Hello, everyone. Welcome back. We are now speaking with Srinivas Rao, the co-founder and co-CEO of Atai Life Sciences. So Atai is a portfolio company within mental health, with a focus that's not exclusively on psychedelic medicine. Recently, the company entered into a partnership, moving it to what we consider to be a leading position amongst the short-acting psychedelic therapies, adding multiple important, late-stage catalysts in the relatively near term. But there's much more going on at Atai than that. So with that, I think, Srini, why don't you give us a brief two to three-minute overview of what Atai is all about? Yeah. Thank you so much, Michael. Really appreciate the opportunity to speak today. Yeah, I think you did a nice job with primarily depression, anxiety, opioid use disorder, and schizophrenia at this point. We did indeed have a platform kind of model. We are certainly kind of focusing considerably going forward. Actually, we have with Beckley that it did indeed give us BPL-003, which is a short-acting psychedelic compound that'll be reading out in well, they'll be completing enrollment of their trial in the latter part of this year. Beyond that, we have a number of other assets internally. So our lead is something called VLS-01. It's an oral thin film or transmucosal film of DMT, N,N-DMT, which is a psychedelic compound, the active moiety in ayahuasca. We're also developing R-MDMA, so the R enantiomer of MDMA. We're developing that for social anxiety disorder, and finally, we're also developing ibogaine, an IV formulation of ibogaine for the treatment of opioid use disorder, so those are sort of the psychedelic or psychedelic-like assets that we're developing. We also have a compound called RL-007, which is in phase IIb currently for the treatment of cognitive impairment associated with schizophrenia. The first two assets, VLS-01 and EMP-01, the R-MDMA, will be kicking off phase II trials later this year, and we anticipate readouts in the middle of next year. BPL-003, again, wrapping up the enrollment later this year, and you can anticipate readout shortly thereafter, and then finally, RL-007, large phase IIb readout, middle of next year. All right. A lot of bit going on. That there is. So, I would actually like to start in that vein. Atai is something of a unique company within mental health and within psychedelic medicine. You have a number of assets, both fully owned and partnered. So can you talk just a little bit about the broad Atai strategy and why this might be attractive for investors? Yeah, I mean, again, you know, we certainly, and when this company was founded, it was much had a broader kind of platform feel to it. We did have a number of subsidiaries, and to your point, we had a range of models, right? So we had internally incubated, wholly owned subsidiaries, all the way to investments in, you know, stakes in public companies. And indeed, we still do have a stake in Compass Pathways, and that's mainly historical, that the companies kind of grew up together, as it were. And we had a stake in the company that was pretty substantial initially, but of course, with subsequent rounds and them going public, our going public, you know, that stake has been reduced. Generally speaking, we're focused going forward on the internally developed assets, and that was, you know, VLS-01, the DMT asset that I mentioned, EMP-01, which is the R-MDMA, and DMX-1002, which is ibogaine. BPL-003, we, we have a one-third stake in Beckley at this point. We have opportunities to bring that closer if we choose to do so. So we have warrant coverage that takes us close to, I think just under 50%. Mm-hmm. And we have a ROFR structure that does allow some additional flexibility to again bring the asset in closer if that's where we choose to go, potentially based on the phase IIb results, which I mentioned. So RL-007 is in a separate entity called Recognify, a very interesting asset. Majority-owned. We have a lot of input both at the board level as well as in terms of the team that's focused on this. So in some ways, I consider it an internal asset. But most of the other, you know, so you know, the model has shifted. Where we're going forward is really kind of focusing on these assets that I just mentioned. So you've essentially found the assets that you think are the most value for the investors? Yeah. Yeah, I mean, I-- that's a... Yeah, exactly. I mean, certainly, it's been a process. You know, we've had very high bars for all the assets. We did have a more diverse portfolio, as you pointed out, early in the company's genesis. But for a range of reasons, including sort of natural attrition, we've pruned that portfolio back. We haven't really added anything to it other than Beckley. You know, we've known Beckley for quite some time, like the team, understand their asset, their lead asset very well, fits very closely into our paradigm, which I'm sure we'll be getting into, and thus made that investment early this year. Mm-hmm. Now, as you were just saying, I would actually like to get into that a little bit because you have focused quite a bit on these shorter-acting psychedelics. You have the 5-MeO with Beckley, you have your own internal DMT, as well as the IV psilocin. Yes. Can you talk about the importance of short acting within psychedelic, and is this kind of the focus? Going forward, getting compounds that fit into that two-hour window? Yes, in short, on the latter point. So yes, we're focused on assets that fit into a two-hour window in the depression space. So all the assets that you