Atai Beckley N.V. (ATAI) Earnings Call Transcript & Summary

Thank you for standing by. My name is Tina, and I will be your conference operator today. At this time, I would like to welcome everyone to the AtaiBeckley BPL-003 Phase IIb Open-Label Extension Study Data conference call. [Operator Instructions] It is now my pleasure to turn the call over to Ashleigh Barreto, Investor Relations at AtaiBeckley. Please go ahead.

Thank you, operator, and good morning, everyone. Before we begin, I would like to remind everyone that this call will contain forward-looking statements, which are subject to risks and uncertainties. Any statements regarding future events, results or expectations are forward-looking statements. Please note that these forward-looking statements reflect our opinions only as of the date of this call. We undertake no obligation to revise or update these forward-looking statements in light of new information or future events, except as required by law. Information concerning factors that could cause actual results to differ materially from those contained in or implied by such forward-looking statements are discussed in greater detail in our recently filed 10-K available on our website or sec.gov. I'd now like to turn the call over to the host, Dr. Srini Rao. Srini, over to you.

Good morning, everyone. I'd like to start by welcoming you to today's webcast, our very first as AtaiBeckley. I'm joined here with Dr. Kevin Craig, Atai Beckley Chief Medical Officer; and Dr. Rob Conley, our newly appointed Chief R&D Officer. On the course of the next few slides, will walk you through the results of the open-label extension of the Phase IIb trial of BPL-003 in patients with TRD. Next slide, please. All right. This slide provides a summary of the results of the open-label extension. In summary, a second dose to 12 milligrams administered 8 weeks after the initial dose of 12 mg, 8 mg or 0.3 milligrams in the core study resulted in rapid, clinically meaningful additional antidepressant effects. These effects were sustained for upto 8 weeks and resulted in a response rate of 63% and a remission rate of 48% in those subjects to receive either 8 or 12 milligrams in the core study. The drug was well tolerated with the majority of treatment-emergent adverse events occurring on the day of dosing. Most were classified as mild or moderate and they were transient in nature. BPL-003 has a potential to fit in to be established to our interventional psychiatry treatment paradigm as we'll see in subsequent slides. Finally, just to remind everybody, BPL-003 was recently granted Breakthrough Therapy designation by the U.S. FDA for results with treatment resistant depression. This is a recognition of its potential to deliver substantial improvement over existing therapies. Okay, I'll now hand it off to Kevin, who will provide an overview of the results of the CORE study. Kevin?

Thank you, Srini. So I'm going to now talk a little bit about the study overview and the focus on the core study. This is a review of what we discussed previously, that is a setup for the open label discussion later on. Next slide. So in terms of the study design, this is one of the largest -- or the largest study of [indiscernible] it was a study that was conducted globally across 6 countries. We randomized 193 participants. Those that were eligible were washed out of their medication. This is a monotherapy trial, and then they were randomized to 1 of 3 doses, either 0.3 milligrams, which is the controlled arm. This was chosen in conjunction with the regulators to have rather than a placebo, some chance of receiving a [indiscernible] drug on all 3 arms. And then the 2 active arms, the 8-milligram and the 12-milligram, these have chosen explicitly to be active and to be in the therapeutic range. So although we were expecting there to be a dose response, we very much wanted to look at 2 doses that were likely to be efficacious. Participants were assessed after dosing on day 1, they were assessed [indiscernible] at day 2, day 8, day 29 and day 57, so an 8-week blinded follow-up period, and the primary endpoint was the 29-week [indiscernible] assessment. After completing that double-blind period, participants had the opportunity to roll over into the open-label extension, where they received a single dose of 12 milligrams and were followed up for a subsequent 8 weeks. Next slide. So the final results on efficacy are shown here. The first thing to point out is the control arm, which we see as a fairly reasonable decrease from baseline in the control group. And I think this is very encouraging to us. This looks very similar to other psychedelic and TRD trials where we see a decrease as expected. So I think we were encouraged that there was no so effect here, and this was a robust and that this is a robust trial. Moving on to the doses. What we saw was a rapid decrease from baseline to day 2, they really reached its maximum around day 8 and it was very sustained thereafter, 2 week. There was more numerical difference between 8 and 12 at the day 29 endpoint. But I'd point out that this is really not a statistically -- statistical difference. This is really just a numerical difference with it seeming to be slightly better than 12. But what is important is that this was really sustained all the way out to were statistically significant, really from day 2 or to week 8. Next slide. Moving on to the responders and remitters. What we saw here on the list, the responder rates, this is patients who improved by at least 50% on their [indiscernible] dosing. We saw about 1/3 of participants by day 8 reaching responder status, and that was really sustainable the way out. And there's no difference really between the 8 and the 12 from day 8 all the way out to week 8. On the remission rates, we saw a numerical improvement here of the 8 relative to the 12 with about 1/4 of participants meeting remission status again by day 8 and remaining fairly sustained upto week 8. Next slide. Just moving on to a summary of the safety for the core study. What you can see here is, I think, a very well-tolerated study. We had more than 99% of treatment emergent adverse events were either mild or moderate. We had no serious adverse events throughout the trial. But what you can see here is now a beginning of a separation in terms of the doses. So here, we saw that 12 had adverse events than in 8. And for example, if you look at the anxiety rates in the 8, they were fairly low, higher in the 12. So what we see otherwise is a pretty expected list of adverse events in nausea, vomiting, headache, anxiety. We also had administration like pain and discomfort that comes with the nasal delivery of the compound. And we had an increase in blood pressure as again expected for the class. Blood pressure increases were transient. They really were returning to normal within about an hour and the majority of these adverse events occurred on the dose dosing? Finally, really important for our product profile was the time to discharge. So we looked at that with a specific measure. And the majority of patients were deemed ready for discharge at the 90 minutes post-dose assessment, which I think fits into our idea of making sure that these patients can be dosed and be ready for discharge within a roughly 2-hour type period. I think looking at the safety profile, unlikely efficacy, we really do see the benefits of the 8-milligram here in terms of safety with very similar efficacy. And it is for that reason that we are proceeding with the 8-milligram dose in future trials. Next slide. So finally, then just to talk a little bit about the study design or the setup for the open-label phase. As I mentioned, those have completed the core study were eligible to move into the open-label phase. Not all sites have the open-label phase available at the beginning of the study. Once they were available about 126 participants were completed and ready to move into the open label. And of those 107 were dosed for the second dose, and now was followed up again for another 8 weeks. The intent here was primarily to look at safety after a second dose, but also to look at the effects in terms of efficacy on a second dose. And with that, I'm going to hand over to Rob.

