Okay, we're going to get started with the next session. I'm Andrew Tsai, senior biotech analyst at Jefferies, and it's my pleasure to have Srinivas Rao, CEO of AtaiBeckley, joining me today. Welcome, Srini.
Thank you very much, Andrew.
Maybe to start, as usual, people may be not as familiar with the AtaiBeckley story, so help talk about the strategy, overall strategy of your psychedelic company, what programs you're working on, and how might you be differentiated from other programs out there. Milestones too, as well.
Of course. Sounds good. Thank you everybody. Just stepping back, AtaiBeckley is a company that's focused on mental health conditions. We have a pipeline that consists of three psychedelic assets. Those are BPL-003, which is an intranasal formulation of 5-methoxy-DMT. We have a second asset, VLS-01, that is the transmucosal oral formulation of DMT. Finally, we have an earlier stage clinical asset that is our MDMA in an oral format currently. Again, the mandate for the company from its inception was mental health conditions and those with high unmet medical needs. Currently, the focus is on TRD, or depression writ large for both BPL-003, the lead, and VLS-01. Looking at a relatively novel indication for psychedelics, which was social anxiety disorder for EMP-01.
In terms of where things currently stand, BPL-003, we actually just initiated our phase III program as of today or at least announced that as of today. We had a very robustly positive phase IIb trial that we announced the results of about a year ago. We had an end of phase II meeting in between. We actually got Breakthrough Therapy designation along the way as well. Essentially that trial is starting off now, guiding for top-line results in early 2029 for that program. The second program, VLS-01, is in phase IIb currently, and we anticipate top-line results for that program, for that trial rather, at the end of this year, basically Q4 of this year.
The path from there on out will be the same thing that we, rinse and repeat, essentially what we just did with BPL, the phase II meeting and kicking off the phase III program. With EMP-01, we had a phase IIa readout earlier this year, that was in social anxiety disorder, as I mentioned. It was an 80-patient study, 40 times two essentially. Positive results on the primary, which is a regulatory endpoint for social anxiety disorder, the Liebowitz Social Anxiety Scale. Very robust effect sizes also seen on some of the subjective or patient-reported outcomes, and we'll be guiding a little bit more shortly in terms of next steps for that program.
Okay. Thank you. Big picture question to start is, as you reflect over the past few years, how has the regulatory environment evolved? What have been your own FDA conversations been like? Why is it favorable for investors to invest in now kind of thing?
Yeah. I will say that I guess across two administrations, essentially, the regulatory interactions have been very positive. I think that there's a lot of support for the development of psychedelic therapies that has manifest in the breakthrough designations that have been given out to the various assets over the years, including got some folks from COMPASS here with their COMP360 program, but even preceding that. There's always been support. Our interactions with VLS-01, with BPL-003, the pre-IND meeting for VLS-01, as well as the two meetings for BPL-003 have been incredibly collaborative. There was a lot of good input. It wasn't necessarily them mandating anything. There was just a lot of enthusiasm for those programs. The very fortunate bit is that the leadership hasn't changed. Tiffany Farchione is basically heading that, and she's been there.
There's been some people that have left, of course. I would say that generally the stability is obviously a really important thing for us. There have been obviously a lot of statements made around psychedelics and the enthusiasm for the psychedelics at the HHS level with R.F.K. Jr., et cetera. How that translates to the approval pathway, et cetera, currently is not entirely clear. I mean with the CNPVs, there was a recent executive order. The CNPVs ostensibly allow for faster review cycles. We'll see how that actually manifests. I think the most important thing in the executive order was post-approval. The DEA process is probably going to be streamlined, so that I think is a huge one.
Right. People are starting to feel more comfortable about the viability of psychedelics. Just looking at SPRAVATO as a potential proof point, $2 billion in sales and growing. By the time your lead program, BPL-003, is approved, how exactly do you envision leveraging the infrastructure? By that time, COMPASS technically should be approved.
Anticipate it, yeah.
Yeah. Is there anything you can leverage from their build-out? I don't know.
