Hello, everyone, and welcome to the fifth annual H.C. Wainwright Virtual Neuro Perspectives Conference. My name is Patrick Trucchio, and I'm a senior analyst at H.C. Wainwright and your host for the event. We have a robust agenda at the conference this year, with more than 20 companies presenting, with their sessions available on demand through the conference portal. In addition, we're expecting a full day of panels and fireside chats on the day of the conference, June twenty-seventh, with a broad neurology focus across many indications, from depression and epilepsy to Alzheimer's disease and ALS, along with novel methods of drug delivery to the CNS. This is by far our strongest agenda ever. So with that, it's my pleasure to introduce our next speakers, Srini Rao and Florian Brand, co-CEOs of atai Life Sciences, a clinical-stage biopharmaceutical company aiming to transform the treatment of mental health disorders with a broad pipeline of compounds addressing anxiety, depression, substance use disorder, and cognitive impairment and schizophrenia, among other areas. So maybe just to start, if you could begin, tell us about, a little bit more about atai, the founding of the company, and what differentiates atai from other companies in this mental health care space. Sure. Happy to get us started, and thanks for inviting us, Patrick. So atai basically was started 2018, seeing kind of the unmet need and the lack of innovation firsthand, kind of through friends and family members suffering and not finding the appropriate care they needed. And basically, we started atai to address that kind of mental health gap by following an approach which is focused on compounds with prior clinical evidence, so prior evidence in humans, from a de-risking perspective, on an asset level. And then we built a broad portfolio, so now today you get exposure to 8 clinical stage programs that all address, as you mentioned, Patrick, a diverse set of indications. For us, it's always important that we are tackling significant unmet needs when deciding to develop a compound and are very excited about many of the compounds that we're going to talk about today, I'm sure. More recently, when you look at the depression space, when it comes to differentiation, also from other companies, we have more and more honed into the 2-hour in-clinic treatment paradigm that was successfully established by Spravato. Spravato has guided on more and more successful rollout of their or J&J, rather, guided on a more and more successful rollout of Spravato. So, we were quite intrigued by that paradigm already 2019, with the approval, designed our internal DMT program. We also want to fit into that paradigm. With them now guiding to achieve beyond $1 billion of sales this year and more than 4,000 clinics certified, we believe we have a very compelling infrastructure that we can leverage with this compound. And then through the strategic investment in Beckley Psytech, we added two more that also fit into that paradigm, BPL-003, 5-MeO-DMT, as well as ELE-101, that also kind of fit or is designed to fit in that approximate 2-hour in-clinic window. So let me pause here because I know you want to cover more. Yeah, no, that, that's really helpful. I think just maybe we'll go through some of these compounds one by one. Just first with VLS-01, maybe you can talk a little bit more about VLS-01, what makes it differentiated, psychoactive compound. Yeah, so this program actually also started quite a, quite a while ago in 2019. We were looking for compounds, exploring indicators that could fit into a two-hour window. And inherent to that is you need to, to pick a, an agent that's got a short inherent half-life. Of course, psilocybin has, when given orally, a much longer half-life, so we were really looking for something that was quite short. There are two obvious choices there. One was, DMT, the other one is 5-methoxy-DMT. At that time, in terms of prior evidence in humans, there was a double-blind, placebo-controlled trial of ayahuasca in treatment-resistant depression. So ayahuasca's primary, you know, alkaloid, the active alkaloid in it is DMT. So that's what really kind of motivated our decision there. There were some other technical reasons that made it a little bit easier to pursue DMT versus 5-methoxy-DMT for our route of administration, which is, you know, an oral thin film, a transmucosal administration, that's placed on the buccal surface and allows for systemic absorption. Right. Interesting. So then, what indications is VLS-01 being pursued in, and why? What are the next steps for this program? Yeah, so we're pursuing treatment-resistant depression, but the agent obviously has broader applicability. But we're going to be starting in terms of the first indication is treatment-resistant depression. We reported the results of a phase 1A study, the first phase 1 study, in the fall of last year. That was around a prototype version of our oral transmucosal film, very much ad hoc, and it was really to learn things about this film in humans. We took those learnings and created a new film, one that's suitable for phase 2, for phase 2 use, you know, multi-site use. We tested that in the second phase 1 trial. We'll be reporting some of those results in the not-too-distant future. We did change guidance recently that we'll be kicking off a phase 2 program with this asset a little later this year. Oh. So excited by the interim results that we've seen there. Great. And then there are several partnered programs. I wanted to go through maybe a few of them one by one. So the first was BPL-003, and this is a part of a relationship with Beckley Psytech, which is also presenting at this conference. Maybe you could just start with