Thanks very much, Kevin. Now I'd like to go over our top line findings from our open-label extension study. The next slide, please. This study, which, as Kevin mentioned, was really a subset of our core study, has very similar demographic profile. And of course, same population, more or less, somewhat female-oriented, very chronically ill, moderate to severe depression going into the overall study. Next slide. What you see here is the change over time in our group meets. The top gray line, you can see the group that got psuedo placebo, the low dose in the first study, you see that core on the left. And then you see they improved quite a bit when they got what was to them the first dose of active medication in that second open-label study. And you can see the shape of the line is very similar to what we saw in the first administration of the active drug homes, which is somewhat reassuring of our effect size and change over time. In the 2 active drug arms, however, we did see even more improvement after we gave the second dose. You see an improvement in the 12-milligram arm, which is the dark line. And then in the light green line, which is the 8-milligram arm quite a robust improvement over time. And importantly, with the one dose being given at the beginning of the open-label study, you see this as continued improvement out to 2 months. So we really do have 16 weeks of good follow-up with improvement in depression with just the 2 doses during that time. With all of this data in front of us, we have decided to move forward with recommending an 8-milligram dose for our Phase III studies. The next slide. Now it just looks at our response in a somewhat different way. This looks at our responder rates. And again, response here is defined by at least a 50% loss of the initial MADRS score, the depression score. Left-hand side, again, you see our core data 1 more time. Now you see after the second dose on the right-hand side that you get this greater improvement with all of the cells going up, particularly the 8-milligram sell, you see we actually get to an 81% responder rate over time. This is this improvement of response, again, with just that 1 single second dose. So again, very encouraging for persistence as well as improving response over time. Next slide. Next slide looks at the remission rates. Again, remission is this very high definition of response where people have a MADRS score of 10 or below. Again, on the left-hand side is our core data, which you've seen before, a good improvement over time, but that improves much more after that second dose. Again, you see all the dose cells going up. Again, particularly the 8-milligram cell getting to a 67% response rate at day 57 with the 1 redosing. So again, this does support our decision to recommend the 8 milligrams as the dose we're going to move forward into a Phase III overall. Next slide. Now we're going to look at our side effects. Again, like before BPL-003 was generally well tolerated. The majority of our adverse events were characterized as mild or moderate. They were transient. They tended to resolve on the first day. Again, the most common side effects were mostly at site administration in the nose. We had 1 serious drug-related adverse event. This was a person who had a history of not only depression, but panic anxiety and suicidal ideation. And sometime after dosing, she had a return of those symptoms, and it was decided for that reason to briefly hospitalize her. She was hospitalized and for that reason, it became a serious adverse event. However, the side effect itself, the serious adverse event did resolve the next day. So fortunately, the subject did have a resolution [indiscernible], but it was a hospitalization and therefore, an SAE. Overall, though, the other side effects were mild to moderate, as I said. And again, our average time to discharge like in the initial study was within about 2 hours of dosing. The next slide. So where we are right now is the BPL-003 has demonstrated this rapid robust and durable therapeutic benefit for at least 4 months after 2 doses. In fact, again, you see this really improvement of response over the time of 4 months, and very favorable tolerability and side effect profile. So we do think that this open [indiscernible] extension does show that this redosing paradigm can be very useful for improving response in people. We have shown in these 2 dose administrations, a 2-hour timing clinic that can be expected, which is very similar to the SPRAVATO treatment paradigm. We have been fortunate to be granted breakthrough therapy designation by the FDA in October of this year. And we do think our overall data set supports advancement of 8-milligram dosing into Phase III. So for upcoming key program events, we intend to have a meeting -- end of Phase II meeting feedback from the FDA anticipated in the first quarter of next year. And with positive feedback from the FDA, we hope to be able to initiate Phase III studies in the second quarter of next year. With that, I'd like to turn things back over to Srini.

