Thanks everyone for joining us. Apologies for the late start. Welcome to the Neuropsych Corporate Panel of the 44th Annual TD Cowen Healthcare Conference. Today, we have participants from atai Life Sciences, GH Research, and COMPASS Pathways. From atai, we have CSO and co-founder, Srini Rao. From GH, we have CEO, Theis Terwey, and from COMPASS, we have CEO, Kabir Nath. Welcome, gentlemen. Thank you so much. We're gonna—like all of our corporate panels, we're gonna start with some thematic questions on not just the neuropsychiatry landscape, but sort of the intersection between that and psychedelic drug development today, given the compounds that you guys are bringing forward in the clinic towards FDA approval.
This past year, in that intersection, we saw a surprise CRL in the neuropsychiatry space, specifically in MDD, one that might have been related to durability of effect on the clinical benefit seen in major depressive disorder. Given the guidance recently issued, how important is durability to FDA reviews of your compounds within neuropsychiatry, specifically depression and related compounds? Kabir, can we start with you? Because you've got that Phase III ongoing, reading out this year. You've got 05 reading out this year, so that's in your crosshairs.
Sure. No, thanks, Ritu, and thanks for the invitation to be here. So I think first thing to say is I, you know, I, I know there are some people who say that the CRL you're referring to is kind of down to durability. I actually think it was much more straightforward as returned to risk-benefit, and that was just-
Yeah
... not proven for that drug.
Yeah.
and that-
We're talking about the effect size.
Yeah, and relative to where they'd had to push the dose and therefore-
Mm-hmm
... the safety profile and so on. So it's not clear to me that it was a durability question per se. That said, look, I think, you know, the way to think about durability is what matters to patients. And, you know, we are endeavoring with COMP360 to see in our Phase III what sort of robust durability we can see. You know, in the IIb, as we know, we measured out to 12 weeks and saw close to a quarter of patients in a remission then. In the Phase III, the first one is a single dose. We obviously have the second study with an additional dose that may even potentially extend that out. So I think the first thing is, let's see where our assets can actually deliver robust data in terms of durability for patients.
Secondarily, from a regulatory perspective, I have no concerns about our ability to meet whatever bar is required with COMP360 from that perspective.
I guess, you guys announced your Phase III design. I think literally 2 weeks later, the guidelines came out.
I mean, they were absolutely superimposable, the design and the requirements. So-
That was good news.
I can only imagine maybe you had a little few conversations beforehand. Can you address the most important parts of that guidance that are absolutely mission-critical to incorporate? Is durability one of them, and how is safety sort of rolled up into that?
I think the most important is to acknowledge the FDA said there were not different standards-
That's right
... being applied to psychedelics. I mean, the most important is the psychiatry division, which is relatively conservative for reasons we all understand. Essentially said that they were gonna apply the same rigor and discipline to psychedelics as they do to other psychiatric drugs. So that's the first and most important thing I would say. You know, underneath that, there's clearly commentary around design and what looks like, you know, acceptable design, given some of the specific questions around functional unblinding, around therapy, and so on. And, you know, I think clearly the agency still has some questions, particularly around the therapy question, and-
Mm-hmm. Yes
... what you actually see is that being worked out to some degree in the guidance. But for me, I think, as I say, the most important is that they are gonna expect people developing, sponsors developing psychedelics, to adhere to the same rigor as anyone else. And, you know, durability, as I say, will be something that we learn in time in the trials that we do, and it's gonna be different for different assets.
Another key investor question that I've spoken to some of you about in the audience is IP. Maybe, maybe we'll pitch this, this one to GH and Theis. What are the methods that sponsors are most commonly using currently to protect IP of these naturally occurring first-gen, naturally occurring first-gen compounds, when you can't get, you know, the sort of composition of matter patent we're used to in biotech?
Yeah, exactly. We all know that we work with the naturally occurring compounds, where we can't get the core chemical IP anymore. There are various things you can consider. Most of the companies certainly work with a very conventional approaches, like formulation IP or about some crystalline patterns of the API, which also could convey some protection. Depending on when you came in, you had also some further opportunities, I would say. So in our case, specifically, we certainly didn't have clinical trials with mebufotenin run before we started our program, and that allowed to file some broader concepts as well. Really relying on the novel and surprising findings that we developed in our studies and were core of our foundational IP.
