Welcome to the Cantor Global Healthcare Conference. I'm Pete Stavropoulos, a Biotech Analyst with Cantor. With us, we have atai Beckley , still atai, correct?
At this moment.
Okay. Soon to be atai Beckley. Please introduce Srinivas Rao, CEO. Let's start off with a brief introduction of yourself and of the company for those not familiar.
Yeah. Thank you very much, Pete, for having me, and thanks for everybody for joining. My name is Srinivas Rao, and I'm the CEO and co-founder of atai . Background, MD, PhD, neuropharmacologist. Did a lot of work with some of the same pharmacology as part of my PhD. Came on board, obviously, pretty early on. The company was more of a fund initially, and then I came on board to transition it to an operating company, which, of course, we've done. Atai, at this point, has a core pipeline of three assets. One, actually, as you alluded to, is from Beckley . We'll be merging with them here before the end of the year. That's our lead, that's BPL-003. That's for treatment-resistant depression. We have VLS-01, sort of behind it, also for treatment-resistant depression.
We have EMP-01, which is the third compound, and that's for social anxiety disorder. All psychedelic or psychedelic-related compounds.
All right. Starting off, just a broad question. You've been at atai since its start, one of the Co-founders, and you sort of watched the space evolve. Just curious to hear your perspective on experience on how people view the potential of psychedelics for psychiatric indications, how it's sort of evolved over the past five or so years, from interactions with the broad psychiatry community, let's say, interactions at medical conferences. Has the interest grown? When you did a presentation five years ago versus today, how's the room sort of shifted in interactions?
Yeah. I mean, I think even as early as our latest 2017, there was a lot of skepticism. 2018, somewhere in that ballpark. Indeed, Compass Pathways had transitioned from a not-for-profit to a for-profit company at that point to develop COMP360 or psilocybin for treatment of treatment-resistant depression as well. They were not able to raise funds at that point. In fact, that's actually how atai was originally formed as a vehicle to help fund Compass. Again, completely different era. By the time 2019 rolled around, there were a lot more people showing up at conferences, particularly like ACMP, where there's a lot of KOLs, thought leaders. It's the American College of Neuropharmacology Conference. It has steadily picked up since then. I think it's kind of gone out to more of the rank-and-file psychiatrists in particular.
Obviously, there's been a lot of stuff in the lay press in the intervening period that's also helped.
Right. I'm also curious, when you started, even with Compass Therapeutics , the clinical structure, the clinical trial infrastructure, how has that evolved? You only had one company, and now you have multiple studies that are ongoing. How have you seen that evolve?
Yeah, that's a great question. Compass did all the heavy lifting to get the first psychedelic trial up and running. That was a huge lift on their part. Part of it was done during COVID, so kudos to them for getting that up and running. You're absolutely right. There's more infrastructure now, but there's also many more trials now. There's not necessarily proportionate scaling of the two. There's definitely a lot more competition. It's interesting that normally you think of competition within the same indication. That's how you normally think about it. It's like, oh, well, these guys are doing two TRD trials, or one's depression, one's TRD, blah, blah, blah. Here, you also have to think about just the psychedelic aspect itself because it's more intensive. There's basically a room and some folks that have to watch the patient for a period of time.
You have to look more broadly across psychedelic versus just specific indication.
Okay. In June, you did announce a merger between atai and Beckley. Just walk us through the strategic rationale and what the combined entity is positioned to deliver. Can you elaborate on what those efficiencies translate into, better execution or a faster path to commercialization?
Yeah. We have been focused on short-duration psychedelics in particular. That's our lead compound, VLS-01, which is exactly that. It's an oral thin film formulation, transmucosal administration of dimethyltryptamine, or DMT. Beckley was developing an intranasal formulation, also rapid onset, offset of 5-methoxy-DMT. We were interested in that compound as well. We liked their approach broadly. We actually announced an investment in them in January of last year, in 2024, of $50 million. It basically got us about 1/3 of the company. We anticipated doing something all along, and it just made sense to announce a transaction in advance of our data readout, which we did. That was basically a full acquisition or a full merger of the two companies. It was contingent upon the phase II-B results. Those results were robustly positive, we'll say. Yes, we've obviously announced that we'll be moving forward with that.