Thank you, Rob. Let's now talk about the commercial opportunity for BPL-003. We'll talk about this in the context of the competitive landscape, starting with a brief discussion of SPRAVATO. Next slide, please. As many of you know, despite a slow start, SPRAVATO has become a successful key franchise for J&J. SPRAVATO achieved blockbuster status in 2024 and has already exceeded $1 billion in sales in the first 3 quarters of 2025. This product falls into the interventional psychiatry paradigm, where administration occurs in the doctor's office. Product offer administration involves a drug being delivered intranasally by the patient under medical supervision and then per label, the patient has been monitored for a period of 2 hours. At the end of that period, the patient can be discharged if and medically and psychologically stable. There are approximately 5,000 clinics certified under the REMS to deliver SPRAVATO. Last year, approximately 50,000 patients were treated with SPRAVATO in the United States, resulting in about $930 million worth of sales. The challenge with SPRAVATO therapy is the sheer number of administrations that are needed to both induce a response and then maintain that efficacy. Induction occurs over the course of 4 weeks and involves 2 administrations per week each in the doctor's office. Maintenance follows thereafter. The first 4 weeks of the maintenance period require administration every week and then it's as needed thereafter. However, recent data suggests that most patients are getting the arms for SPRAVATO every week to 2 weeks to maintain the efficacy long term. Next slide, please. We believe BPL-003 and secondarily VLS-01 are uniquely suited to leverage the 2-hour in-clinic paradigm established by SPRAVATO. We anticipate each visit for these 2 compounds to be very similar to the ones involving SPRAVATO, where there's a single administration and the resolution of physiological and psychological symptoms should occur in 2 hours or less. This paradigm addresses the scalability concerns that are present with longer duration products like [indiscernible] and also address the complexity of same-day multi-dose paradigms. The benefits of the simplification included the ability for increased utilization by site and importantly, improving the quality of life for patients with TRD to the much reduced burden, including travel, et cetera. Next slide, please. We're excited to come together as Atai Beckley with our focus on short-duration psychodelic therapies. We've been discussing BPL-003, of course, as it is the most advanced asset in the pipeline. And as noted previously, we anticipate initiating Phase III next year after an end of Phase II meeting. However, I'd like to take this opportunity to mention 2 other assets in our pipeline, namely VLS-01 and EMP-01. VLS-01 is a buckle form of DMT [indiscernible] being developed for treatment-resistant depression. It's currently in the Phase IIb trial, and we anticipate reading out in the second half of next year. EMP-01 is an oral form of R-MDMA. It's currently being developed for social anxiety disorder. It's presently in a Phase IIa trial, and we anticipate reading -- that trial reading out in the first quarter of next year. All right. With that, I will now open up to questions. Operator?

[Operator Instructions] Our first question comes from the line of Andrew Tsai with Jefferies.

Congratulations on the data, and congrats on the overall execution this year, including the breakthrough designation. My first question is on the FDA meeting that you will have. Can you remind us the key questions that you'll be asking the agency? And more specifically, what kinds of alignment are you hoping to get as it relates to expediting the pathway. For instance, do you think you will ask if this Phase IIb can be considered a pivotal study? Or do you think you can file a rolling NDA because I think another sponsor just got to buy in for that?

Thanks, Andrew, for the question and your kind words. It has been a very eventful and very positive year. So we're very excited about that ourselves. In terms of the specific questions that we'll be asking of the FDA, of course, we're not -- we won't be divulging that. What we have committed to is in Q1 of '26 providing an update on the online plan forward, the plan that's aligned with the agency once minutes are received. There has been some discussion around a single trial approach that involves the Phase IIb. The companies and the sponsors have said as much. Let's see how that goes. I mean, I don't -- all we're not going to do is change our plan vis-a-vis a 2-dose -- I mean 2 trial approach. So we will go ahead and kick off 2 Phase III programs. Just the detail [indiscernible] 2 Phase III trials is just the details of the trials may differ a little bit depending on some of the discussion around that. So maybe Kevin, I'll let you pick it up from there. If there's anything to add?

Yes. Thanks, Srini. I think you've covered it really. I mean as you say, there's a lot to talk about there, and you're mainly aiming to align with the plan. And as you mentioned, I think we still need to run 2 Phase III trials. And that's as much to do with the safety database, if anything else. But the further details, really, I think, got for the discussion. And although we've seen some movement in other -- from other sponsors, I think it's really certainly at that meeting that we'll get some clarity.

And my follow-up is that one case of suicidal ideation, can you describe this patient whether she had a meaningful efficacy response and which dose she was exactly on? And would you expect a suicidal ideation to happen in Phase III blinded portion with a lower 8-mg dose?

Maybe I will start. So as you know, Andrew, suicidal ideations are unfortunately part of the clinical presentation [indiscernible] depression and certainly those with more severe format depression like TRD. So this is obviously quite prevalent in other programs, particularly the SPRAVATO program. There were multiple instances of suicidal ideation actually, behavior as well. So Rob, maybe I can hand it off to you for a bit more color on the patient.

