Good morning, everyone. Thanks for joining us today for the Atai Life Sciences fireside chat, at the TD Cowen Novel Mechanisms in Neuropsychiatry and Epilepsy Virtual Conference. I am covering analyst Ritu Biral. I am joined by my associate Athena Chin, who works on Atai with me. From Atai today, to discuss recent developments, we have CEO Srinivas Rao, CEO and co-founder, and Kevin Craig, Chief Medical Officer. Thank you, gentlemen, for joining us this morning. I want to get right into it, into your most recent, very positive Phase II-B TRD data of BPL-003. This was a Beckley Psytech Limited partnered, now acquired, program. I do want to spend a few minutes just on the logistics of that transaction, timelines and stuff like that, but I want to focus first on that data. This was eight ml dose data showing a profound MADRS difference of 6.3 versus subclinical control of 0.3, at day 29. The open-label data, the durability data, is expected sometime in Q3. If you could review a little more, a few more details of that top line MADRS data. As we think about this eight-week data coming, what would good durability look like? What do you think the bar is for either response or remission at that eight-week time? Yeah, it's a good question. I mean, as you said, we were very excited by the core study results, the eight-week study. It showed good response at four weeks, but actually durable out to eight weeks. We are looking forward to the open-label data where everyone now got a second dose. There will be a group of participants who got a second dose and then those who got the first active dose. I think what we're really looking for is, again, to confirm that durability with a second dose. It goes out to eight weeks, but also, you know, we'd be very interested in whether there's an incremental improvement with a second dose because I think, you know, we want to make sure that over time, we're driving remission rates to the extent that we can. There's the potential for higher remission rates after that second dose, like a stepwise increase in response. Exactly. In phase III, we'll be going out re-dosing at intervals over a year. I think in practice, it may be longer. We really want to make sure that each time someone gets a dose, they're actually getting a bit better. I think that would, we'd hope to see, driving remission rates over time. I think it would be great to see remission rates of 40%, 50% with a second dose. If we get that signal for that incremental change, then I think we'd be confident that repeat dosing may further drive remission over time. Are there other key analyses beyond just that long-term MADRS and remission and responder numbers? Obviously, we looked at lots of things in the trial. We're interested in anxiety and anhedonia, in particular. Also, disability, just general improvement and that sort of thing. There are a number of other scales that were taken and assessed during the study. I think we're going to be looking at that data as well to see to what extent certain subgroups of people may be particularly helped by the drugs. Will the trial have any further extension, or the patients be enrolled in any further extension beyond that? No, that's it for this trial. They had the eight weeks and then a second dose and another eight weeks. That's the end of this trial. There's no sort of open access for this so far. It's still a phase II study. I think that's where we stopped. Of course, now looking forward to the phase III is where we will have an open-label extension that'll play out for more than a year. You mentioned anxiety and anhedonia. What scales and data are we going to get with the extension? I think investors aren't used to looking at anxiety data yet on those scales. What's meaningful, especially as it overlaps with TRD? What's meaningful on your anhedonia scale as it overlaps with TRD? Yeah, yeah. I think the first thing to say is that we didn't select particular patients that either had anxiety or had anhedonia. The signal is not the same as depression where we were selecting people who met a depression score. We know that both of these things are highly comorbid. Many, many people with treatment-resistant depression also have anxiety. We're very interested to see how that changes. We took a patient-reported outcome in the study, the GAD-7. Similarly with anhedonia, what we hear when we speak to patients is that this is one of the big issues, the sort of energy, motivation, enjoyment in life, which is not really well captured with the depression scales. The scales measure depressed mood, but this absence of positive enjoyment in life is not well captured. We've used the SHAPS, which is a well-established scale for that. With the caveats around not selecting these patients particularly, I think it'll be interesting to see whether these things move. There's been a big problem, especially with anhedonia, with traditional oral antidepressants, that many of the other mood symptoms improve, but anhedonia can really stick around and be quite a problem. We're excited to see whether that shifts with these drugs. Got it. Have you requested an end of phase II meeting yet with FDA? Yeah, go ahead. Yeah, we did gather that we're going to be submitting in this quarter, and that's pretty much all we can say at the moment. I mean, again, lots of data has come out of this. When we talked about some of these other endpoints, they were not specific to the open-label extension. They were