pointed out are targeting you know, either MDD or TRD, right? So, and the reason for that is actually pretty straightforward. When we started Atai, I mean, there was, you know, this is sort of in the two thousand and eighteen kind of timeframe. You know, we just had Spravato getting approved. I think that was early two thousand and nineteen. We knew that there's a lot of commercial might that J&J can bring to bear. They basically, you know, if you look at Spravato's label, there is a two-hour paradigm that's outlined there. So the patient comes in, they get dosed, they have to stay in the doctor's office and be monitored for a minimum of two hours, assuming stability of the patient, you know, medically, psychologically, then they can be discharged. Given the fact that this was a J&J thing, we assumed that that would be something that they would be able to actually fully implement, and indeed they have, right? So the run rate this year is $1.1 billion worldwide, and almost 60% growth year-on-year in the United States. So really impressive results, and, you know, obviously, next year will be potentially larger still. So that's where we focused initially with VLS-01, but then also with BPL-003. We want products that are essentially drag and drop- Yeah into that, Spravato paradigm. So Spravato, again, you come in, it's sprayed into your nose, and then you hang out for two hours. Now, why are we looking at DMT and 5-methoxy-DMT? The challenge with Spravato is it's a lot of doctor's visits. So in the first four weeks, it's eight visits. You have to come in twice a week, then the subsequent four weeks, it's another once a week. So, you know, over the course of eight weeks, you've visited the doctor 12 times. It's a substantial amount of the day, if you think about it, 'cause, you know, you add on the commute times on either end, there's gonna be some time in the doctor's office. It's just a lot of visits. It's a lot of logistics, both for the doctor and for the patient. So our conjecture is that a psychedelic compound will give you much better durability. Mm-hmm. How much durability that it will be is something that we're gonna determine. That first phase 2b from with BPL-003 is gonna be an important, really important data point in that regard. We anticipate something a lot easier to work with. Same paradigm, something you can drag and drop in, but markedly increasing throughput and scalability from the doctor's perspective, markedly improving, you know, logistics for the patient. Do you- So that's kind of been our stick with this. Do you have a sense of how many centers out there are currently equipped to administer either ketamine or Spravato? The data is a little more shaky with ketamine itself, but Spravato, if you look at the REMS, it's on the order of five thousand currently. Mm ... that are, that have been through this REMS process from what we understand. So, you know, it's a substantial number, but it's not... You know, this is an interesting point. It's not so many that a small company can't actually have their own sales force and approach it, right? Yeah. So this is not like, you know, having to detail to twenty-five thousand psychiatrists and primary care doctors who sort of function like psychiatrists. That's a big sales force. This is something that is tractable for a small company. So that was another appeal to this space. Mm-hmm. Got it, so you know, as you may know, the rejection of the MDMA-AT from MAPS was disappointing for the space, but there were many issues surrounding trial design and handling the protocols, functional unblinding, among others. I wanted to ask if do you anticipate these challenges will persist in this space, or does Atai have strategies in place to sort of mitigate or overcome these issues in program designs? Yeah, I've been saying that this is, and many others have been saying, that this is really a Lykos issue. So if you think about the big picture around functional unblinding and other things, I mean, these are known phenomena with all classes of psych, you know, psychological drugs or psychiatric drugs, right? So, olanzapine, which is a typical antipsychotic, you know, if you're in a trial, one person takes a drug, you know, or a placebo. One person takes a drug, and in two weeks, they've gained several pounds and they're sleepy. You know which drug they're on, right? So it's just, it's a known phenomenon. There are ways of mitigating that. I mean, doing dose ranging is important, looking at durability of response is important. So there's a number of different ways that one can address it, and indeed, these have already been addressed. I think that's the important thing. So a lot of what we talk about with psychedelics has already been, you know, addressed by J&J with Spravato. Spravato or esketamine is kind of a psychedelic light, right? So there is a dissociative phenomenon that occurs, and it occurs in the majority of patients. There is functional unblinding due to that, and it does get better as time goes on, and the number of administrations goes up. But nonetheless, there's a functional unblinding that occurs there. Long and short, the J&J put together a data package that went through an AdCom easily. It was fourteen to three, I believe, is the final vote on their AdCom, and, you know, they went through first-round review with the FDA with breakthrough designation, so just a completely different, you know, trajectory compared to Lykos, and it just comes down to the quality of the data that they put together, right? The data package was substantial. I