Yes, happy to. So she, as many people with TRD and as Srini just mentioned, she didn't have new suicidal ideation. In other words, this is -- unfortunately, it was part and parcel of her illness. And she actually had a -- not so much a treatment plan as a treatment outline if she was filling anxious, severely depressed, more severely depressed or suicidal. And she began to hear that she had these thoughts. And actually, contacted her clinicians, and they activated and cleared that same thing happened before in her life, which is this [indiscernible]. So for her, again, certainly [indiscernible] not backing away from that, but it wasn't a novel thing. Fortunately, she not only responded well to this intervention, she was having none of these thoughts within the day. And even when she was describing these idea, she was initiating protective action, meaning she was asking her parents to help her getting the treatment. She was not trying to harm herself, she [indiscernible] want it not to. So she did well in that regard. She actually was a responder overall. She ultimately had an improvement in her depression. She is on the higher dose, she's on the 12 milligrams. So I'm not -- so while we're analyzing this, I think it's important to now have done a lot of large studies in depression. This is part and parcel of the illness. We never want anyone to have these bad thoughts or actions, of course, but it literally does happen. So it wasn't a novel thing. It was a return to a prior thought pattern as it were. She was an overall responder, she was on the higher dose. And fortunately, everything resolved okay.

And our next question comes from Ritu Baral with TD Cowen.

Congratulations on this data. I don't -- you guys specified whether you were going to pursue redosing in the Phase III. If you are, are you going to -- given the overall AE profile, would you redose with the total? Would you redose with the 8, given what you've seen? If you could clarify how you're thinking about that in Pivotal. And then I've got a follow-up.

Thank you Ritu, and it's good to hear from you. So we have basically shelved the 12 at this point. So even if we did a redosing paradigm, it would be 8 and 8. We did present some data that involved redosing of the open-label study that also looked at 12, but these are all things basically designed prior to the Phase IIb data. So at this point, 12 is essentially shelled. The redosing paradigm is something that we are looking at. We're certainly going to have some discussions around that. There's potential efficacy that I think one could argue we are leaving on the table by doing only a single dose, but there's just additional complexity if you do a multi-dose paradigm. So these are some of the things that we're trading off at this point. I don't know, Kevin, if you had any additional thoughts on that.

Yes. No, I mean, I think you're absolutely right. I mean the interesting -- we've seen this data, and it's the IIa open-label data and it is encouraging that we can get maybe a bigger efficacy effect with 2 doses. But as you say, we need to trade that off against the complexity of coming in, let's say, 2 or 3 weeks after your first dose. And I think ultimately, it would be good to have a label that allows for either a single or 2 dose induction and then the maintenance thereafter. So as you say, I think we're kind of -- we're sort of working through that at the moment and how exactly to implement that in our development program. But certainly, it's something that's on our mind.

Yes. I think one other follow-up to that...

Go ahead.

So just one quick follow-up to that is, of course, this is something that also is short, right? It's a 2-hour paradigm. So we're certainly open to that notion. This is different than a much longer acting compound as an example. So the whole idea here is to fit in this SPRAVATO paradigm. Obviously, folks that are taking SPRAVATO are getting 8 administrations over the course of 4 weeks, and they're getting very similar efficacy to BPL with a single dose. So we do have some flexibility in that regard.

So my follow-up is sort of a safety and commercial blended question. You mentioned that those patients were out in 90 minutes. Can you quantify for us what percentage of patients did not resolve outside of, say, that 2 hours SPRAVATO time frame or 2.5 hours because I understand that SPRAVATO is like -- SPRAVATO suites are booked for, I think, 3 hours at a time. And then the patient with the SAE, did she have any sort of adverse reaction during her first dose? I'm wondering just about intra patient reaction?

Okay. So I will let -- actually, Kevin, do you want to jump in on this?

Yes, sure. I can talk certainly the first part. I mean in terms of the proportion, I mean, the majority of -- ready for discharge quite early on. I think 2 things to say. There is -- there's a proportion of 10%, maybe 15% kind of required longer so it went beyond 2 hours. And that is dose dependent. So we did see differences between the 12 and the 8, and the 8 being better in terms of people being ready for discharge. And I think also we've maybe refine the scale that we used. We used a multifaceted scale that looked at psychiatric effects, neurological effect on pressure, and a sort of global assessment by the commission [indiscernible] discharge based on the adverse events, et cetera. And we've seen that some of those are more sensitive than others. And I think as we go forward into the mix to the studies, we would refine that based on some of the learnings we've had from with this one. But what we do know is that some sort of structured assessment is going to be necessary. And so that's very much a topic of discussion. So I think that's -- I think we sort of pretty confident that the 8 milligrams in particular has fewer of those people at the tail who need to stay around. But it's important to remember that even in compounds like SPRAVATO, there is a tail of people who are not really at 2 hours, but the 2 hours are sort of the minimum time that people need to stay under assessment.