In our case, we have filed a broad method of use claims for mebufotenin for the relevant disorders that we're aiming to treat, including major depressive disorder. We've recently made an announcement that we were granted initially now by the European Patent Office, a broad claim covering the use of mebufotenin for major depressive disorder and treatment of resistant depression. This is a concept that would really cover all routes, all dosages-
... all, all dosing approaches.... But it goes beyond that, where we have additional claims, looking into rapid onset of effects, durability of effects, treatment intervals, and further clinical concepts that would go into method of use claims. Then, depending on what the companies work on, what kind of delivery methods they apply, there are certainly additional parameters and concepts that you can apply. In our case, the prime product is GH001, which is delivered through the inhaled route, and that offers further opportunities on aerosol aspects, aerosol composition of matter claims, device-related claims, drug product-related claims, and so forth. So there's, I think, significant possibility to protect in this space, certainly versus generics, potentially also versus parallel developments or versus other companies who would be interested in development such molecules.
Kabir, to pick on you again, just because you're the closest to potential filing, can you describe the COMP360, the main COMP360 IP strategy?
Yeah, sure. Ours is around the specific polymorph, Polymorph A, and when the company was founded, that was the initial work that George and Katja did.
Mm-hmm.
To establish that there was something that was novel. So we have, you know, significant formulation around that, methods of use as well, as Theis referred to, and those, we believe, are robust. They take us into the late 2030s with our patent term restoration. And again, there's now sufficient precedent for polymorph patents standing up. We also, you know, we think, we believe we'll be the first psilocybin to file, so that will give us NCE exclusivity as well for differing periods in the U.S. and Europe.
Srini, given the breadth of your platform, there must be multiple IP plays-
Yeah.
- at atai. What do you see as the sort of strongest, essentially, that you've deployed across the pipeline?
Well, I think the strongest is to make sure there's multiple angles, right? I think that's really pretty critical, not relying on any one patent application, but really trying to get multiple avenues in. So, salt patents can be quite useful.
Is that the same as polymorph or no?
It is not.
It's not.
So it's actually the counter ion-
Okay.
- instead of the Polymorph, which is around the crystal.
Yep.
So the salt patent can be very useful because the definition of an API actually incorporates the counter ion.
Okay.
So a generic player can't actually use your molecule-
Mm-hmm
If that particular counter ion is patented. So that makes it more challenging for a generic player, because you don't get AB equivalents and all that. So, so that, that's actually quite important. Then the polymorphs, et cetera, can be very critical for production in particular. There are other elements that, you know, these drugs have complex administration paradigms. There are things that one can patent around that. We're obviously very interested in the digital angle, so, you know, try and incorporate elements of that into the label is something that we're exploring as well.
Thanks, guys. The next key safety concern is the immediate post-treatment period of psychedelics, such as MDMA-assisted therapy, and psilocybin is the emotional lability in these patients. Is there a consensus explanation for these findings across trials, and what can be done to mitigate these potential effects? Maybe start with you, Kabir.
Yeah. So you should really start with the physicians on the panel. I actually think. But I mean, first, I think we have to be absolutely critically clear. There are some patients for whom this is not a good experience. Yes?
Mm-hmm.
We are very clear to guide. This potentially can be a profound subjective experience that takes time to work through thereafter. And so I'm not sure that there's scientific consensus on the mechanisms or why that is the case, but let's acknowledge, both in a trial setting and in a real-world setting, that that will happen. You know, that's why we have focused always in our trials on this whole nature of safety for the patients, psychological support. We've distinguished it deliberately from therapy because it is not therapy, but there are elements of the preparation, the support that's provided during dosing, and the integration afterwards that are meant to address precisely that.
But I think let's also acknowledge that when it comes to the real world, when it comes to, you know, if any of us are ever lucky enough to commercialize some of these, you know, a patient journey with serious mental illness is not a once and done treatment. It's not you have a profound experience on psilocybin or 5-MeO or whatever it may be, and that's it. There is an absolute requirement for that patient to be integrated back into care.
Srini, do you have anything to add to that?
Yeah, I mean, I think the point is well taken, that it's very individual, and as we know, all of these drugs can tap into something that maybe the patient's not aware of, right? So this is a recurring theme, whether it's uncovering past traumas, et cetera, it's something that keeps coming up. You know, this fundamental notion of preparing the patient, making sure that they understand that this can come up, making sure that they have some strategies for dealing with it acutely, I think that's really important. Setting intentions is important, so-
Mm-hmm
... they have a sense of what they're working towards. But also on the other side, the integration really is important.
Yeah.
Of course, if there is something that is not handled adequately in integration, of course, standard of care would dictate that, you know, the patient does receive the appropriate follow-up care. I mean, that's just, that would be, you know, that sort of standard.
So this was a signal that was discussed at ACNP around the MAPS data, the integrated MAPS data, as presented on the last day. And, I'm going to go... Sorry, I'm going to go off script here. I want to know-
Whoa!
Yeah.
Okay.
Imagine that. What do you think is going to happen with MAPS Lykos later this day? So it's a MDMA-assisted psychotherapy for PTSD. Their filing was accepted, given priority review August PDUFA date. Srini, what do you think? Is it getting approved?