In terms of what it's bringing to the company, that is our furthest asset at this point. Our internal asset VLS-01 is about roughly a year behind, give or take, compared to BPL. We have two different approaches, two different compounds, but now we have one that's going into phase III. We have one that's in phase II-B, and the third one is actually in phase II-A. We really do have a nice spread of these compounds.
All right. You did have the data, like you mentioned, phase II-B data that I read out earlier this summer.
Yes.
Yeah, just walk us through the details of the study design and the efficacy outcomes.
Yeah. The trial was actually very similar to what Compass did. I mean, again, as I mentioned, they're the guys that really put this, they were really the pioneers, or they are the pioneers here. It's a single administration of this compound in patients with treatment-resistant depression, so failed two drugs in the current episode. They're a single administration. Primary endpoint was at four weeks, and these patients were monitored for an additional four weeks or eight weeks total in a blinded fashion. There's an open-label extension, and they could be, if they chose to go into it, and the vast majority did, then they would get an additional dose, and they would be followed for an additional eight weeks. We looked at three separate doses.
There's a functional placebo, which is a subperceptual dose of 5-methoxy-DMT that was 0.3 mg, intermediate dose of 8 mg, and then a higher dose of 12 mg. Those two doses were picked because both of them had very robust psychedelic effects, but it was really a question of, you know, could the safety of the two be discriminated? What we found is that, indeed, efficacy-wise, 8 mg was the same as 12 mg, in fact, numerically a little bit better. Indeed, the tolerability was certainly improved over the 12 mg. That is actually the dose that we're going to move forward with.
Okay. What were some of the tolerability issues?
Yeah. A lot of them are sort of class effects. There was some nausea, vomiting, and headache. Those are kind of the main things. There was also some that are directly associated with the route of administration, so nasal irritation, some nasal discomfort as well. In all these compounds, all of them, including SPRAVATO actually, there's a transient increase in blood pressure. We saw that as well.
Okay. 90% of the patients completed the core study, 85% went into the open label. How does that sort of compare to other psychedelics in development for these indications?
I don't think we have very good data on that just yet. We will soon with Compass in terms of the open label and the rollover. The only one that I guess is available is GH Research, but it was a very different trial design. They only had a one-week sort of blinded period. Essentially, I think the vast majority, if not all of the patients, rolled in there, but that was a very sort of truncated trial.
Okay. Dosing was fixed for the OOE. If you rolled over, you got 12 mg, I believe.
12 mg.
There was no trigger in terms of, let's say, hitting a certain score on MADRS. What's the rationale for that design and dosing?
It was to really understand better the tolerability of the 12 mg dose, particularly with the repeated administration. I mean, we know that with SPRAVATO, you do get better tolerability over time. That was part of it. It was also to understand what the impact on efficacy would be, albeit in an open-label context. You know, it's an interesting question around criteria. Now, SPRAVATO is kind of the leader here, of course, the progenitor of a lot of these. They do have redosing criteria, which is the MADRS. You basically have to maintain remission. In reality, that doesn't work quite that way. I mean, it's mostly doctor, you know, it's mostly kind of doctor judgment on that, you know, talking to the patient and trying to understand what the patient needs. That's certainly how payers handle it and look at it as well.
It's not that there's a specific MADRS cutoff that they're looking for. My general inclination is to be more sort of flexible on this with respect to redosing criteria. We will be asking the agency some of these questions and see where it nets out. I'd rather have something that's a bit more scheduled, if you will, than strictly driven by criteria, but we'll see how it goes. Patients tend to, you'll notice this, that patients, their scores, their severity goes up when there's any question of getting a redose, because they start to get anxious whether or not they should get it or they want to redose, and they don't, you know, there's a question about it. You see this little kick at the end if there's a question about a redose.
If you don't give them that option, which is what we did, you know, which is what happened in this trial, you don't get that kick.
Okay.
Yeah, that's the increase in severity. It's interesting.
I guess one of the important questions when it comes to psychedelics is treatment and length. Treatment is the length of treatment session. You know, how long does a, I guess, a trip or a session?
Yeah. Again, stepping back for SPRAVATO, per label is two hours in clinic. That was dictated by, you know, in that case, dissociation, right? That's kind of the subjective effects you get with ketamine. It was also driven by, you know, blood pressure and everything else, as we talked about. Here with BPL-003, the psychedelic or subjective effects, I should put it that way, seem to fully resolve in the vast majority of patients. In the majority of patients by 90 minutes, in the vast majority of patients, about 85% by two hours. That's what we are looking for. We want to basically be able to match that label. That's what really drove this initial interest in short-duration psychedelics. We anticipated back in the day that there would be infrastructure that J&J would set up for it.