talking about, yeah, BPL-003, what makes this a differentiated psychoactive compound, and maybe a little bit about the collaboration with Beckley? ... Yeah, so- Okay, go ahead with the collaboration. Yeah. Yeah, with the collaboration maybe? Yeah. Sounds- Okay. Sounds good. Then I'll so earlier this year, if you recall, we entered into an agreement with Beckley Psytech, really thrilled by their approach so far and their team. Some really strong capabilities in our perspective. And as I alluded to earlier, it's basically tripling down into that 2-hour in-clinic paradigm of interventional psychiatry. So they have ELE as well as BPL-003, ELE-101 and BPL-003 in development. BPL-003 is a 5-MeO-DMT, so it's an intranasal, also transmucosal administration of 5-MeO-DMT, and has in our perspective, some advantages that over some others that also develop 5-MeO-DMT in that space, and we can go into that in a second. I think it's important to emphasize that we, around year-end, will have 3 phase 2-stage assets then that fit into that two-hour paradigm, so that's, that's very exciting. So with VLS-01, where we guided initiations around year-end, and then ELE-101 is the other compound that Beckley is developing. Just recently, last week, we announced that we initiated the phase 2, and obviously, with Beckley Psytech, we reported out phase 2A data a little earlier this year, in March, where we showed remission rates of 45% in a small open-label study based on a single dose of BPL-003, and fitting approximately into that two-hour window. So, very excited about the collaboration with them so far, and looking forward to the next data readouts out of this. Yeah, interesting, and maybe you can just kind of frame for us some of the expectations around the phase 2B trial and TRD. Is this data still on, or I think the enrollment is on track for the second half, and maybe you can What is the bar? You know, it's, it seems like we're now finally getting really interesting and really good data in phase 2 studies with various psychedelic and psychoactive compounds. So what, what is the bar that you think you need to show here in this phase 2B trial that just in terms of remission and response rates, that'll give confidence to bring this program forward? Yeah, I mean, obviously, we haven't guided on the details, and neither has Beckley, right? So, but if you... You know, this is a great trial. It was very much modeled on the work that Compass had done, so very much analogous. So it's 3 doses. The lowest dose is sub-perceptual at 0.3 milligrams, an intermediate dose of 8 milligrams, and a high dose of 12 milligrams. Primary endpoints at 4 weeks, and the double-blind section goes on to 8 weeks, and there's an open-label extension beyond that. So, really elegant design for the study. In terms of what we're looking for, I mean, you know, at 4 weeks, we would obviously like to see a robust efficacy, certainly something that's comparable to Spravato. I think it's important to note that unlike Spravato, you'll... You know, for Spravato, you'll have gone in 8 times during that period, for the first 4 weeks. In this case, you'll have gone in 1 time. So it's a significant improvement in terms of logistics, both for the doctor as well as for the patient. So there's a lot of benefits here, but comparability in that context, I think, would be quite reasonable. Yeah, interesting. And, you know, there's just... Talking about ELE-101, just, you know, you also have the ownership in Compass Pathways, COMP360, so... And we're gonna ask a few questions about that program next. But I guess what I'm wondering, you know, because the active is similar in both- Yeah ... so how, and but also alluding to this shorter kind of duration of treatment with ELE-101. So how are you seeing ELE-101 fitting within sort of the portfolio of these different compounds that you have, and what are your next expectations there in that program? Yeah, I mean, I think it gets down to what's first generation and what's second generation, right? So, psilocybin or COMP360, clearly first generation. Made a lot of sense to pursue that, at the time with Compass, right? So, you know, this is the compound that had the most data behind it, that still fit into reasonable parameters from a commercial perspective. All of the other compounds, the VLS, BPL, and ELE, are all sort of second generation. They're reformulations in many ways, but reformulated to optimize for a certain commercial paradigm, which is specifically the Spravato paradigm. So, again, all of these do that, looking for some, you know... The Compass is gonna be out significantly in advance of these other three programs, by a couple of years. I think it'll be a very successful program for all the reasons that are kind of obvious. It's but these will be able to pick up additional patients that may not have been able to work within the paradigm, or maybe even pick up sites that may not have been able to work in the paradigm that was, that's required for Compass. Right. No, that, that's really interesting, and makes a lot of sense. So, just talking about COMP360, this asset is in phase 3. It's in, being evaluated in TRD. I think the first phase 3 trial is gonna read out later this year- Yeah ... and then the second one middle of next year. So, you know, maybe remind us what the ownership level is with Compass and, you know, just sort of what your relationship is with the company and why the ownership interest was taken. And then, maybe you could talk about the data generated so far and the reasons to believe. ... Yeah, happy to start on the, I guess, structure again, and then handing it over to Srini for the data. So Compass was actually our very first exposure to psychedelics. So