I think that ultimately it will get approved. So I had some concerns initially, and the reasons for those concerns were that the Phase III program was unusual. I mean, very small trials. I mean, it's very. You know, this is a company that had that was basically funded through donations for a very long time. This work was started in the mid-1980s and has culminated in a Phase III program, and Phase III results are a result of the NDA being filed at the end of last year. So I did have some concerns going into it. I think what has changed for me is an understanding that they've had a lot of regulatory interactions. You know, that's been brought up a few times. So I think they're in pretty good shape from that perspective.
Mm-hmm.
They have a lot of, you know, they have a lot of political tailwinds-
Yes.
That help, too. So whether or not it's reviewed on first cycle, I think... I mean, that I can't speak to, but I think they will get approved ultimately.
Theis, what do you think?
Yeah, I probably-
What are some of your learnings from everything they've done in this?
Yeah. I probably would agree that they would eventually be approved because of the strengths of the data, the character of the signal, and the high unmet need in PTSD, and the provisional support, probably. The one issue that I would see with their approach is a strong combination with psychotherapy.
Yes.
It was very clear that you have to demonstrate the contribution of drug and therapy, and that they haven't provided yet, right? And then the way they studied it, they also can't really separate those two.
Yeah.
That could be a remaining question. They have, their guidance has even suggested that you do Factorial Design studies where you look, to identify the individual.
Is that even possible when you think of-
It's challenging because you can't-
It's very difficult.
You can't blind psychotherapy, right? And that's why it's possibly challenging to actually do this. You know, and even in the studies that are currently run, where you could argue that you run drug plus therapy or support versus control plus therapy or support, there are still some questions because the support or the therapy is path dependent in a way, right?
Mm-hmm.
In the active arm, you would do integration of the actual psychedelic experience, and in the control arm, you don't have that experience, so it's a different kind of interaction during those integration sessions. So it's not equal in that sense. So there may be some questions on how to dissect that, and that's probably the biggest headache I would have with the...
Okay.
Yeah.
Though I'd only say the integration sessions occur after the initial front end is done.
Okay. Interesting. Srini, we'll start with you on the next one as well. Many short-term psychedelics, including the Beckley compounds, which you guys recently signed a license, have options on, are being investigated for TRD and MDD, your BPL, your ELE, and also Theis's GH001. Given these are shorter acting versus the COMP360, like six hours, what is the effect size that you expect, and what do you need, just given the balance of treatment burden versus what is needed to make it a compelling therapy? Can these short-term assets, I don't want to say get away, but basically, are they, can these short-term assets justify their use case with a smaller treatment effect?
Yeah. So fundamentally, we don't have a good sense of the relationship of the duration of psychedelic effect to the magnitude of change, the magnitude of benefit, or the durability.
Yeah.
I mean, I think that's a general statement. And what I mean is there's nothing that certainly compares to Compass's Phase IIb trial. There's a smaller data set from a company called Small Pharma that was ultimately acquired by Cybin that did like a DMT, IV DMT. Showed a pretty large effect size, but that was, you know, a very tiny trial.
Mm-hmm.
So I don't think it's direct. It's really not directly comparable. So that's something that needs to be explored. I mean, obviously, what are we looking for? You know, we're looking for generally significant changes, but you want it to be comparable to other therapies. It doesn't necessarily need to be comparable to psilocybin. If it's, you know, in some ways easier to use and repeated use. I mean, one of the things that may be different with a short duration compound is that you can use it, say, every two weeks, every four weeks, use it a little bit more frequently than one might anticipate using psilocybin, and thus get the benefits that may be comparable. So again, it's just an issue of how this is gonna be dosed out.
One of the reasons for our enthusiasm for the very short duration compounds is it does fit into an existing paradigm quite neatly.
Mm-hmm.
That's the one that's been established by Spravato. Spravato has 12 administrations in 8 weeks, so a lot, and it's not like you're driving home at the end of this, right? You do need to make, you know, you have 2 hours in the clinic, you've got some additional time on either side. You've got to deal with transportation, you've got to do that 12 times. So we're anticipating many fewer administrations.
Mm-hmm.
I mean, certainly, you know, over the course of eight weeks, you know, two or three administrations at most, but that may drive additional optimism.
Got it. The GH data set doesn't really support a conversation about a lower treatment effect. You have had tremendous data in Phase I, Phase II. But as you think about setting up your next trials, you're in a Phase IIb right now, but as you think of pivotal trials and a shorter treatment burden, does that make finding centers easier, faster to set up from a clinical trials perspective?