We were fortunate to be correct on that because they've done a great job. It took a lot of marketing might and a lot of capability to set that up. Again, it's great to be able to ride their coattails on this.
All right. I guess, sort of one question is, you know, are you seeing, you know, when you do speak to your KOLs and colleagues, are you seeing a larger interest in interventional psychiatry? You know, from both the established clinicians, as well as the younger ones coming in?
Particularly the younger ones coming in, right? Psychiatry has changed a lot over the last several, I mean, the last decade or so. It's changed because of the new interventional paradigms that became available. There was always ECT, but that was very rarely done. rTMS, transcranial magnetic stimulation, came along. That was one of the first kind of real interventional psychiatry approaches. Intravenous ketamine or intramuscular ketamine as a sort of off-label kind of approach was certainly adopted by many psychiatrists. In 2019, once SPRAVATO hit the market, that changed things pretty significantly. There is a lot more interest that we're in talking to younger docs. We're seeing that. We have, through a philanthropy type thing with MGH, sponsored some folks, fellows and things coming through. Definitely a lot more enthusiasm for it.
Okay. All right. Now back to [crosstalk] atai. You mentioned that the majority of patients were ready for discharge at about 90 minutes post-dose. Could you just talk about what this means from an operational standpoint? How does this sort of impact site throughput, cost, and payer potential, payer discussions?
Yeah. Basically, what we have heard from most docs is they want the ability to have more than one patient go through per day, right? Having something that's sort of in the two-hour time frame, theoretically, in a normal workday, gets you up to four patients in a day. Most docs don't really do that. It is useful to have some additional time at the end. We talked about the fact that it's a two-hour paradigm for SPRAVATO. What that means is people are dose-heavily monitored for two hours per label. They're medically assessed at that point to decide whether or not they should go home. Even with SPRAVATO, you will get anxiety reactions that require someone to be settled down. Their blood pressure may take a little longer to come back to baseline. You want a little bit of cushion. Docs like that.
Even if it's two or three administrations per day, certainly that was well- received by the doctors. It's well- received by the patients as well. It's a much shorter experience, right? In terms of payers, the question there was, basically, there are now codes for reimbursement of the time that someone sits with the patient. Less is better, as long as you don't have to keep doing it over and over again. What we've demonstrated with that phase II-B trial was that this short-duration psychedelic had the same magnitude of efficacy as a longer one like psilocybin, but it also had the same durability. We don't anticipate more frequent redosing with a short-duration compound. I think that's a big benefit. Should be viewed beneficially by the payers as well.
All right. In terms of the study designs and what you expect in the future, how many monitors are there per session and what are their functions?
The FDA put out guidance a couple of years ago for psychedelic drug development. They had stipulated two people in the room, so to speak, one of whom had an advanced degree of some kind. They can be an MD, they can be a nurse, they can be a therapist of different sorts. If they are not an MD, there has to be an MD around.
Okay.
The other person could be much more junior and, you know, Bachelor's Degree plus something else. This was really dictated by old literature from Johns Hopkins and other places that kind of stipulated this. This was something that was advocated for by MAPS/Lykos. Part of the reason, and there's a long sordid history on why that came to be. Now, the agency, you know, again, it's an unusual thing if you think about it. I mean, people develop, well, they develop SPRAVATO. SPRAVATO is a dissociative anesthetic. You're not worried about all this stuff, you know, particularly things like assault and things in the case of that compound. You can develop an anesthetic and no one's worried about all these things there either. It's a very unusual sort of phenomenon that has a long history and is driven by that.
In our case with BPL or Beckley , they had a pre-IND meeting about a year prior to VLS-01. Beckley did. There they did require two people in the room. Ours, they had actually softened the criteria. They needed someone around, one, you know, as long as there was a video monitor, and then one person in the room, but that could be the more junior one. I think the FDA's position is slowly changing. There's recognition now that this is not therapy. It's not that dissimilar to what you see with SPRAVATO. The patients are kind of doing their own thing. It's sort of an internal experience. You see that with all these psychedelics, whether it's psilocybin, LSD, or the compounds that we're developing.