also in the core study. It's a bit of data that we're going to incorporate into that, that we're incorporating into that meeting request and the briefing book, obviously. Is this the appropriate time to ask for breakthrough therapy designation and the appropriate time to start talking to the regulators about the commissioner's voucher? Yes, I mean, on the latter, I think it's fair to assume that pretty much every company did apply for that. I mean, it was a very straightforward application. You know, it took us, I don't know, Kevin, about a couple of hours to bang that out. At the time, it was actually for both Atai's VLS-01 as well as BPL-003. Yeah, I think everybody applied for that. Having heard back, I did hear recently that there was some guidance that that would be forthcoming, but I can't, I don't know. It's kind of the long and short of it. Got it. As a general statement in terms of breakthrough therapy designation, I think it is, you know, you do need good double-blind placebo-controlled data. That's obviously something that we have at this point. I guess I can leave it at that. That's definitely, we needed these data to really even apply for that at this point. You have your meeting, you get your minutes, and at that point, will we get a regulatory update independent of the announcement of the final phase III program? I think that's still TBD, but the most important thing, obviously, is getting alignment with the agency on the phase III plans. That's something that's quite material to the company. We would definitely PR that. Got it. Got it. The differentiating factor of BPL-003 is its lack of dissociative effects. In your Phase II-B, patients met the discharge criteria within about two hours. Given the different treatment paradigm from Spravato, ostensibly less frequent, who do you think the ideal patient is for BPL-003? I think it's a, you make a good point. I mean, in some ways, it's very similar in terms of the infrastructure. We're really sort of targeting that interventional psychiatric clinic, and I think it fits well into the Spravato paradigm. There is a convenience aspect to this where instead of coming in every week or every two weeks, you know, we could expect someone to come in every eight to 12 weeks, for example. I think that suggests a group of people perhaps who are relatively high functioning, people who may be in work or have long family commitments and that sort of thing. People who actually need to get back into life and, you know, I think require less of a commitment coming for treatments less frequently. I think that is certainly a group that we're very interested in treating. As far as contraindications for Spravato that would allow for BPL-003 treatment, how should we sort of compare and contrast either somatic side effect considerations or exclusion considerations? No, I think in many ways, they're very similar. I think the thing that we think about a lot are the cardiovascular effects, the hemodynamic changes, blood pressure and heart rate, which look very similar between ketamine, esketamine, and psychedelics. Similarly, some of the psychiatric comorbidities that we've been quite careful about, like a history of psychosis, I think they apply for ketamine and esketamine as well. In fact, the patient population in that way seems very similar. I don't see a big divergence between the two patient populations. Would you anticipate, if you think about infrastructure and monitoring, the monitoring needed for the two hours post-dosing, would it be the same level of monitoring versus something more intensive with other investigational therapies? Yeah, I mean, this is something we're spending a lot of time on at the moment. We're trying to aim to sort of get that right size. Really, what are the things that people need to intervene with? What are the competencies that they require to do that? Is it blood pressure? Is it anxiety? I think much like Spravato, they've got a sort of counseling or prep session, maybe enhanced support coming in just to tell people what to expect. We certainly expect to have to do that with psychedelics. There's the in-session monitoring and then a follow-up. I think we're still working very hard to try and get that to be safe but reasonable. As you approach the phase III design in your end of phase II meeting, how are you thinking about control arms? Different programs seem to be doing different things. We just heard from SIBEN and they're using a placebo versus, say, Compass's subtherapeutic dose in a dose and the need for dose ranging in phase III. Have the FDA's preferences or recommendations evolved from the published guidance a couple of years ago? Yeah, I think there's a subtle maybe change. The guidance talked about a subpsychedelic dose, which we saw with COMPASS and actually literally drove Beckley’s 0.3 ml control arm as well. I think that there's a recognition that if we really want to control for some of the unblinding effects, we really need a dose that is psychedelic. It has similar amounts of psychological effects, but is less effective. The idea of having a dose response becomes more important than having a subpsychedelic dose. I think that has been a subtle change, which means that we definitely would prefer, and I think it's certainly tractable to use a true placebo as the control arm. Then we need a middle dose, if you will, that is psychedelic but not effective. I think that's, I see that in a number of other sponsors that