean the therapist may say at that point, you know, just remember what we talked about, box breathing as an example, you know, counting to four on the inhale for whole, you know, corn. Yeah. Exhale, etc. Let's go try and do that or just take a deep breath hold.
Just having them practice some of these skills prior can just give them some additional psychological mistake. So I mean, I think that's what good looks like until we know more. I mean, maybe the prep work is not that critical, I don't know. But right now the anecdotes are there and they are that. So let's kind of run with that now in terms of the follow up stuff does come up and maybe exploring some of that can be useful like, you know, what was. What can you describe about the experience? It might jog some things that might be useful for therapy afterwards. Yeah, it would definitely be useful for understanding if the patient has any, if there's any concerns around psychological safety.
[00:32:31] Speaker B: You're just kind of scanning for anything that.
[00:32:33] Speaker A: Exactly, exactly. Just, you know, patient safety is from.
[00:32:38] Speaker B: The stutter, of course.
[00:32:39] Speaker A: Always. Yeah.
[00:32:40] Speaker B: Now the last thing I wanted to know about SED is just given there isn't a lot of work that's been.
[00:32:45] Speaker A: Done, how do you even go about.
[00:32:46] Speaker B: Approaching trial design, endpoint selection, anything like that?
[00:32:50] Speaker A: Whole set of questions. Well, there is a regulatory endpoint because there were three drugs that were approved. So there's something called the leroy Social Anxiety Scale. FDA is very comfortable with it and there have been some recent programs that have used that as well.
You know that you kind of re upped if you all made sure that the FDA is comfortable with it. So that's what we're looking at. I mean, we're looking at some other things as well, but certainly it's a.
[00:33:14] Speaker B: Good place to start.
[00:33:16] Speaker A: The trial in question is really proof of concept. It's a early stage trial, so really trying to see how the patients respond to the drug and how they, you know, what kind of a signal we're getting. Right. So it'll really help guide and inform the next trial. In particular, it's early days for one. Yeah.
[00:33:35] Speaker B: Can I take you to the next one in your portfolio here?
[00:33:37] Speaker A: Course.
[00:33:38] Speaker B: Let's talk about cognitive impairment for schizophrenia. And looking at the portfolio, one might say schizophrenia feels a little bit different than anxiety, depression. How did you end up there?
[00:33:48] Speaker A: So when a tie was, you know, when we talked a little bit about Ty's model transitioning to an operating company, we had a pretty broad mandate at that point across mental health disorders. And we have a pretty broad mandate in terms of the business model as well. So we were doing partial and back, we were doing investments. We had stake ultimately in a public company like form of Compass. But you know, again, we had these. We were taking, you know, majority stakes in a number of these academic small startup companies as well.
Again, really broad across mental health. And Recognify, which is the company that's developed, that's got the R007 was an example.
Really fascinating compound. A very unusual compound that was phenotypically characterized. I mean most drugs these days are pharmacologically characterized. We talked about 5ht 2a agony. So that's pharmacological characterization of the drug. This drug was put into a lot of animal studies. Basically they showed low doses, procognitive, high doses, analgesic, and that's. It didn't hit any of the usual receptor screens. And then they, they did some additional works in the procognitive settings and the analgesic settings. You could put antagonists in and you could sort of see that, oh well, you put a gaba, the antagonist in it seems to go away, the benefits go away. So you can surmise what the pharmacology is. But it wasn't direct. Right. And then there was all these clinical studies that actually showed procog effects. There was three at that time. Right. So you put it all together, it's like, wow, that's a really interesting thinking about. And there's a huge, huge, huge un. Medical need in cognitive impairment schizophrenia that is literally ubiquitous. And folks, rights with schizophrenia. Yeah. It's just an issue of when it becomes impactful. Yeah. If you were supposed to have an IQ150, then you lose 2sigma or 3sigma, you're doing okay. Yeah, you're just fine. If you are normal or below normal and you lost two or three sigma.
[00:35:45] Speaker B: Right.
[00:35:45] Speaker A: Each one of the sigma, there's 10 points you're impacted and diversity.
So that's how to think about it. So it's 85% of people are impacted. It's one of the. It is one of the major drivers of institutionalization, the disability, the costs associated with the patients. That's a major driver. So anything that we can do to even incrementally benefit the patient is going to be huge. It's going to be huge. So I anticipate this ideally in the context of some kind of occupational therapy, if it can kind of bend the trajectory of the patient over time. Doesn't have to. You know, it's like, you know, there was these models for the meteor or an asteroid in this case coming towards the earth. You just put a small rocket booster on it and you just do it for a long time. Right. You can change the trajectory even now, even that is fantastic for this population. If you can just change it. Absolutely.