mean, one of the challenges that I always saw, and, or maybe a factor that I never quite understood, is the small size of the trials that Lykos submitted. The trial sizes are sort of, you know, they if you put them both together, I think they're on the order of maybe patients each, including placebo, so a hundred and sixty subjects in the phase two program, that's smaller than Compass' Phase 2b. That's smaller than, you know, than the BPL-003 phase 2b. So these are tiny studies. It precludes a lot of opportunity to do subset analyses and things of that nature, really understand what the drug is doing. So there were a lot of issues here that I think were very unique, and some of it comes down to the model, right? So you know, MAPS previously and then Lykos was really wanting to get this drug developed without traditional investors doing this strictly through donations, in essence, which didn't allow them to raise a ton of money. And you know, doing large phase 3 trials is really expensive, right? They didn't have the sort of cash that was necessary for that. So there's a lot of reasons for why they ended up where they were, but a lot of these issues are really Lykos specific and have been addressed by other companies, Compass, J&J, among others. And of course, we have, you know, coming in behind them, we've taken all the lessons learned and we've adapted those into our own trials. I'd like to shift gears here and start talking a little bit about your classical hallucinogen programs. I guess, in particular, starting off with VLS-01, can you talk about some of the differences between DMT versus 5-MeO-DMT? And then what are the advantages of using an oral thin film? Is this just to have another option for dosing, or do you think there are any that will be particularly differentiating about it? Yeah. So, you know, starting with the first question, there are marked differences in pharmacology between 5-methoxy-DMT and DMT. 5-Methoxy, you know, they hit different serotonin receptors differently. 5-HT1A, in the case of 5-methoxy-DMT, that's sort of primary. In the case of DMT, it's really much more the receptor 5-HT2A, which is thought to underlie the psychedelic effect. Subjectively, there have been differences noted. However, there are also compounds from the pharmacokinetics. Mm-hmm. So many times when people are taking 5-MeO-DMT, it's a very rapid, it's an inhaled process, so it's taken into your lungs, it's absorbed almost instantaneously, very high concentrations available in the blood. So that's going to have an impact on the subjective effects. And then if you think about DMT with Ayahuasca, it's almost exactly the opposite, right? It's a multi-hour thing, and relatively low levels of DMT at all points. So there are differences subjectively, but it's you have to dissociate that from the pharmacokinetics. Going back to the pharmacology, you know, it's entirely possible that there will be differences in efficacy and efficacy profile. 5-HT1A, for example, has been associated with certain for anxiety, for example. I mean, buspirone and other compounds actually hit 5-HT1A. Will that have relevance here? Don't know. So, certainly, you know, it's something that we're looking at. We're in a very unique position to actually assess this because we have two separate products, BPL-003 and VLS-01, with very similar pharmacokinetics, but two different moieties. So this is something that we'll be talking about a little bit later. Now, in terms of the formulation, we picked formulation. So DMT, of course, is not readily available, so you can't- Yeah ... take it as a pill. And also, if you want to keep something short, right, if you want to keep it as a two-hour, you know, within a two-hour window, oral isn't great because it takes, you know, fifteen, thirty minutes, up to forty-five minutes if the patient's eaten something sometimes to get things absorbed. So you want something else. We wanted something that would be patient-friendly, that would be doctor-friendly, so we avoided things like injection, whether it's subcutaneous, certainly IM, IM can be painful. We also, for the internal program, wanted to avoid intranasal. I've done work with intranasal in the past. And, you know, some people have irritation. They have some nasal irritation, some people just don't like it. So if you look at Spravato, it's on the order of 10% or 15% of patients do have some degree of AEs, depending on the trial, associated with nasal discomfort. Oral thin film is a complex formulation, but when done right, it's very easy, and it's basically like a Listerine strip that's put on the buccal surface, the inside cheek, cheek surface. It's a strip that actually dissolves away on its own accord, and it releases the drug over a period of time. And, you know, again, we got very good pharmacokinetics with our formulation. Again, you know, it was really around making sure that this is something that was scalable, well-tolerated by the patients, easy to use, easy to apply for the doctors as well. Mm-hmm. There are a few others advancing the same compounds. Could you just talk a little bit about how your DMT and 5-MeO programs compare to other short-acting offerings in the market, such as those from Cybin or GH Research? Yeah. So GH Research is doing an inhaled, their lead, actually, at the moment, the one that's in their phase 2 study, is inhaled 5-methoxy-DMT. I had some experience with a previous company, that was developing an inhaled, product, and actually for very infrequent use. So this was, an atypical antipsychotic called, loxapine, which