there was some sort of a co-genesis moment of those two companies, Compass Pathways and ours. We had a more broader portfolio approach, and Compass was one of those very first investments in this, in, in that space. We were actually one of the very first investors, and continues also investors. Had varying degrees of ownership, and the company, Compass Pathways, is now public, as you know, and we're much less involved, and the interest or our interest is really limited to an equity ownership now. Having been involved on the board previously, that's no more the case. However, as Srini alluded to, we are still very intrigued by the potential that COMP360 might have and very much looking for the data readouts while kind of being in that shareholder capacity at this point. And you mentioned the kind of ownership percentage is around about 12%, as per the last filings. Yeah. Right. Interesting. Yeah. Yep. Yeah, just very quickly on the data, you know, as I mentioned, psilocybin is a compound that had the most information behind it, the most, clinical studies are academic, but nonetheless, that was where the, the bulk of the data was. Compass reported out their phase 2b several years ago at this point, and, you know, this was the largest study of psilocybin and the best-conducted study, I should say, in depression, in treatment-resistant depression, in that case. 233 subjects in total looked at a, again, sub-perceptual dose of 1 milligram compared to 10 milligrams and 25 milligrams. The latter two did, in fact, have robust psychedelic effects, both of them. And their primary endpoint was 3 weeks, then they had a 12-week follow-up period. At the 3-week endpoint, they actually had a very robust difference between the 1 milligram and 25 milligram dose. It was a -6.6 points on the MADRS, which is substantially larger than what's been seen, for example, with Spravato, which is around 4. Three weeks, and Spravato's endpoint was at 4 weeks, so just that little delta there. But nonetheless, it was a, it's a very robust finding. Obviously, then they took those data, went to the end of phase. You know, went to the FDA with an end-of-phase 2 meeting, and then initiated 2 phase 3 trials. The first is referred to as 05, the second, 06. The first one is a placebo-controlled trial, so it's 0, you know, versus 25 milligrams. Primary endpoints, it's 6 weeks, and then the second trial is analogous in many ways to that first phase 2b. So there's 1, 10, and 25. There's a redose, however, at 3 weeks, and the primary is at 6 weeks. In both cases, I believe it takes them out to 26. I think it takes them out to about 6 months of blinded, from what I understand. You know, basically blinded kind of monitoring, and then beyond that, there's open label extensions. So again, very nice, robust trial. I should also mention on the phase 2b, they had a very nice dose response, so that's important. You've mentioned, you know, I suspect the Lykos AdCom will come up at some point, so one of the questions that came up there was dose response. These guys showed a very nice dose response, so 10 milligrams is not nearly as efficacious as 25- Right ... but maintained the psychedelic effect, so that's really an important, really important point. Yeah, interesting. Yes, we'll have a few on that. First, though, I would like to ask a few on RL-007. So this is a really interesting compound, I think, really interesting approach here in, you know, cognitive impairment in schizophrenia. So maybe you can talk a little bit more about the mechanism, how this compound became part of the pipeline. Yeah. So this came out of AbbVie, you know, from years ago. It was a compound. It was Allergan, a compound that was partnered with BMS for a while. It was discovered through phenotypic screening, so that's a bit unusual. The way it worked was they were looking for compounds and assessing them in different behavioral models to see what the compound did. In this particular case, they found that in rodents, it had 2 activities. At low dose, it was pro-cognitive, and at higher doses, it was analgesic. So, the program was really shifted towards the analgesic indication, and there were a total of 10 trials, which I'll get into, 9, 1 of which we conducted. And most of them were focused on pain. There was one phase 1 that was specific to cognition. That was a so-called scopolamine challenge trial. The scopolamine causes cognitive impairments, it causes changes on EEG. They gave RL-007 in that context. They showed improvements on cognition and some alterations on EEG. And there was also a large phase 2b trial that was conducted. There was 160 patients total. These folks had diabetic peripheral neuropathic pain, so they were pretty much all diabetic, of course, and relatively poor control. They had vasculopathy, which of course, resulted in this chronic pain state. That also tends to cause central vasculopathy and some degree of cognitive impairment. They found a improvement in certain measures of attention as well as verbal memory. Those are the same things that were found in the scopolamine trial. Then finally, there was one other study that was conducted. It was another phase 1 study, completely healthy volunteers, not on scopolamine, and they found a very similar pattern of cognitive impairment, sorry, cognitive improvement, in that trial as well. So these were the data that we found very compelling. I mean, if you think about it, DAO inhibitors, GlyT1s, the amount of data that was present, you know, positive clinical data was de minimis before they went into phase 2 trials in CNS, right? Just because of the nature of those compounds. Here, there was actually clinical data in humans, I mean, like in patients, I should say, that was showing a beneficial effect. That was motivating to us. We did a smaller study that was, in some ways, a replication of the scopolamine challenge trial that was in patients with schizophrenia. We were looking at EEG changes. We did find some that replicated, in a broad sense, what was seen in the scopolamine trial. Found some pro-cognitive signals there as well that was supportive, and that allowed, that, that was the basis for initiating our larger phase 2b study. 