Stepping back for a moment, we characterize our products, certainly BPL and VLS, as sort of second-generation products, right? What we mean by that is there were alterations in formulation that resulted in alterations of pharmacokinetics. If you look at psilocybin as well as LSD currently, the formulation is relatively straightforward in the grand scheme of things. It's oral and an ODT formulation respectively. The pharmacokinetics are probably not that different than what's been previously seen with both psilocybin and with LSD. We intentionally chose to modify the pharmacokinetics of both BPL-003 and DMT, or VLS-01. These are both molecules that have inherently very short pharmacokinetics. They get cleared very quickly. We put them into formulation technologies to really fit within the two-hour SPRAVATO window and kind of maximize it. Right.
The angle from the very beginning, this is in 2020 when we started this process, was that there was an anticipation that J&J would be able to get the infrastructure in place, and we wanted assets that we're going to be able to drag and drop into that existing paradigm completely. That's what we've done. With BPL-003, interestingly enough, the end of phase II meeting, the agency was actually comfortable with our discharging the patients in two hours if they met criteria.
Right. That's a big win. VLS-01 is very similar to BPL-003. Of course, the phase II results are going to be pretty critical there. I think that's a big point of differentiation between us and both COMPASS and Delix. To your point, there will be more of a build-out of infrastructure support, longer duration compounds, without a doubt. We continue to believe that there will be benefits of the shorter duration ones, and that's kind of amplified by the discussions we've had with certainly the high- volume clinics et cetera, where the bulk of the economics is coming from actually the drug itself. Right? It's a buy and bill kind of model. Higher throughput is something that they have certainly emphasized, at least in the clinics than the folks that we've been discussing with.
Got it. Maybe digging deeper into BPL now, which is the 5-MeO-DMT program that you just started phase III today. Maybe just summarize what you saw in phase II that makes you think you have maybe even a superior product in terms of the efficacy profile from the phase II-B.
Just kind of stepping back, the phase II-B was actually very similar in some ways to the phase II that COMPASS had actually run with COMP360 or psilocybin. Single administration and three different dose levels. In this case, it was a sub-perceptual dose of 0.3 mg, then there was an 8 mg dose, and a 12 mg dose. The dose selection was interesting going into this program. We had no idea what the doses should be, right? Because this is a new formulation. It looked more like a traditional phase II trial. With a new chemical entity, what you typically do is you do your phase I, you find what the maximum tolerated dose is. You typically run that in your phase II as kind of the top dose, and then you pick something else underneath. In this case, the 12 mg was the MTD.
The eight-milligram dose actually had subjective effects that were very similar to 12 mg. It was kind of the lowest dose that gave that. That was how that dose was picked. Then there was the sub-threshold or sub-perceptual dose. Primary endpoint was at four weeks in this trial, MADRS, which is pretty typical here. The trial went out in a blinded fashion out to eight weeks. What we found at four weeks was essentially comparability to both SPRAVATO in their monotherapy trial, COMP360, as well as other things. We had a -6.2-point delta on the MADRS placebo-adjusted at four weeks.
Again, very similar. Really nice, robust responses that persisted out to eight weeks. Actually, stat sig, we did actually step down statistically, we do actually have stat sig out to eight weeks. With the open label extension, there was an additional dosing of the 12 milligrams. We saw additional benefit.
Those that got 0.3 originally had a benefit that looked very comparable to what we see in the core study. Those that got eight originally, and 12 secondarily, actually saw a more substantial benefit that actually improved over time. At the end of the 16 weeks, we kind of followed those patients for another eight weeks. We had an 80% response rate and roughly 66% remission rate. Again, really nice results. Obviously, have to see how that plays out in the phase III.
Right. To me, the phase II-B data on a single dose out to eight weeks was one of the strongest TRD data sets I've seen. It's just that you're starting phase III, you're a few years behind COMPASS. What is the guidance to data? Remind me, and then is there any way to expedite?
Yeah. The current guidance is top line basically in the beginning of 2029. Big picture, if you think about it, most of the trials, I think COMPASS included, but also the BPL data sets and others, it's around two years, give or take, from first patient dosed to top-line result. One of the challenges with Schedule I compounds is that there is a process. We initiated the trial today, right? That's regulatory approval as well as ethics approval. There is a period of time in between that and when you can actually start dosing that involves the DEA. That is variable, and it can be a little bit slower. It's both at the federal level, which is relatively straightforward, but then at a local level as well. That kind of slows things down a little bit.