was to be used when a patient comes in agitated into an emergency room. And this is something you could just basically, they could breathe it in. It was essentially vaporized and then it would be absorbed. So same kind of concept. FDA really hated it. The pulmonary division is very persnickety about things going into the lung. So when we started developing the LSD one, we certainly looked at inhaled, but that was one of the concerns. I'd had this experience previously, and I knew that the FDA had issues with that. And that's been borne out to some degree. We know that. I don't know the details, obviously, but publicly, we know that there's been some talks, discussions with the FDA. So, in the United States, the lead that's inhaled is on clinical hold, at least the last time we checked. So, pending some pulmonary talks. So that was the first thing. The other thing was around pharmacokinetics. I, you know, with compounds of this nature, I've always been a little reticent to have very rapid pharmacokinetics. The sort of pharmacokinetics that could actually result in sort of patient obtundation, you know, and that's not necessarily something that is, you know, the best thing for the patients. It actually came up with the, at the AdCom, you know, there was concerns about potential, for, you know, abuse, you know, sexual assault, et cetera. I mean, if the patient is not arousable, that's obviously something that's, more likely to happen. It didn't come up in the context of esketamine, interestingly enough, even though that's a dissociative anesthetic, but, you know, something that we were certainly keeping in mind. So those are the sort of two considerations that kind of, led us away from, inhale. Very different profile, very rapid PK, does come off more quickly, but potentially more redosing in the same day. Cybin is doing a different indication, so they're doing anxiety, GAD, and theirs is also intramuscular. And again, that was just something that we wanted to avoid because intramuscular can be painful, and, depending on the volume, it depends on where you-- I don't know where they're injecting it. If it's a very small volume, you could do in the deltoid. Otherwise, it's more invasive and, intrusive, if you will, if it has to go into the gluteus or something. So these are some of the considerations we had, certainly, and those are the points of differentiation. Mm-hmm. Now, I'd like to also ask about your non-classical hallucinogen program, specifically R-MDMA. Why go for the R enantiomer? What interesting differences are there between R and S and racemic MDMA? This is also an area where we saw some interest from others in the space that is MindMed. Yeah. Yeah, so it's a really interesting question. When we started this, we were... The idea was that-- So stepping back for a second, you know, again, MDMA has these two enantiomers. Like many other enantiomer stereoisomers, they have very different pharmacology. S-MDMA seems to be more amphetamine-like, and R-MDMA was found in animal models to be more serotonergic. So S-MDMA is more dopamine, dopamine and norepinephrine. So our initial hypothesis was that you might be able to get better tolerability while maintaining the same kind of beneficial effects of MDMA, of racemic MDMA, insofar as the hypothesis was that those are being driven by the serotonergic activities. So we did a phase one, and it turns out to be very difficult to isolate R-MDMA, so we couldn't do the normal thing, which is just, you know, basically use a column to separate out the R-MDMA. We actually had to do synthesis of it, stereoselective synthesis. We produced it, we tested in the phase one, and we had completely surprising results. So obviously, we can go to much higher doses because we got rid of the stimulant, right? So, you know, if you think about the normal, the dose that was used in Lykos, it's on the order of 150 milligrams. That means you have 75 milligrams of R and 75 milligrams of S. We were able to go to two hundred and twenty-five milligrams of R because we got rid of all the stimulants. What we found was a profile that was completely different and from what was seen with MDMA. So much more inwardly directed, much more in common with a psychedelic compound. If you've looked at the standard measures, 5D-ASC, things like that, that's just a standard measure of the intensity and nature of a psychedelic experience. There's subdomains in it. When you look at it broadly, very much like a psilocybin, very different than MDMA. Other aspects were measures of emotional breakthrough, which has been associated with efficacy and affective disorders like depression, anxiety, self-compassion measures that showed some persistent changes out to a week. So there are a lot of interesting phenomena that we saw with this compound. That is what actually got us thinking about where we could take this. Initially, we had guidance around looking at PTSD, still on the you know still something that we're considering, but there were other indications that this profile kind of opened up, one of which is social anxiety disorder, and that's where we've decided to take this forward. So we think of social anxiety disorder, I mean, I think people have a general sense of what that is. You know, it's a fear of social interactions. I don't think what's fully appreciated or hasn't been appreciated until relatively recently is how impactful that can be. Mm-hmm. And how pervasive it is. I mean, it's upwards of eight million people in the United States that do meet criteria for social anxiety disorder. It's kind of come into the fore really since COVID, right? 