[00:36:39] Speaker B: Now maybe talk to me a little bit about why start with schizophrenia per se? I know that cognitive impairment presents itself in a variety of other indications. One would say schizophrenia might be the hardest to kind of do this research on. Why start there?
[00:36:54] Speaker A: That's why.
[00:36:55] Speaker B: Okay.
[00:36:56] Speaker A: No.
[00:36:57] Speaker B: Okay. I love it.
[00:36:58] Speaker A: It was hard.
[00:36:59] Speaker B: Do the hard thing first.
[00:37:00] Speaker A: Yeah, it's hard. And that's what causes a lot of people to shy away. But the need is so big, and it behooves us to go after that and see if we can help those patients in the best of all possible worlds. Do a couple of different. Yeah, that would be fantastic. Yeah. It was outside of our mandate and stones outside of our mandate to think about outside version things. But dementias of different sorts would be great. Right. Be wonderful to try a couple different things. There is more heterogeneity in some of those medications than there is in schizophrenia, which is not. I mean, schizophrenia is not our genes, but there may be a little less there. And certainly some aspects of the pharmacology of this drug do tie into some degree the underlying deficits that can be seen in schizophrenia. So there's very broadly some alterations in inhibition versus excitation in the brains of folks with schizophrenia. This drug is impacting one aspect of that, the inhibitory side. And all the drugs are being pursued for this indication at this point. There's. They're either gladiatorgic or they're gab. So in excitation or inhibition, I love.
[00:38:07] Speaker B: The kind of framing of we're doing it because it's hard. You know, one of the things we say at power is that if it was easy, there wouldn't be an opportunity there.
[00:38:14] Speaker A: Exactly, exactly. Yeah, exactly.
[00:38:17] Speaker B: Totally. Everything that's worth doing is probably hard right now.
[00:38:20] Speaker A: Yes.
[00:38:21] Speaker B: Yeah.
[00:38:21] Speaker A: Yes, that's right.
[00:38:23] Speaker B: Now I want to zoom up a little bit here. We've kind of taken a quick scan through the portfolio. Triggers depression, social anxiety disorder, cognitive schizophrenia. How do you think about portfolio construction writ large?
[00:38:37] Speaker A: So, I mean, again, it's been an organic process at a time. Right. So it was a broader portfolio for a very long time and a diversity of models there.
We've obviously slimmed that down pretty significantly over time. And a lot of that was really organic. So we did have some negative results. We had very high bars for working directly. Yeah, things didn't work and that's okay. Yeah, that's a normal course. What we didn't do was replace.
Right. So there was a realization that. I mean, biggest complex and you know, complex is obviously. Well, it's complex. It's hard to. It's hard to manage the time. So going back to one of my organizing principles, which is kiss, it's like, all right, let's really try to simplify this down. We've got a really nice portfolio at this point. I think there's really good drugs, good approaches at this point point. Complimentary things and depression. Something that is orthogonal with rmdma, different pharmacologically than everything else that's being developed. Different indication. I like that. I mean, there's a number of different psychedelics that fundamentally are all. You know, I have a lot of similarities. I said that the market size is big, and that's true, but having something that's going in a different direction is also nice. And then of course, there's ibogaine as well. And then of course, R007 is completely different. So I think we're in a pretty good place. We're well funded to get these phase two readouts, everything that we've talked about. So certainly the LSO1amp 01 Toro 7, which is ongoing. So all of these phase two trials are either about to be initiated, but all of them recovered, will read out over the course of the next year. Ish. Pretty good place from that perspective. Yeah.
[00:40:16] Speaker B: And tell me a little bit about the. Maybe desire not to replace at all. Again, keep it simple. But any temptation here to tuck another.
[00:40:23] Speaker A: One in, there's always temptation. Of course there's always temptation.
There's always, you know, you start thinking about and this gets back to actually I think what Glenn had mentioned.
[00:40:35] Speaker B: Right.
[00:40:36] Speaker A: It's easy. I love doing that. Right. I love the creative element. I like blue sky. I like coming up with, you know, cool new ideas with the team. Right. But you know, in the end you've got a finite amount of resources. There's only so many people in the company. And yeah, we got to focus on where we are and what's going to be the most meaningful in terms of inflection points so that we can continue to raise money to continue to develop the drugs and make sure they get to people as quickly as possible.