Yes, I think that's really good point to highlight. Yes. Sorry about that. I was just going to say I think roughly 85% or so from the summary basis of approval, but I would need to go back on that with SPRAVATO that we're ready, so to speak, at 2 hours. So it is indeed kind of a floor. It's not by any means a number [indiscernible].

And then intra-patient safety?

Yes. Yes. So Ron, do you want to take that or either one?

Yes, sure. I mean [indiscernible] So this particular patient, you're right, this thing happened on the second dosing. And again, I think what you're seeing is probably the effect of this one individual who unfortunately has the suicidal ideation as part of a depressive condition. Fall over the course of 4 months, 1 of these things did happen. It didn't actually happen after the first dose. She wasn't [indiscernible] she had a bad effect and then another bad effect. She actually did relatively well in the first dosing period with some response, did have more response after the second dosing that had this 1 episode. So yes, so it wasn't -- there was not a phenomenon for doing poorly and then doing worse. It was more -- this just happened over the course of the 4-month period. Also one thing to add to everybody's earlier answer, and Kevin had touched on this is important to note because this is how we differ from some of the other sponsors. There's a lot of people who have talked about the duration of the psychedelic effect itself, which we certainly can talk about in kind of a miss or a different context, but the [indiscernible] is very short with this agent, also with the other agents we're developing in the time frankly. The [indiscernible] effect is over with in almost literally everyone within an hour. And usually, it's much shorter than that. What we're really looking at here is a dischargeability scale that we're still working on actively with the FDA to finalize it there. The [indiscernible] effect has to be able with cardiovascular affects, blood pressure, heart rate, a neurologic exam and then a global assessment of being ready to go home. All of those things have to be in the green, shall we say for a person will be considered dischargeable. So that's where when Srini was saying, there's about 85% within that window we're talking about. It literally means they are ready to go home. It doesn't mean that the people who [indiscernible] go home are still having a psychedelic effect. That's just not the case. In this Phase II study, we learned a lot of things. Some of it was that a lot of investigators really interpreted cardiovascular effects going away that they're going totally back to baseline. And any time you're checking with somebody's heart rate or something that can be a condition where you want to be conservative, so you want to make sure. So we've seen the people who are tailing off as it were. It was more they weren't quite considered back to baseline until -- just to let you know after the 90 minutes, the first set [indiscernible] the majority of the next check, which is at 120 minutes, people were right. There were a few people that tailed out. A few people tailed out because they didn't have a right home literally, and the most together said, well, that means they're not ready. We can't discharge them on their own. We're waiting for other person. So we remain pretty conservative about being ready to go home. We'll work on that. We'll have that in the label. I can tell you from this early data, I feel fairly secure. We obviously have to look in Phase III, but I'm pretty secure this part of the thing will become SPRAVATO-like shall we say. So it's not that you have to keep people around for a long period of time. You can let them go when they're clear. We did look at 90 minutes in SPRAVATO, first looked at 120 minutes. We will probably continue a look like that in our studies. So we think that the overall time of the clinical be relatively short. So sorry to jump back to the first half of your question, but I wanted to put a little more detail on there.

That's awesome. Thank you so much for all the color, very helpful.

Our next question comes from the line of Pete Stavropoulos with Cantor Fitzgerald.

Congratulations on the data. First question is when you look at the responder and sort of remission rates from the core study and for those that were on the 8- and 12-milligram dose cohort, is there a consistency in terms of those that were responders or remitters on the 57 in the core study and those that were responders and remitters in the OL lease at day 57. And I'm partially asking to see if the original responders and remitters were resilient?

Yes, that's a great -- well, first of all, thank you for the question, Pete. That's a great question, whether there was sustained response. I don't remember that data specifically. Kevin, I don't know if you have seen that?

Yes, I can say a little bit, and I'm sure to say some more as well. I mean, so on average, we've looked at this and we haven't done a specific looking at people who were defined to sustained responders algorithmically. But looking at the data, we do see that those who responded after the first dose, are those indeed who have a sort of subsequent improvement after the second dose. So there's a group who I think with all drugs may not respond to the drug at all and those that do respond -- to respond to subsequent treatments as well.

Yes, this is Rob. I'll add to that. Kevin is completely right. And what we found so far, and this is a very preliminary analysis that in essence, most people did respond. The vast majority of people did respond somewhat. So first part of your question, is if you didn't make much of a responder criteria in the first dose, and you still have a pretty good chance to have some response in the second dosing, but it appeared that if anything, responds predictively response. What I mean was it if you were a relatively robust responder in the dose -- first dosing period, you really got a very good response in the second dose. That is part of what suggested as the 1 versus 2 dose induction is at least worth thinking about because of that. So -- there are -- there were definitely some people who just don't respond to this medication like any other medication. That's fortunately a very small number. Most people did have some effect on the second dose. And if the people were a partial responder, they tended to be even a more robust responder on that second dose.

All right. And one follow-up question. Thinking about the Phase III study design, [indiscernible] will be conducted. Will they follow the current paradigm of one against placebo? And the other against a subclinical dose. And will retreatment be based on a clinical sale threshold? And are you thinking about monotherapy studies or allowing concomitant standard of care and the questions?