'Cause there was a lot of discussion, particularly among younger individuals, kids in high school, et cetera, that were really impacted, right? They kind of missed out on some key years for social interactions in high school and, you know, or even grade school, and they were kind of left with a lot more social anxiety. So big picture, we kinda think of social anxiety disorder as being an indication that is sort of like 10 years behind depression, right? So 10 years ago, depression, yeah, it wasn't really... We all knew that it was out there. There was treatment-resistant depression, we knew that. Yeah, a lot of approvals, kind of a lot of years ago, just like social anxiety disorder, there were SSRIs and SNRIs. Yeah. Cognitive behavioral therapy works great for depression, seems to work pretty well for social anxiety disorder. Yeah, it's kind of difficult to scale up. So that's where it is right now. We're really excited about the possibilities there with EMP-01. ... No, this is actually, this calls back to a conversation we were having earlier about just how much of a problem social anxiety disorder has become, and you've seen COVID stunting, the loneliness epidemic, social media, and online interaction, all of it contributing to rising prevalence. Yeah. Now, you're planning to launch not just one, but two of those phase two studies by the end of the year, the treatment-resistant depression, but also the social anxiety. I'd like to touch on that one a little bit more, and just how you expect our MDMA might be applied in this condition. Because there are a number of avenues you can go down in social anxiety, whether it's chronic or as needed, and then what sort of endpoints you would be looking at, such as some of the traditional measures like LSAS-Liebowitz or SUDS. Can you talk a little bit more about that plan design? Yeah. So, it's a really important question because you had brought up MindMed as well. So MindMed is looking at social anxiety disorder in the context of autism. Mm-hmm. And my understanding is it's much more of a low dose, kind of chronic or subchronic type of paradigm. So we're doing kind of the opposite. It's much more of an acute and sort of intermittent paradigm. Relatively high dose, so very much like a more traditional psychedelic, or indeed, what Lykos/MAPS did with the PTSD study. So higher dose delivered once, twice, et cetera, and ideally getting some marked resolution of the symptoms that hopefully is quite persistent, and that's what we're really going for. The point, the question around endpoints is really a very salient one. Given the nature of the indication, the way we're approaching it, where it's more of a, we're looking for improvements in a chronic, you know, on a chronic basis as opposed to a situational basis, right? Which is what Vistagen is doing. So Vistagen is doing SUDS because they're really doing it on a PRN type thing. Yeah. If you're going into a situation where you know it's gonna cause social anxiety, you're gonna go to a party or something like that, you would take it just prior. We're looking for kind of a long-term benefit, and as such, we're actually doing the LSAS, using the LSAS, so the Liebowitz Social Anxiety Scale. That was the basis of approval for those old SSRIs and the one SNRI that I mentioned. So the FDA is very comfortable with that endpoint. All right. So unfortunately, I don't think we have time to get into RL-007, which is perhaps one of the more exciting parts of Atai's story, just given that near-term data, and I know Joanne is quite disappointed. We won't be able to get into it. But could you leave us with what are the next steps? What are the upcoming catalysts? And I guess, in particular, give a little bit of extra focus to RL-007, since we didn't get a chance to discuss it. Yeah. Yeah, there's quite a bit coming up. I mean, you know, big picture on the psychedelic side, a lot of the readouts will be next year, right? So we have, Compass' phase 3 readout is either at the beginning of this year or around the end of this year or early next year. The second phase 3 is middle of next year. So again, we still hold a stake there. BPL-003, again, kind of, the trial will be wrapping up this year, readout shortly thereafter. RL-007, large phase 2b study, two hundred and thirty-four patients, so seventy-eight times three, looking at a standard regulatory endpoint, which is the, MCCB. That'll be reading out around the middle of next year. And then we have the two phase twos that we just discussed will be reading out around the end of next year, and we'll give more guidance, obviously, as those trials progress. So big year for us, for sure. Lots of different readouts next year. Lots of readouts actually in the space as well. I mean, as you mentioned, Joanne, there certainly were, you know, the Lykos PDUFA decision obviously was a damper on the space, but I think things will change a little bit as we get more data and get more exciting results over the course of next year. And there are, again, there's gonna be quite a bit from GH Research, Compass, as I mentioned, as well as other companies. Got it. Just where can investors find out more details about Atai's programs? Do you have any upcoming conferences or talks? Yeah. So, we'll be at the Jefferies Conference in London in a few weeks, and we'll also be at Citi in Miami. I think that one's early December. I think those are the next two. All right. Well, thank you very much. Lots of exciting news to come. Thank you so much.