78 times 3, so we are... You know, and we found, we actually recapitulated the fact that lower doses are below 100 milligrams were the ones where the pro-cognitive effects were most pronounced. So we are going forward with 0, 20, and 40 milligrams. 20 and 40 milligrams were, they both were found to be pro-cognitive in our trial. Slightly different profiles, which is why we chose to test both of them. That trial, you know, is obviously enrolling at this point. We're anticipating a readout towards the middle of next year. Oh, you asked about pharmacology. I mentioned that it was phenotypically characterized. There's been some work to pharmacologically characterize it. GABA seems to be playing an important role in a lot of these compounds. If to some degree, inhibitory, excitatory balance, I mean, the other ones are impacting, you know, the GlyT1s and DAOs are impacting glutamatergic transmission. This one seems to be more impactful on GABA. It's not a direct agonist or positive allosteric modulator of GABA receptors, insofar as it doesn't have the normal side effects that one would anticipate there, which is sedation and, you know, and the like. So again, very interesting compound. Very excited to see those results, in, you know, on the order of a year or so. Got it. Great. And just, you know, in the interest of time, I think we'll move on to some of these Lykos Adcom questions. I just have a few here I'd like to get through. You know, so on June fourth, there was the Psychopharmacologic Drugs Advisory Committee that's reviewed the NDA for MDMA-assisted psychotherapy and PTSD. The vote was overwhelmingly negative. There were some interesting read-throughs I thought that emerged, and I think there's some important nuances that we think investors should be aware of. So I think first, you know, it seemed like a few problematic areas that emerged were, you know, functional unblinding, expectations bias, and selection bias. And, you know, you'd alluded to with the COMP360 program earlier, that there was this, appeared to be this good, good dose response. And the FDA does have guidance for psychedelic drug development. So can you talk about... And, and there's a kind of a multi parts to this question, but maybe- Mm-hmm ... just to frame it, you know, what is the MDMA-assisted psychotherapy in PTSD? How is this different from some of these other assets, compounds that we were talking about earlier, COMP360, BPL-003, ELE-101, and VLS-01. How does what is being done in those programs differ from this MDMA- Mm-hmm ... assisted psychotherapy? Maybe we'll start with that. Yeah. So obviously, this program is unique. It had a very long genesis, if you will. I mean, I think the IND was filed in 2001, so it's been around for a long time. You know, Rick Doblin is a, you know, I mean, he sort of epitomizes perseverance. You know, this is something that he pulled together with donations only, and that has limitations, right? I mean, you know, they were always a bit strapped for cash, and that is reflected in some of the clinical trials. They also had a belief system around. They do have a belief system around MDMA as well. So, their positioning of this product is MDMA-assisted therapy or or MDMA-AT. Now, that's a little unusual right out the gate because therapy is not something that's regulated by the agency writ large, right? So that's a bit of a challenge unto itself. Now, there are approvals that are out there for things that are used on top of therapy, and the most obvious one are things like buprenorphine or opioid use disorder. Those are all to be used in something called MAT or Medication Assisted Therapy. That's fine, except the therapy bit in those cases is standard of care, so that's a pretty normal therapy. The challenging thing here was that the therapy was ad hoc. It was something that was new, essentially. It wasn't a standard of care therapy for PTSD, you know, previously, and in addition, it was highly, highly variable. There was a guidance document or a wide... You know, a manual for the therapy, but it allowed a—there's a lot of latitude in what was allowed there. So, one of the concerns that was raised was that you've got sort of two actives, one of which is poorly characterized. When you have more than one active, you have to do something called a factorial approach, which is you look at each drug individually or each therapy individually. You have a double placebo as well as sham on each piece, and then the combined. They didn't do that, and so, you know, one of the big picture, what is the advisory committee trying to do? They're trying to assess benefit and risk. They couldn't quite figure out the benefit because they didn't know how to disarticulate the two different moieties. Now, let's go back to the blinding bit, because it's really important. There's two forms of functional unblinding. One is just patient functional unblinding, and this happens all the time. This is not new to psychedelics. It may be more pronounced with psychedelics, but every drug that a CNS out there does this, right? So if I give you an olanzapine trial, and you take the drug, and you're completely snowed the first day, I know which drug you're on, and so does the patient, right? because it's heavily sedating. paroxetine