Yes, of course. So the more recent studies, the more recent Phase III trials have not used a subtherapeutic dose paradigm. So we're not necessarily anticipating that, but of course, this is one of those questions for the FDA. So we'll -- that's something that we'll obviously provide some color on. In terms of the open-label extension, with other sponsors, there has been -- there have been some criteria. This is something that we are looking into as well. So we'll provide more color on that as well in the first quarter. And then what was OEM monotherapy versus [indiscernible] therapy, same kind of thing. I mean, this is kind of like Kevin was suggesting for the 1 versus 2, it'd be great to have the option of either. And the question is how to get there most efficiently in the context of 2 trials, we will take a look. I mean, do we do this in the context of these 2 trials? Do we do this in the context of an ANDA with a separate study [indiscernible].

Our next question comes from the line of Harry Gillis with Berenberg.

Congrats on the data. You've been very clear that you're going to proceed with the 8-milligram dose. But I was wondering whether there's any indication or signs you may also examine a dose below 8 milligrams given the 8 and 12 produced a similar effect? That's my first question.

Yes, it's a good question. So the agency as a general statement does like to see a dose response, right? That's one of the ways that you address concerns around functional unblinding. And the example that I give here is the COMPASS data, right? The Phase IIb, they both -- they had the subtherapeutic or [indiscernible], I should say, or 1 milligram dose, but then they had 10 and 25, both 10 and 25 were mostly psychedelic, but the 10-milligram dose did not have the same degree of efficacy and indeed did not hit that fig, whereas the 25-milligram dose did. So I think that is an important kind of data point. We are -- it's again, another question for the agency how to proceed on something like that. Kevin, I don't want to know if you have anything to add on that point?

No, I think you've covered it, Srini. I think clearly, we -- looking at some of the other sponsors that sort of mid dose that is psychodelic, but maybe less efficacious is a consistent paradigm that we see across a number of the other companies in Phase III. And so I think that's certainly something that is likely to be on the cards. And we have really good data from Phase I. We know the sort of subjective intensity in the PK meeting from 0.3 up to 14 milligrams has been studied. So I think we are in a good place to sort of pick a dose that is intermediate between 8 and 0 or 8.3 that meets those criteria. And as you say, that's something that's going to be coming up in the conversations with the regulators.

Understood. That's really clear. And then if I could just ask, so VLS-01 obviously had some delays. I was wondering, one, how that's progressing? Obviously, you've reiterated the readout in the second half of next year. And then as we think [indiscernible] just given everything we know the FDA end of Phase II meeting, potential Phase III start first half of next year. What's your current base case in terms of FDA filing and then eventual launch if everything goes to plan from here?

So on the second point, on BPL-003 time line to launch, we don't want to provide any color on that until we have clear guidance from the agency. So stay tuned on that point once we have those -- the minutes in hand. On VLS-01, no change in guidance on that. We're looking for a readout in the second half of next year.

And our next question comes from the line of Elemer Piros with Lucid Capital Markets..

So what I'd like to ask Srini and the team is how the noncompleters were treated. I think in the first 8-week period, you identified 90% completion rate. I don't know what it was in the redosing paradigm? And how you treated those who didn't make it to the end of the 8-week period?

How we treated those? Okay. So let's see, maybe Kevin, I don't know how best to handle that one. Obviously, we have attrition as we would in any study. So normally, it's something -- in this case, it's -- we don't really model it not like the primary analysis we have in MMRM, et cetera. Here, it's more an observed case. So the data that you have is the data that you have. But I don't know, Kevin, if there's anything else you can say on that?

No, it's a very good question, and that's exactly right. So we obviously have a model we're comparing statistically 3 doses in the core study. The analysis in the open label is, as you say, observed data. So we had a similar withdrawal or dropout rate in the open label, so about 90% to the end. But the values for each of those time points or actually kind of observed data rather than putting a model to that.

Okay. Okay. And Srini, I just wanted to make sure that you are still undecided whether it's going to be in the Phase III of 1 dose or a 2-dose paradigm at this stage?

Correct. At this moment, we're not sure. I'd say that one of the big picture considerations is time line of the primary endpoint, right? So obviously, with SPRAVATO, the primary endpoint was at 4 weeks, and that's in the original Transform 2 as well as the subsequent monotherapy SMDA trial. But the other sponsors have been -- seem to have a 6-week end point. So the inclination is that if it's a longer primary endpoint, there may be utility in doing a second dose, if it's a shorter one, perhaps a single dose may supply. So that's, again, not something that we've discussed in detail yet, and we're just kind of considering these different things. And of course, we'll have that discussion with the agency.

Our next question comes from the line of Sumant Kulkarni with Canaccord Genuity.

It's great to see you advancing the science and all the progress [indiscernible]. Does the response on the 12 mg dose, especially on the retreatment part, have any read-throughs for frequency and time point of future dosing in terms of perhaps the ceiling effect. It's not what might explain the results in the 12 mg -- plus 12 mg dose versus the 2 other groups in the OLE? And then I have a follow-up.