[00:41:03] Speaker B: Now I've got to ask, when I look at your portfolio versus maybe some.
[00:41:06] Speaker A: Of the others, I see a mix.
[00:41:08] Speaker B: Of psychedelic, non psychedelic work. Was that always the vision to kind of do a broader thing about that?
[00:41:13] Speaker A: Yeah, yeah. Initially it was broader. Obviously again, over time, just because of. For a range of reasons, we kind of pulled that in a bit. And there's some other benefits as well. So we have focused on. There's some other nice things about psychedelics and that is that they're what I refer to as a tractable commercial problem. So if you think about a normal SSRI or something like that, it is a lot. You have to hit a lot of doctors. So when you think about commercial scalability, it's tough, right, because there's 25,000 ish psychiatrists and physicians that sort of function like psychiatrists too detailed. To actually reach all those doctors with the sales force is a big undertaking. It's a 2,500, 3,000 person sales force versus you know, I said 4,500 clinics so far. Even if that doubles, this is a much more, this is a much smaller kind of sales force. Could be okay. I mean I, even I, my understanding is even J and J is like no more than 100, maybe 200 sales reps. That's what I envision here. And we now have some synergy. Right. So it's difficult to justify sometimes the cost of a salesforce with just one product. But now that we have more than one, it actually starts to work. Assuming that we're fortunate enough to have more than one of these get to market. But if that happens, where you start to see some real financial synergies there. So again, kind of keeping that in mind as well.
[00:42:41] Speaker B: And the goal is to grow the commercial org once you get there.
[00:42:45] Speaker A: I mean, if the appropriate opportunity happens then.
But yes, I Mean, I would love to take this board into the commercial space ourselves. Part of its pragmatic, retain as much of the economic upside as possible and.
[00:43:00] Speaker B: Not closing any doors today.
[00:43:02] Speaker A: Of course not. We're too early in this game. So. Yeah.
[00:43:06] Speaker B: Now maybe the last kind of set of questions here. I'll just hear you talk a little bit about the transition to CEO and how you deal with that.
[00:43:13] Speaker A: Well, I mean, I've had the role in previous companies and have been basically very much startup person all the way through.
It's been Florian and I for the last five years and we've had these discussions all the way through about co CEO. Even around the ipo, I pushed, I was like, yeah, that's kind of weird. Let's not do that.
Because we brought very different skills, very complimentary skills and very complimentary personality styles. So it was, it's been a, it's been a fantastic journey with Florian and we, you know, very proud of what we built together. But as the portfolio is kind of, as the company's turned into more of a traditional pipeline play, it just makes more sense to kind of winnow it, you know, to, you know, you don't necessarily need all of that now, the acumen on the business side, which is really critical for all this, you know, with this complex business romp. So, you know, it makes sense. I've always been involved in many of the CEO type functions as well, like all the fundraising, you know, all of that has always been basically Florida myself. Got a good team behind me, everybody knows me.
[00:44:25] Speaker B: Right.
[00:44:25] Speaker A: Which certainly helps.
[00:44:27] Speaker B: Yeah.
[00:44:27] Speaker A: You know what I mean? So, I mean, as far as transitions go go, I think this one's a pretty nice one. And of course there's been a good overlap here as well to really kind of properly hand off responsibilities.
[00:44:40] Speaker B: So looking into the future, what are you most excited to continue investing in?
[00:44:43] Speaker A: I mean, the portfolio that we talked about.
[00:44:45] Speaker B: Right.
[00:44:45] Speaker A: So we've got some, we'll have some really good readouts over the course of the next year to 18 months. And that's obviously that's going to drive where we head next, but I like the multiple opportunities here. We've got a lead, we've got something that's behind that actually. I guess in this case there's sort of two of these. One, it's like that way can the other one also. But I think that those readouts will help really define the company and change, you know, obviously define the course after the next 12 to 18 months.
[00:45:15] Speaker B: And outside of your own readouts, what are you most closely Watching.