That is something that we are pushing on. There was an act that was passed last year called the HALT Fentanyl Act that should have expedited this process. So far, it has not. It's something that we're pushing on. That would obviously be a factor that improved things. There are some other elements that we negotiated with the FDA that are likely to facilitate things and potentially expedite the process a little bit. We have not publicly disclosed that just yet because of competitive reasons.
Oh, interesting. Should I rule out an interim, though, of the.
We haven't planned for that at the moment. Interims are interesting. They sound great on paper and when you actually try to implement them, they are usually of mixed utility. It's certainly something that we could contemplate, but it's not really something that we've espoused at the moment.
Okay. Off of that, I guess in my notes, RECONNECT is your phase I, RECONNECT-2 is the phase II. I was looking for the other day, it looks like RECONNECT might be 350 patients, give or take.
Yeah, 340, yeah.
There are three arms. RECONNECT-2, it's two arms, 230 patients. Could actually RECONNECT-2 read out first, relative to the first one?
Yeah. I would say they're right on top of each other in terms of predicted top-line results at this moment. They're almost exactly on top of each other for exactly the reason that you outlined. RECONNECT 1 is starting a little bit sooner but RECONNECT- 2 is not far behind.
Because of the smaller size, it'll make up that gap.
Yep. Can you remind us how long it took you from start to finish the phase IIb?
It was just under two years. Again, from first patient dosed to top-line results was just under two years.
Got it. With these studies, how are you powering each study, drug versus placebo?
We have not as of yet guided exactly what we're doing in terms of powering assumptions. We will do so in time. You can take a look at the I don't think it's rocket science to kind of back calculate from the size of the trials, the size of the arms, what that probably looks like.
Yep. RECONNECT-2, is it two upfront doses?
Yeah. Both trials have a four-week primary endpoint. RECONNECT, single administration. RECONNECT-2 is two administrations, two weeks apart, then primary.
Would you expect RECONNECT-2 to show stronger efficacy than RECONNECT?
That is certainly the expectation. I don't think it's going to be massive. I'm not expecting 50% greater or anything, but I would expect a few percentage points certainly, in terms of benefit. You should see somewhat better stats as well, only because variance can go up as a function of time.
Right? Obviously the time is halved here since the last dose. Maybe, but I don't know that there's massive expectations there.
Yep, then would you also expect better or longer durability?
That's a really good question. That I don't think we really know yet, honestly. The way these trials are structured, I've been talking about up to primary. Beyond that, there's another eight weeks.
It's 12 weeks is the core. There's an open label extension, and the open label extension starts with a dose. Everybody that goes into the open label extension gets a dose. That takes the pressure off the patients in a way.
They know they're going to get that dose at that point. Actually, we have flexible redosing of eight or 12 weeks. We do have criteria, again, we haven't really disclosed the details of that. The unique bit here is that no matter what the drug is, there's going to be a subset of individuals whose efficacy will lapse by the time they get out to 12 weeks, right?
We've seen that decay curve among different programs, right? That's been something that's been relatively consistent. This gives the opportunity for those patients that need it to have a dose sooner. Obviously, why did we include that? It's because this is a really short experience, right? It is literally like SPRAVATO. It is the same duration. We know that folks that are being maintained on SPRAVATO, 70% plus of those folks are getting it every week. Our thought is that certainly eight weeks for the same kind of duration of administration should be quite palatable to the patients.
Right. RECONNECT, again, with three arms, does include four mg and then eight mg versus, is it placebo?
Yes.
Do you expect the four mg to do anything, or is it like a decoy dose?
I would expect something there. This was included on the base of discussions with the agency. They do want to see an intermediate dose. They do want to understand dose response. It's a smaller arm, right? We got eight, four, and placebo. It's two, one, two. It's not like we're looking for statistics, it's just an eyeball.
Eyeballing the data, essentially. There's no regression or anything that's being done there.
Yeah. That's basically per mandate, if you will.
I see. 12-week blinded phase, but the primary endpoint is week four. The open label phase, I was taking a look at it, the schematic the other day. I think in the open label phase, I think patients have the option to treat month two to three. It's a fixed interval it sounds like, rather than-
Very, yes. You're right.