have initiated phase III trials more recently, that seems to be where things are settling out. Of course, we haven't had that conversation, but. How do you preserve blinding across the study and anticipation then? I mean, if anything, it should drive sort of broader, I guess, effect sizes. You don't want the agency turning around and saying like, is this the real effect size? How are you guys thinking about balancing that? I think the comparison to the middle dose will be able to sort of help us tease out how much is the expectation. If both arms have a psychedelic experience, but one gets significantly better and the other doesn't, then we can answer the question of unblinding and expectancy with that comparison. When we come to safety comparisons, the sort of effective dose versus placebo is going to be key. I think this helps us, I think we get a cleaner study design in terms of the effect size of placebo versus drug and in the safety profile of the drug versus placebo, while at the same time being able to look at that middle dose and see how that influences the expectation and unblinding. A good example here is actually Compass, right? They really did blaze a trail here in many ways. Their Phase II-B, they actually have a 10 ml dose in addition to the 25 ml. 10 ml s is pretty psychedelic. It's comparable in many ways to the 25 ml dose, but its efficacy was much less. That's how you address functional unblinding. If you have a subperceptual dose, you haven't actually accomplished that much beyond saying to the subject or the patient that yes, you are going to get drug, albeit some of that you may get a drug dose that doesn't do anything. It doesn't really accomplish much. The other important element that Compass nailed is the longer term blinded durability, which I think is also quite important. The Beckley trial, the BPL-003 trial had that as well. For our clients on the line, please feel free to go ahead and email me questions, and we'll go ahead and get them addressed. Timeframes for the phase III, guys. What's a reasonable time for phase III start? I think we have written that we expect in the first half of 2026, but then sort of enrollment requirements given the planned size and timeline to top line data. Right. Yeah, go ahead. No, go ahead, Kevin. Yeah, I mean, I think obviously we're scrambling to get the meetings in and the studies planned. I do think that targeting about a year between the last patient or top line results of the two B and, you know, patients being dosed in the phase III is about right. That's pretty much a standard, and we are certainly targeting that. Looking at, you know, study initiation early next year, I think really patients coming into the trial around the middle of next year. We've obviously got with the Schedule I licenses here a certain time lag to get these sites up and running once we've got a fully approved protocol. Of course, the size of the study and the sort of, you know, the end date is going to depend a lot on, you know, alignment with the agency. I think it's really hard to say much about what that looks like. We've got some ideas, but I think it's very, very early days. Speaking of alignment with the agency, what do you think are the most notable changes or amendments to the industry guidance from that draft guidance? Beyond, you know, we talked about the drift is the wrong word, right? Change, I would say evolution of requirements for placebo versus subclinical dose. What other key considerations in the evolution of FDA's evaluation of psychedelic programs should we consider? Was there anything notable, especially now that, you know, there's a CRL in the public domain, any lessons learned from the LICO's review? Yeah, I mean, I think some of the sort of main themes were reinforced by the CRL. I think the importance of abuse potential and redefining that and how you catch your adverse events is going to be key. That's in the guidance, and it was, as I said, reinforced. The importance of that. That hasn't changed? It hasn't changed, I don't think at all. Similarly, the sort of durability of effect as a sort of mitigation for the unblinding, I think that came through in the CRL as well and is in the guidance. Apart from the placebo control, I would say there's some sense that maybe there is more openness now to dosing these drugs with underlying antidepressant drugs. I think a number of companies have done some studies. They're small, there are no large studies at the moment, but I get a sense that people are enrolling patients who are on underlying antidepressants. The guidance had some views about the need for pharmacodynamic studies, and that may not be the case anymore, but that's speculation. The area that I think is important to look forward to is exactly, as we discussed, the monitoring piece. The agency has got some guidelines there, and I think that is a piece that has evolved over time. Sorry, you mean the safety monitoring for the actual sessions? Correct. How that will translate into a final like REMS or whatever. Yes, at the moment there's some very strict qualification requirements. Observers, male-female, stuff like that. How do you see that evolving? I’d like to see a conversation about what are the competencies required, what do we need to actually safely do this, and to get that sort of appropriately set up in phase III so that we can actually translate that into the healthcare setting later. I think that's a point of conversation