Do you monitor the patient's blood pressure and so forth?
Yes, we do.
Just out of curiosity, are they actually hooked up, or do they have a wearable device?
No, we have telemetry for that. It's an automated cuff typically. Usually, you have pulse ox as well just to make sure that you can track blood pressure and everything else. That is not that dissimilar to ketamine clinics. Most of the ketamine clinics, certainly that I visited, the sites and things do just put a pulse ox monitor on and a cuff. Pretty much the same thing.
Okay. What are the other methods and protocols you use in the phase II-B, and you know, you plan to use in the phase III to sort of mitigate the various forms of bias?
Yeah. The one that's come up a lot is functional unblinding. There's a concern that with a psychedelic compound, you know, everybody will know what drug, whether they got drug or placebo, which is not actually true. Many people on placebo, many being, you know, 20%, 25%, will actually have a full robust psychedelic effect just because of being in, yeah, it's just, it's one of those things. It does happen. I mean, there's suggestibility. Suggestibility is pretty strong. There's a percentage of people that do get the drug, even a higher dose, for example, with psilocybin that didn't have a psychedelic effect. I think that's an interesting piece. In neuropsychiatry, functional blinding is pretty common. I mean, think about olanzapine, which is the antipsychotic. I'll give you that drug and then two weeks later you come back and you gained, you know, 14 lbs.
We, you know, and you're sedated. Both the patient and the doctor know what drug you were on in all likelihood. Regardless, a couple of things to mitigate that are making sure the patients are naïve, ideally naïve, or at least have a very distant history of psychedelic use. In the case of the phase II-B, it was 95% were psychedelic naïve. That certainly helps. That kind of increases the suggestibility. You get a response with placebo. You want to get dose response. I think that's an important element. Compass did a really great job there. They had the 10 mg dose. They demonstrated that despite being robustly psychedelic, it didn't have very good efficacy. It's demonstrated that some sort of different, you know, there was a disconnect there. We'll do that. Durability is really critical as well. The long duration of blinded follow-up is a really critical element.
All of the programs have, certainly all the phase III programs have that embedded in them.
Okay. The phase II-B was conducted as a monotherapy. I guess patients had to discontinue their antidepressants. What was the rationale behind that? Is monotherapy how you're sort of currently thinking about the phase III?
Yeah. There is literature, and it's mostly observational literature, that indicates that the presence of an SSRI and certainly an atypical antipsychotic will diminish the magnitude of the psychedelic effect. There's also literature that suggests the psychedelic effect, the depth and intensity of the psychedelic effect, is associated with efficacy. There have been concerns about that going into phase II trials, certainly. You want it to be, if you're thinking about adverse events, etc., a relatively clear, clean population. That's really driven a lot of this. There is no double-blind placebo-controlled data on add-on therapy at this point. There's a lot of open-label data that suggests that the suppression or diminution of the psychedelic effects does not seem to happen. It's just a risk thing at this point. A couple of companies are doing add-on, like Cybin, I believe, is doing adjunctive therapy. Other companies like Compass are not.
It's a bit of a mixed bag where it's one of those things that we're discussing at this point internally, how we want to proceed.
Do you think there's, I mean, it's small data sets, but you did have a, let's call it a cohort, you know, on SSRIs. It looks like, just visibly looking, there may be a little bit more efficacy.
Yeah. Numerically, that's been the case in these open-label data sets. It does look like it's increased. I think that's really intriguing. Compass, I believe, showed something very similar. There was one other data set that also suggested as much. It's not double-blind placebo control. There's the adverse event thing. It's certainly something that we're looking into and we'll explore. It's a point of discussion with the agency as well.
For the phase II-B, it was conducted at 38 sites across six countries.
Yeah.
I'm just curious to know if there was consistency across all sites and all geographies.
The analysis that we conducted to date is more limited, but it does show that the U.S. and the outside of the U.S., which is Australia, U.K., a couple of countries in Europe, broadly, those two buckets were the same. That's encouraging.
Were you in Eastern Europe?
It was not Eastern Europe. It was Germany, Portugal, and one other place, I believe. You'll have to, don't quote me on which countries it was, other than Germany. That one I'm certain of.
All right. I guess from a clinical perspective, durability was observed at the eight weeks with a single dose. How are you thinking about the maintenance dosing for the phase III? I know you mentioned, or you provided your thoughts on why you had the phase II as is.