Why pigeonhole yourself? Because I'd imagine that could inform the label of having a fixed dosing interval, but maybe not necessarily. Why not give them the option six months later? For instance, instead maybe they, quote unquote, "need to." I don't know.
They don't have to get it, of course.
That's true.
Right?
No, I talked it out with you.
If they're doing really well, they don't need to get it. That's not a problem. Yeah, I think across multiple companies now, it's a 12-week re-dose. Again, we wanted to give the option of the eight-week just because we felt we could, because it's so short. That's it. It's eight or 12. You might ask why we didn't do it more variable. It just turns out to be logistically much more complicated to provide that flexibility or additional variability. This encompasses everything that we think we need to accomplish, and that was obviously done in discussion with some of the KOLs as well.
Got it. Okay, that's very clear. Right. I talked it out with you. It's okay if the patient doesn't need it in the first eight to 12 weeks, maybe the second 8- 12 weeks.
Yeah, absolutely. They can stay in and get dose done, no problem.
Yeah. In your FDA discussions, did they kind of support or suggest that the existing phase IIb that you have on hand can be viewed as a pivotal study in that eventually one phase III is enough kind of thing?
The big picture was it's really around the safety database. That is a way to really think about it. They did want to see on the order of 300 plus at the six months and the 100 at the year. In other words, this is the so-called ICH kind of guidelines. We're not beholden to the acute exposures, and all that kind of stuff. They did want to see a decent database at those time points. That kind of provides a framework for how big the trials need to be. To get out to that number, you need 500 plus patients. Could you theoretically do it all in one trial? Sure, I suppose you could, but the agency also likes to see different trial designs.
They really like the fact that the first one had dose response with the intermediate dose, and then the second trial actually has dose response by virtue of having two doses.
when you compare to the first one. That structure was really appreciated by the Agency.
I see.
It's really about the size of the database more than anything.
Let's just say you made it through phase III, the eventual label, is it just TRD broadly? Is there any for mono or adjunctive TRD? Is it just TRD is how you envision it, specify like one or two upfront doses, or the option to do one or two? Like how do you envision the label?
Well, we'll see how things go with COMPASS. Right? This was sort of stolen from them in a way, right? We have the one and the two across the two phase III trials. My anticipation is that that would allow for flexibility, and that's what it's all about, right? A given patient may only need one dose; they may need two for induction. This gives them that. F Lexibility on the back -end maintenance. If you look at SPRAVATO label, there's induction, which is the first eight weeks, and then there's maintenance beyond. The maintenance would be 8- 12 weeks, in terms of redosing i s what we anticipate. It's again, we want to provide maximum flexibility for both the patients and providers.
Yes, sure, you're providing flexibility, giving the patients or physicians option to redose ultimately, but the phase IIb data was out to 12 weeks, and it was just durable.
Eight weeks.
Eight weeks. It was durable after a single dose. It would be nice to kind of explore how long that is durable. I guess we will find out in phase III. My question is how long do you think for the average patient this can last a single dose?
I think that's a good question across the class at the moment, right? Most of us are in a position where we understand that 8 - 12-week window very well, and then there's varying levels of open label data that go beyond that. In the case of COMPASS, I know it is a blinded piece, but it was a bit more complicated because of flexible redosing. Beyond that, the open label elements I'm not aware of all the data there. It's an open question at the moment. I think all of us are making some guesses around it. All of us are making some of those guesses around phase II data and beyond, and it's very reasonable guesses. We will see over the next little bit.
This applies to all your programs, VLS and our MDMA program. Describe the patient experience in their room. Is there preparation before the delivery, integration afterwards? Can you talk about the patient journey?
Yeah. In all cases, as you've suggested, there are Well, I think it's a little different between VLS and BPL at the moment, but it'll get harmonized. Essentially one or two visits prior. The second visit can be the morning of, and then there's a safety check the next day, and then a week later in the case of BPL. With VLS, we've actually shrunk that even further. It's a visit, just one visit 24 hours later. It's not necessarily integration. Obviously, the patient can discuss whatever came up for them. It's really more around psychological safety.