that's of interest to me. I don't know how the agency's evolving on that, but I think as we've now experienced a number of these trials, they're being run in site networks, very established sites. I think that some of the concerns maybe are less salient these days. I think that's a piece that we would like to see some changes. Is this something that the professional agencies are looking at as well, especially given how close a lot of these programs are to potential commercialization and how long it takes, like guidelines to be written, et cetera, given how, in my experience, concerned neuropsych leadership is with the safety aspects? Is this something that you guys know might be in the works? It seems someplace where professional organization guidelines would weigh heavily with the agency. I think that data. I think one of the difficulties at the moment is there's no real data to say these are the things that happen during a session, these are the interventions that occur with this frequency. I think as us, as the sponsors have begun to sort of run these trials and develop data, we can have a much more data-driven conversation, which was obviously very difficult when these things were set out. Understood. I'd like to add, these things came from sort of distant historical trials, right? This is some of the guidance documents that came out of Johns Hopkins a number of years ago, were based on very old studies. Of course, some of this also was from LICO's. They kind of instituted a lot of these things. Of course, some safety considerations have come up along the way. This was a de novo drug class. I don't think this would have even been an issue. Just keep in mind that many of the anxiety reactions that you see with psychedelics during the administration of the compound, you will also see with Spravato. People do have anxious reactions and do require some settling down. You see blood pressure changes, as we talked about. I think some of this is just based on historical precedent. Hopefully over time, as Kevin was saying, as we generate data, some of this will change. Got it. With that, I'm going to turn it over to Athena for next programs. Yeah, so moving on to VLS-01, your oral transmucosal DMT, also in development for TRD. Maybe for those who are unfamiliar, can you review its mechanism in this indication? Yeah, so I mean, maybe stepping back just to think about the two different products. So one, you know, we've been discussing BPL-003. That's 5-MeO-DMT, and VLS-01 is based on DMT. These are two separate compounds. Even though they sound somewhat similar, very different pharmacology. Both of these, in terms of the drug products, are transmucosal. BPL-003 is intranasal, like Spravato. As you said, VLS-01 is an oral transmucosal thin film. That's kind of the big picture in terms of mechanism. Of course, that's a little bit, you know, not fully vetted or fully understood, even with SSRIs, but certainly with psychedelics. Mechanistically, certainly both compounds do hit 5-HT2A, albeit at different potencies. Both are very robust psychedelic compounds. There's some additional data around DMT. Prior to this trial with BPL-003, I think the data sets around 5-MeO-DMT were a little less robust. DMT had an older study looking at ayahuasca, the active psychedelic moiety, and ayahuasca is DMT. There was a subsequent study from another sponsor with IV DMT, also in depression, showing some good effects. How does the psychedelic experience differ from 5-MeO, and what about the safety side effects? That first one's an interesting question. If you look anecdotally, obviously people do point to differences between sort of this toad venom stuff, where it's really more of a vaporization process and a very rapid onset, pharmacokinetically speaking, to DMT, which is traditionally ayahuasca. Of course, the compound there is just this markedly different pharmacokinetic profile. There are more recent anecdotes because you can basically purchase these things in vape pens that have DMT, 5-MeO-DMT, or some combination thereof. People do report differences in subjective differences in these molecules. One, 5-MeO-DMT being much more, I mean, ostensibly a little bit more ego-dissolving versus DMT kind of giving you a more structured psychedelic experience. I don't know how true that is. I think what we can say is that at least in the respective phase I, there seem to be differences, but of course you can't, those were not comparative and they were done at different times at different locations. Who knows? This is something I'd love to explore a little bit more. The pharmacology is so different between these two compounds that it's absolutely worth some additional exploration. How did the safety profiles differ? Yeah, so I will say that in the phase I, and again, you know, these are small data sets, in the phase I, we had a very good profile with VLS-01. You know, nausea and vomiting are fairly common with this class of compounds. With VLS-01, with the dose that we're moving forward with, we had very limited nausea and actually no vomiting. There were some nuances to the design of our phase I that may explain elements of that. This is something that we need to explore in a bit more detail once we get into the, you know, once we have the data from this phase II. Walk us through that phase II repeat dose design. What dose did you select, and what do you hope to see in this final data set in order to advance development? Yeah, so in the phase I, the two higher doses were 120 ml and 160 ml. 160ml, you know, basically in terms of subjective effects, there was compression essentially between those two and they were kind of similar. The 120 ml was definitely better tolerated. That's kind of the same story that we're seeing now with the 8 ml and 12 ml of BPL-003. 