Sumant, thank you very much for the question and the kind words. Yes. I mean it's an interesting one, right? So in the core study, we also highlighted that while statistically not different, the 8 and 12, there was certainly a numerical benefit to the 8 milligram. And if you look at the adverse event table that was presented a while back, there was an increased anxiety noted with the 12-milligram dose. So I'm clear, to be perfectly honest with you, whether that anxiety is adversely impacting the efficacy that seems downstream. It's certainly something that one could postulate. I mean as you know, this is a single -- well, the core study was a single administration trial. So normally, when the high dose -- a normal study where it's a daily dosing when the high dose looks worse than the mid-dose, usually [indiscernible] someone dropped out along the way or what have you. But that's not -- that wasn't the case with the core study because it was only a single dose. So that's interesting. I don't know that it materially impacts how we're thinking about the redosing paradigm, however. As noted, we're going to go with the 8 and 8 and leave it at that. Good, robust efficacy that was seen out indeed for reasons that were interesting, I guess, or observation that was interesting is that response remission criteria tend to seem to be getting better as a function of time. I really do you need to understand that, that may just be a result of dropouts, but I'm not certain on that. So anticipating redosing and kind of the 8 to 12 weeks time frame, and that's more or less consistent with what other sponsors are doing?

And then we appreciate the actual time of psychedelic effect with BPL-003 is quite short here, limited to an hour or even less than that. But do you have or expect to have any analysis that attempt to parse out efficacy differences among patients depending on the differences in the duration of their actual psychedelic experience?

Yes, that's a great question. I mean these are all the secondary analyses that we are looking forward to doing and making public, I should say. So you can anticipate more posters as well as publications that come out of this over time.

Our next question comes from the line of Patrick Trucchio with H.C. Wainwright.

Congrats on the data. The first is just on the OLE data showing a deepening antidepressant effect over time. I was just wondering what your interpretation of that progressive increase in remission through day 57 post redose, just your interpretation of that? And then as well, it sounds like -- what we're looking at is a paradigm where we have a more simplified dosing than SPRAVATO and as well perhaps as efficacious results. And so I'm just wondering, are we looking at a paradigm where we're redosing once quarterly. What is this data set kind of pointing to you as we're seeing this longer-term data mature?

Yes. I mean we certainly anticipate something -- let me take the second question first and maybe I'll hand it to Kevin on the first one, the progressive increase. But certainly, that's our conjecture, right, that this will be significantly substantially improved redosing paradigm compares to SPRAVATO. Yes. As I mentioned in the talk itself, SPRAVATO is being redosed very frequently in many patients. It's at least once every 2 weeks. We would anticipate redosing closer to rate to 12 weeks, somewhere in that time frame with BPL. So substantially a substantial improvement in logistics for the patient and by extension, presumably quality of life as well. Kevin, do you want to take the progressive increase there, but our progressive improvement that would be 8 milligrams does?

Yes, absolutely. I mean it is interesting, and it's a slightly different pattern compared to the core study. And I mean we've had a couple of thoughts about that. I mean the one is, of course, it's worth bearing in mind that we are selecting a slightly different sample in the open label. So there were sort of 15% of people who dropped out of the core study, and we had a few more who dropped out who are eligible, but then dropped out for various reasons playing into the open label. And so that, of course, is select for maybe a group that are more prone to response. But I think there are other interesting interpretations. I mean one thing that we do here is that there is increased social connectedness, people to the [indiscernible] coming down quite significantly. And it may be that there's just a virtuous cycle filling up at that stage that they are participating more in activities with life, and that's creating its own feedback loop. So I think certainly something to understand in more detail. But I think as we look at that, that's how [indiscernible] said actually we start getting to people into situation where they're actually over time, getting better more than getting worse.

Right. That's helpful. And then just as a follow-up, if you can talk about the safety profile a bit more, particularly as it relates to SPRAVATO and some of these other short-acting as well as longer-acting psychiodelics et cetera in development?

Yes. I mean I think -- yes, go ahead, Kevin.

Yes. I mean I think on the sort of face of it, the class looks very similar across a lot of the adverse events. So increases in blood pressure and heart rate, nausea and vomiting, we have rates that are quite similar to some of the other reported numbers out there. I think it's unique to this drug delivery is the nasal discomfort, which I think are rates that are -- when we look at sort of things like Nasacort, steroids and other, there are a few internasal things out there. I think it comes somewhat with the territory. So nasal fullmess, it's going [indiscernible] sense of irritation or itchiness, and so we sort of see some of that. The [indiscernible], I think, is something that we've been watching quite carefully. But that is in a small proportion and a very short lived [indiscernible] that pain go away, really been out of dosing. So there hasn't been a lot that looks particularly different compared to the other [indiscernible]. It is somewhat different to the sort of associative folks like ketamine and SPRAVATO in as much as the association sort of these people getting clearly spaced out here in this case, people are having maybe a sort of an intense experience that is less sedating, shall we say. But I think that's a lot of it down to the sort of nature and the business experience. And we spend a lot of time preparing people for that, monitoring people through that and checking in on the most to make sure that they they're sort of well and back in terms of life afterwards. So I suppose, I mean, we haven't seen anything that you're concerned about, and it seems to be very much taking that we're seeing with these kinds of drugs, except in our case, of course, the time that people experience [indiscernible] event is shorter. So in terms of the amount of discomfort that someone has, we're talking about an hour or 2 every, let's say, 8 to 12 weeks, as opposed to an hour or 2 every twice a week or once a week or 8 hours or 12 hours of the dose. So I think our sort of area under the curve for discomfort, if you will, is shorter, but otherwise no surprise.