Yeah. We're still kind of pondering that. I mean, somewhere between eight and 12 weeks is probably where we'll net out in terms of redosing frequency. Again, it's a discussion point. The eight weeks is supported by the data, of course, right? There was robust efficacy from a placebo-controlled perspective. You know, that persisted from four weeks all the way out to eight. That's where our head is at at the moment.
All right. You did have the open-label phase II-A, three cohorts, and now we're waiting for one more cohort of data. Just describe the different cohorts and the rationale for each.
Yeah. The first one was just monotherapy, and it was with an intermediate dose of 10 mg. It was single administration, just like the phase II-B, but monitoring out to 12 weeks. This was 11 patients evaluable. We basically saw pretty robust response and remission rates, roughly 50% from day two that persisted out to week 12. We had the SSRI study, the adjunctive that you had mentioned. In this case, there was a limited set of SSRI only that the patient, SSRIs that the patient could be on, showed essentially the same thing. We are now doing the two-dose induction as well. We did have some two-dose induction. That data is forthcoming at this point. Looking at potentially other cohorts, but right now it's kind of up in the air.
For the two doses, half hour apart, of this?
Two weeks apart. This is, you know, again, induction is a really interesting approach. If you look at the label for SPRAVATO, it does involve induction and then maintenance. Induction is eight administrations over four weeks, and then maintenance is currently, you know, for the second four weeks is once a week, and then after that it's sort of as needed. Many patients get it every week, and the vast majority of patients get it every week to two weeks. That's a lot. That's just a lot of administrations. I like the induction approach because you do get some additional benefit. That's something that we're doing with VLS-01. Our phase II-B does have two-dose induction. We'll get some data there, and then we'll have this open-label data set as well. Again, not sure how we're going to proceed with how to implement this yet in phase III.
Compass did the same thing. One of their phase IIIs currently is single dose for induction. The other one is two-dose induction. We'll see.
How did you choose two weeks apart or not one week apart?
There were some concerns about how quickly you should do that in terms of the experience itself. Ours is a much shorter experience, so we probably could have pushed it to one week. Certainly in the case of psilocybin, it was like, you know, maybe you shouldn't be doing it so close together. There were also some questions about receptor downregulation and changes such that doing it too frequently, or certainly doing it day after day, would be very problematic from a receptor perspective and intensity of psychedelic experience. There's some literature around that. Basically, a little bit further apart is reasonable. Going back to SPRAVATO, they had a primary at four weeks, as I mentioned. Two weeks obviously splits that pretty cleanly.
Okay. You know, sort of zooming out with respect to your phase III planning, what are the key discussion points that you plan to have with the regulators?
Yeah. I mean, we don't typically get into a lot of the details there, but I've alluded to a lot of things that we're certainly contemplating at this point. Big picture, all of the phase IIIs look very similar to one another, right? Irrespective of indication, we have MindMed with GAD, Cybin with MDD, and Compass, obviously. All these trials are pretty similar: one or two doses, six weeks-ish of blinded follow-up, I mean, of primary blinded follow-up out to 12 weeks, and then some form of open label. All of that is relatively fixed, but the devil's always in the details. The induction question, the primary endpoint, SPRAVATO was four weeks. Some of these others have been six weeks. Just trying to understand some of that and really nail that down.
Now, in terms of a pipeline and a product, where do you see 003 going in addition to TRD ?
Yeah, that's a great question. There was a small study that was done with alcohol use disorder that showed very robust effects. These compounds tend to be relatively broad-based. I mean, they're impacting some network dynamics in the brain that are common across many indications, whether it's anxiety or indeed PTSD, etc. There are these common networks that are disrupted at baseline, and these drugs seem to change that. You're absolutely right. There's a lot of indications we could go for. That's something that we're still discussing. Right now, our head's down on getting the phase III up and running. We also have VLS-01. That's another place that we could experiment. We're looking at a couple of different options here.
All right. Running out of time. If we're sitting here a year from now, what do you want to say was accomplished?
We've got the phase III trials going. We'll have the EMP results, the phase II-A results in hand. Phase II-B will be either in hand or very shortly forthcoming. That's what we anticipate getting through the next year.
All right. Srini, thank you very much for joining us. Great seeing you.
Yeah, as always.
Getting the updates, and look forward to the progress.
Thank you very much, Pete.
Thank you very much.