I view it as if a patient had chest pain, you're going to send them to a cardiologist. If they have something that comes up for them during the experience that requires additional intervention, they should see a therapist as appropriate, right? That's really what we're focusing on. It's not therapy intentionally; I think that's consistent across certainly COMPASS and Delix for sure. It is a much lighter lift.
Understood. Can you describe your best understanding the staffing requirement. Of this? Is one person must be in the room for BPL-003, for instance, for the entire two hours, or can there be remote monitoring? Doctors on SPRAVATO. It's a little confusing to me, but it sounds like one person for SPRAVATO can visit multiple rooms but c an that be the case for psychedelics, I guess, and for your programs?
We'll see what happens with the labels, right? It's interesting that the agency has evolved on this. When BPL-003 had its pre-IND meeting, there was a requirement to have two people in the room. By the time we got to the VLS-01 pre-IND meeting, they were like, "Eh, it's okay if you have video monitoring, you can have one person in the room, and you can have one person outside." Yeah, it had shifted a little bit. My hope is that I don't know if it'll be at approval, but in time we can get away from that also. These are such short experiences that pragmatically it doesn't make sense that you need someone hanging out in the room, from my perspective. It's an internal experience. We talk about two hours versus six hours versus whatever, eight hours, et cetera, for the different compounds.
I usually quip that that's wheels up to wheels down, right? That's when the drug's essentially out of the system. In the case of when you're looking at the most intense period of psychedelic effects, it's very short for BPL-003 and VLS-01. It's 30 - 45 minutes, maybe an hour max. It's a very short window. Outside of that, the patient is not necessarily in the throes of a true psychedelic effect. They're certainly feeling a little loopy. It's really short. Presumably, most people don't have to run to the bathroom during that time. It's just a very different experience.
Our hope is that in time, we can actually step away from requiring anybody in the room. Obviously, you need to monitor the patient, and if the patient is having a challenging experience, usually what happens, they start ripping stuff off. They all have eye masks on. Usually, they'll take that off. They might rip their headphones off, and it's an attempt to reground. Obviously go in there. The nice thing here is that because it's so short, you can just literally or figuratively handhold. It's like, "Just breathe. It's going to be over very soon. Just take some deep breaths, and you'll be fine.
Right. Okay. Very good. We have the VLS readout later in Q4, DMT program. It's a thin film, buccal administrative. What's the go, no go threshold for this one in your view before you move to phase III?
The pat answer is going to be the pat answer. It's what is the agency going to be looking for? Obviously they're going to be looking for clearing the minimum clinically important difference, right? That's typically viewed as roughly three on the MADRS, right, the placebo adjusted. That would be the lower bound there. It is a more complex question because it really is a trade-off of the acute efficacy at the endpoint, the tolerability of the drug, as well as the durability of effect, right? Those are kind of the trade-offs, and that requires obviously looking at the data once it's in hand.
After that, let's just say you're comfortable i s the next step phase III, straight to phase III?
Yes.
Would you do a phase II-B?
Nope.
Okay.
That is phase II-B.
Oh, okay.
Yeah.
My apologies.
Yeah. That is a phase II-B. The next step, assuming the results support it, would indeed be going straight to phase III.
Great. Lastly, the EMP-01, which is R-MDMA for social anxiety. Again, like you mentioned earlier, reported some data earlier this year. What's the next step, basically, for this program?
Yeah. We haven't guided on that just yet. We will be doing so in the near future.
Okay.
Very exciting program from our perspective. It's one of the more unique compounds out there. It's not a classical psychedelic. It does have some additional pharmacology. It has some additional subjective effects. It has this entactogenic and psychedelic properties that make it unique amongst the class. We originally were going after PTSD, and I think it was a very good indication and a very good drug for that. We chose social anxiety disorder because there tends to be a sort of lighter trauma element to that indication in many patients. We had good results. We had a very short trial, which kind of impinged on the total magnitude of efficacy. It's a behavioral endpoint. It does take time to manifest. We think that a longer trial would have undoubtedly given us better results.
Understood.
Yeah, we're pretty excited about that.
Okay. Well, thanks for all the updates.
Yeah, absolutely.
I think that's all the time we have, but congratulations on the progress.