[00:45:18] Speaker A: Wow. Compass, obviously. Of course. Yeah, compass, obviously. But, you know, there's quite a few. I mean, there's GH research having their Flynn Foxy DMT readout coming up. Simon has a GAD readout coming up. Reunion has one in postpartum depression. So there's a few that are coming up. I mentioned Alex already from the non. Non health side. So lots of opportunities in the other indications. So definitely watching those is several outside of the space as well. There's a lot of activity and depression, I think. Absolutely. You know, again, unfortunately, a very big. There's lots of unmet medical need. But that's one of the reasons that I'm really intrigued by. In going into some other indication, of course. Yeah.
[00:46:00] Speaker B: Not much has been done for many years.
[00:46:01] Speaker A: Yeah. So finding other indications. Of course, the psychedelics potentially have utility outside of depression, obviously. Right. So we're looking at other indications and thinking about other things for these. These compounds as well.
[00:46:13] Speaker B: So any hints?
[00:46:15] Speaker A: No, I mean, nothing is far enough along to really say. I mean, right now our heads are down on getting these trials, of course, running and executed, but obviously we do continue to do commercial assessments and watch other parties. It'll be, you know, it's going to be a little bit of time before we make any decisions around that. I want to see some solid phase two. Phase two results first, of course, and then, you know, raise money for it, get the phase two program going and start thinking about other phase twos.
[00:46:43] Speaker B: All very sensible.
[00:46:45] Speaker A: Pragmatic Baby.
[00:46:46] Speaker B: Yeah, no, that's right.
[00:46:47] Speaker A: Got a problem solved.
[00:46:48] Speaker B: That'll be the title of the podcast that's Pragmatic Baby.
My last question is Magic Wand. You go to Magic Wand, you can change anything about how research gets done and you're psychiatry.
[00:47:01] Speaker A: What are you changing? Cheer God. The placebo effect.
Oh, my gosh. Yeah. Yeah. It's funny to go back and look at some of the old clinical studies, Right. And you know, they're more like normal studies. Right. I mean, there's small placebo effect. There's really good response with the drugs. The trial sizes aren't very big. And just seeing where that has changed to have us change. And of course, you know, the entire space has changed. It's more complex and there's many more layers within it, you know, with different kind of, you know, the sites and then the CROs and how they all interact and all that. There's just a lot of different layers at this point. But, yeah, I think that's a big challenge to the space. Yeah. You know, you Sometimes look wistfully at some of the other, other indications with very hard endpoints, like obesity, for example. It's like, sure, well, you know, you know, it's pretty easy. It's very hard. There's, well, there is a placebo effect, believe it or not, but it's a, it's not very robust and it's not like this and it's not, you know, you can, you've got a very hard endpoint. So I think that's the biggest challenge. I mean, of course, biomarkers and things of that nature. Yeah, they're not really, they're not robust. It won't be robust for a while here. You've got to ask the patient. Right. So I'm.
[00:48:14] Speaker B: Okay, I got to ask the follow up question. It sounds like the placebo effect has gotten more pronounced.
[00:48:19] Speaker A: It has.
[00:48:20] Speaker B: Take us into that a little bit. What do you think is going on?
[00:48:22] Speaker A: Oh, there's many papers that have been written on this one. I don't know. I mean, again, part of it is what I alluded to that I think the field has changed, the patients have changed, the doctors have changed. I think it's much more industrial at this point. A lot of patients will say what the docs want to hear. There's professional patients that are involved in multiple things. There's a phenomenon of patients, you know, the jot form. There's huge chat rooms that are based, that are around us that tried to take apart what's going on with your trial and figure out what they're on and whether or not, you know, so there's just a lot of different phenomena that's changed over say maybe more than 20 years. I mean, certainly 30 years ago. The trials were very different. There's so many people who spent so much time trying to figure out how to make this better and really nothing.
[00:49:12] Speaker B: Is board approved, lots of paper, something.
[00:49:14] Speaker A: Exclusive, nothing concludes, nothing conclusive. It's an interesting. Yeah, absolutely.
[00:49:20] Speaker B: Well, there you have it. No more placebo response.
[00:49:23] Speaker A: Yeah, that'd be great.
Ten patients, though, make it a lot.
[00:49:27] Speaker B: Easier for you, I'm sure.
[00:49:28] Speaker A: Yeah.
[00:49:29] Speaker B: Well, Srini, thank you so much for taking the time to have us.
[00:49:31] Speaker A: Yes, it's my pleasure. Sure.
[00:49:33] Speaker B: This was brilliant. I really appreciate it, Brandon.
[00:49:36] Speaker A: Yeah, we had enjoyed it.
[00:49:37] Speaker B: That was a great time.