8 ml looks really good and we're moving that one forward. Just from a safety perspective and a subjective effect perspective in phase I, 120 ml looked good. Now, the trial is a little bit different than BPL-003's. We obviously were going to be privy to the BPL-003 data. We had a pretty good, you know, we knew we'd be getting some data on short duration psychedelics, single administration. I personally like the notion of induction and maintenance. These are patients that are suffering quite profoundly in many cases. It would be fantastic to drive them into as much response as you can. There was certainly, even at this point, it's open-label or partially open-label. There's data that suggests that a second dose gives you an incremental benefit. Kevin kind of outlined where we're looking for that data with BPL-003 and the open-label extension as well. If we can drive down the symptom burden, that may allow for less frequent re-dosing, what have you. That's what our concept was with this particular phase II. It is two doses, two weeks apart, primary endpoints at four weeks. We have a 12-week follow-up period from that second dose. You also recently announced that this program is experiencing slower than expected site activation and recruitment. Can you provide additional color on the factors that may be contributing to this delay? Yeah, absolutely. I mean, I think two main factors. The one is obviously we need a larger pool of psychedelic experience sites. Typically, when you're looking at sort of site competitiveness, you think about the indication. There's not a lot actually going on in treatment-resistant depression. In fact, the psychedelic experience sites are doing all the psychedelic studies, and they are very intensive. There is a capacity issue just with the number of sites that we can access kind of as an industry rather than just atai. I think the Schedule I process has been very challenging globally, to be fair. What we see is a lot of variability in approval timelines, even sometimes within the same state. That has been difficult and very unpredictable. You can get good agents who respond very quickly and turn things around and others who don't. It's been quite difficult to sort of build that into any kind of forecast. We only know when the sites are activated. I think those are the two main issues. They are, I would say, in a very complicated trial. We've got central vendors for ratings. We've got the psych support, people with their qualifications that need to be found by the sites. Then there's the Schedule I requirements for each site. We were keen to sort of try and build some of this capacity as well. We have got a number of sites in the trial that had not conducted psychedelic studies before. Actually just getting those sites approved and up and running takes a lot more work and handholding. I think there have been a number of factors that have just been difficult to get through. Understood. I believe there is a client question too. Yes, we have a client follow-up on the BPL-003 program. They wanted you to elaborate a little more about the decision to bring forward the 8 ml dose versus the 12 ml dose. What specifically drove the discontinuation decision for the 12 ml dose? Yeah, sure. I mean, what we saw, the doses were selected, 8 ml and 12 ml. They were fairly overlapping on PK and subjective effects, similar to VLS-01. The aim of the study was to have two shots on goal. What we saw was very similar efficacy for the two, but quite a different safety profile. We sort of assumed that we were over the linear part of any dose response, and we were in the more flat, undifferentiated area for the 8 ml versus the 12 ml for efficacy. Certainly for safety, we saw higher blood pressure increases, more vomiting. Generally, it just had a profile that was not as favorable as the 8 ml. Given the efficacy looked similar, we wanted to select the dose that was most tolerated, I suppose. Got it. We have one minute left. Athena, you want to hit on? Yeah. With that one last minute, you are also studying EMP-01 for social anxiety disorder. Maybe can you outline the market opportunity for this specific indication, how it was selected over GAD? Yeah, so basically, it's a huge market. It's about 13+ million individuals. That's larger than depression writ large. It's even larger than, it's significantly larger than treatment-resistant depression. It's not an area where people are really focusing. There are some unique properties to EMP-01 from the phase I, just to be very clear, that suggested that this could be efficacious in that indication. It's one of those indications that has been looked over in many ways and has been for some time now. It's kind of where depression and treatment-resistant depression was maybe 10 years ago. Something of interest, there was some data around MDMA on this indication. That also helped guide our decision. Got it. With that, we are at time. Thank you for meeting Kevin for joining us today. For those who tuned in, we will be hosting our next fireside chat with Compass at 10:40 A.M. Hope to see you there. Thanks, everyone. Thank you.