is the same thing. fluoxetine would be very activating, you can't sleep properly. So we know these drugs do that. The way you mitigate that from a patient perspective is sort of twofold. I mean, one, of course, is the dose response. If you get the same generally level of side effect, but you see differences in efficacy, that does speak to something else happening. In the case of psychedelics, the other element here is durability. You're giving the drug acutely, you're looking over an extended period of time to see if the benefits maintain. If it was purely driven by psych- placebo effects, you'd expect it to regress relatively quickly because, you know, these are treatment-resistant depression patients. They've been suffering for a long time. Most, by definition, most drugs aren't working for them. So you'd expect some regression. So that's one thing. They didn't really do dose ranging. They had a discussion with the FDA, but MAPS didn't do dose ranging, so that was the first problem. The second was that they didn't have, you know... The therapists were being unblinded because of the MDMA-AT bit. So the therapists were with them multiple, I think it was three visits before, during drug administration, multiple visits after. There were three administrations of the compound. They had a pretty good sense of what was going on. So the problem is that when it's not standardized, you can then start responding to how the patients responded, and that may have caused differences in how the therapists were reacting to those patients that they perceived got drug versus those that didn't. Got it. That's really interesting, and that's really helpful. So I think, you know, something else that came up that I was surprised by was just the problems with the long-term follow-up. Yeah. And I guess there was, you know, inconsistent, you know, blinding or limited controls, you know, issues, various issues that I just don't think many of us expected. So can you talk about just the importance? Because I think with when it comes to, specifically with the MDMA program, you know, they didn't have enough patients enrolled in phase 2 to satisfy- Yes ... the safety phase. So, the idea was that, well, then you have a, this, this less frequently dosed drug, but then they had to put a little more, you know, scrutiny on this long-term follow-up or long-term outcomes. But I think even from a kind of a payer, kind of clinician-patient perspective, I think it just, folks, I think, want to see that these drugs are more durable. So how, you know, in your programs and just kind of what went wrong here, and how is in your programs, how is this different? Yeah, so I mean, the standard approach, and I do want to emphasize that the standard approach, is to typically roll the patients out of the randomized control trial directly into an open label extension and then follow them up from there, right? That didn't happen here, for a range of reasons. There were, in the first trial, in MAPP1, there was a substantial amount of time, I think it was up to, like, 12 months or something before they were then allowed to go into the open label extension. The challenge there was some people took illicit MDMA. There was all sorts of other things that happened. There was an accusation, an allegation, that they were selectively putting patients in that they thought would benefit. So there was all sorts of stuff that went on with that. So, and then the other issue is, of course, the entire database is tiny. So the number of people that went into the open label was also small. So if you think about it, the 2 phase 3s for MDMA-AT were combined smaller than the phase 2 trial that Compass read out and that Beckley's doing now. So, I mean, these, these are - this is a small data package. Right. So again, you know, big picture, I think it's worth mentioning that all of the issues that came up during this advisory committee were also things that were... that J&J dealt with, with Spravato. I mean, pretty much everyone- Right ... except for this weird concept of therapy, right? Right. And they were all dealt with properly, adequately, and they got approval. The advisory committee went well. I mean, it you know, I don't remember the exact numbers, but obviously, it went swimmingly for them, and they got approved. So, I think there was a lot of idiosyncrasies to this program- Right ... some of which we've talked about, you know? Right. That I don't really personally feel are real read-throughs to the rest of the space. Right. No, that's really helpful. Maybe just one last one. You know, there are many programs at atai, and there's a number of readouts coming out. What are investors missing anything about the pipeline that you'd like to highlight? Well, I mean, I think we will be providing, over the course of the next couple of months, a little bit more color on all the programs and where those will... You know, our timelines, for example, and what we're doing in terms of next steps, and detailing a little bit more about some of the results that we've gotten, which we view as being very exciting. So, I think that's gonna help the story. I mean, we haven't given a lot of color to date on these programs, but I think we're in a position to really do that, and, you know, we're obviously very excited by the results and looking forward to the next steps with all of them. Right. Terrific. Well, thank you so much to Florian and to Srinivas for participating in the conference, and it's always an interesting update from atai and the pipeline, so really grateful to have you again this year. And, thanks for everyone for attending. Have a great rest of your day, a great rest of your conference. Thanks, everyone. Thank you, Patrick.