I just want to make a quick addendum here that the patients that actually that we were discussing that have the serious adverse event actually, it was in the 0.3-milligram dose arm initially. So the -- essentially the functional placebo and then got the 12 milligrams in the open label. So just -- it is important to keep that in mind.

Our next question comes from the line of Ami Fadia with Needham.

Congrats on the continued progress that you guys are making this year. It's great to see. My question is just with regards to -- I mean, clearly, this data along with the Phase IIa that you recently disclosed indicates that with an induction dose and then with also a maintenance dose, we see subsequent improvement in response, so what are some of the considerations that may prevent you from -- or sort of that you would weigh in considering kind of induction as well as the maintenance stores in Phase III. And with regards to the maintenance stores, would you consider it to be sort of a time to every 8-week redosing? Or would that be based on some other specific criteria, maybe the business score or some of the criteria for the patient? And then I've got 1 other question.

Sounds good. So yes, in terms of the redosing, this is a discussion with the agency, what they are looking to see. It seems like that the feedback that we've gotten from other discussions is that the agency does have specific or particular views on how 1 approaches redosing. So that's something that, again, we'll be talking to the agency about. In terms -- I think the way I understood your first question was around the induction approach. Currently, correct me if I am wrong, obviously, we're doing a single dose reduction now. There's certainly the notion that you're leaving some degree of efficacy on the table if you're doing only single dose and you may want to do 2 doses to see if there's more. That's something that we are going to look into [indiscernible] happens and how that looks in the Phase III program or something that [indiscernible]. Of course, there's some precedent here. Compass is doing exactly that split across 2 different trials as you, I'm sure you're aware. So there are 5 trials, a single dose, [indiscernible] a 2-dose induction. So again, something that we're looking into, as I mentioned previously, there's going to be some impact on the primary endpoint, whether it's a 4-week or 6-week endpoint is something that we'll also take under advisement as we think about 1 or 2 those paradigms.

Understood. That's helpful. Secondly, with regards to the dispatch time lines, it sounded like there might have been some patients who weren't quite ready. So my question, what I'm trying to understand is that what might have been the reasons. I think you mentioned one example where some patients just didn't have somebody to pick them up at the end of the time frame, and so they weren't deemed the start ready. So in terms of the discussions with the FDA, what are some of the changes in the criteria or the questionnaire that you might explore changing to be able to sort of fit within the existing paradigm?

Yes, sounds good. Rob, do you want to take that one?

Yes. So the agency is interested in several different parameters. That's a good question. And one is, of course, the duration of the [indiscernible] effect. So that's one thing. The second thing is that the person is essentially physically back to normal. So that's more the physiologic characteristics like [indiscernible] and blood pressure. The third thing is the neurologic standing, a person can walk, they seem oriented time in place, different than the [indiscernible] elect, just more of like a neuromuscular effect going back to normal. And then finally, there's just a global assessment that the clinician thinks they're ready to go home, where we found a lot of variance is that ready to go home thing, and we'll define that better in our next trial. We were very open and conservative first time. I think we found that the physiologic and the physical [indiscernible] as well as technological standpoint seem to work well. We haven't worked with the agency through this year. But we did do the study, of course, under an improved IND, and that included this readiness to discharge scale. There wasn't a preexisting [indiscernible] scale, which you can't really have because each drug is different. So SPRAVATO has one, will have one. And I think that's what we'll ultimately work on is to be able to have that home down so people know when people are ready to go home. The final thing about that is important. It's not as if you have to watch everyone until the last person in a Phase III study design was ready to go home. This is much more how soon can you send someone come, which is like what happens is SPRAVATO in the clinic that Srini said earlier, the vast majority of people with SPRAVATO can go home within a couple of hours. There are a few people that aren't ready and then they stay longer. So that's what we're expecting in the clinic. And when we'll work and we're actively going to work on that scale with the agency.

I will now hand the call back over to Dr. Rao for closing remarks.

Thank you very much. Yes. I mean, obviously, very excited about these results, very excited also about this very first call, this very first webcast that is Atai Beckley, so as mentioned earlier, this has been a very eventful year. It's been a very good year for Atai. Overall, we've had lots of positive momentum over the course of the year. So clearly looking forward to continuing that in the next year with multiple readouts and multiple kind of important inflection points. Not the least of which is the end of Phase II meeting manage that we've been talking about, but also the EMP-01 readout, which will be in the first quarter of next year as well as [indiscernible] readout for the Phase IIb in the second half of next year. So again, looking forward to following up with everyone as these various milestones are achieved. Thank you so much.

Thank you again for joining us today. This does conclude today's presentation. You may now disconnect.