Yeah, absolutely. I think this is what we now learn from Intexo's our side, that exactly that's what they find attractive. It is, the shorter treatment burden during the shorter dosing day, for sure, that's something that's very feasible in their setups, but also in the way we give it, where we have really removed all the requirements, at least around the structured support, preparation and integration sessions. And we really see that rather in the context of standard of medical care. So we removed any kind of specific approaches and give it really to the hand of the physician, which is trained to perform informed consent. And that's, of course, always specific for the drug and the their effects and side effects. And that's not different what they would normally do, and also the support for side effects.
It's something that physicians always, always have to deal with, and that's also not fundamentally differently. So that's why we implement GH001, really in a pure pharmacological approach, where the support is provided for standard of care, and I think that's what physicians find highly attractive, and that's really supporting recruitment into our studies. There's one further point where we apply this individualized dosing approach.
Mm-hmm.
That's certainly a very pragmatic approach, but also something physicians can really relate with. That's how they are used to treat these diseases with compounds they had available already now. I would add one point. Given this, the huge unmet need and the large market size of TRD, I don't think that we have to really compare these different profiles of long-acting and short-acting.
Mm-hmm.
Those are different approaches, different profiles, probably different patient populations, where they would be applied. The opportunity is huge, so we're not really competing with each other here, rather build the market together. What we're rather saying, we should all look how do we compare with the standard of care, and that is Spravato. And J&J has recently guided for peak sales going up to even $5 billion, and even that is a small single-digit % of the market share, right? So there's a huge opportunity for multiple new entrants, and I think we all pave the way together for this and rather benefit from each other's successes than there would be a direct competition of the different approaches.
So feeding into that $5 billion is going to be the payer's perspective on all of this. Kabir, what have your payer interactions, payer surveys to date been like, and what have you seen from their receptivity, on their receptivity? And then we'll get into the CPT codes a little bit.
Sure. So I mean, first, clearly, because we don't have a full data set in hand-
Yeah.
There hasn't been much specificity about our relationship with payers. We have talked to a number of them, we've done payer advisory panels and so on. So a, a few things, I mean, to pick up on Theo's point, TRD is a huge problem. Yes, the number of people out there with significant chronic refractory depression is very large, and for many of them, there is a significant economic cost associated with that in terms of potential hospitalizations, visits to ER, and so on and so forth. So at one level, you know, you can construct, you know, ICER appropriate cost-effectiveness models-
Mm-hmm.
If you like, and at some level, we're all gonna have to do that because there does need to be that element, and particularly as you start to look outside the U.S., that's gonna be important. But I think more fundamentally, we've also got to actually change the nature of this discussion and point out around just all the comorbidities or the other things that you can do, and really how if you can start to relieve some of the symptoms of treatment-resistant depression or PTSD or some of these other really, really intractable, serious mental illnesses, you're actually creating such a strong pathway towards better patient health, and that's what we've got to do. Now, your response to that is, United couldn't care less about patient health and so on. And at some level, that's true.
Mm.
At the same time, you know, there is... In the zeitgeist, there is so much talk about behavioral health and the need to treat behavioral health alongside physical health, that I think we are pushing at least a semi-open door on some payers. But yeah, let's not minimize the work that's gonna have to be done to get this on formulary-
Mm-hmm.
and get payers to pay for it. You know, they're probably getting excited about the GLP-1 sort of pressure right now.
GLP-1s will fix everything in this world.
I think. Yep.
We'll stay on you, Kabir. I'm gonna move to the company-specific questions. Oh, you know what? It's a company-specific question, the CPT codes, that you're-
Yeah
... basically helping inform, developing together with Lykos. Where will the sort of data collection be towards the end of the year as we approach the Lykos PDUFA, and your own Phase III data? How close to conversion to the CPT I will we be?
It's a great question, and we don't know the answer to that. What I would say is clearly a Lykos approval-
Mm
... and the start of significant use in a commercial environment will be very helpful towards that.
Mm-hmm.
So that's probably a key factor for us-
Mm
that, you know, Lykos does get approved, and we start to see the significant use of that. But, yeah, there should be a reasonable body of evidence being started to build around the use, what it actually takes to deliver these medications and practice.
Got it. So your 005 study, top-line data now due in Q4, pushed forward from, sorry, pushed back from mid-2024. Can you remind us on the driver of the recruitment delays and how you have addressed that?
Sure. Yes. I mean, this is a TRD population, as we know, and well, that's a regulatory definition. It's, you know, at least two, 2-4 failures-
Mm
In the current episode. We are doing the same as we did in the Phase IIb, which is we require really robust documentation of those two failures. So we require specific drugs, specific dose, specific duration, and documentation of failure to respond. The challenge is those records are not typically in the same place or easily accessible in the U.S. in particular. So what we have done is, you know, we put in place traditional old-fashioned vendors who are incentivized to get that data together more quickly from patients.
Is that basically the patient has to authorize you to go back to their psychiatrist and then potentially another psychiatrist and get the chronic-?
You had to go to the pharmacy because-
Oh, so-
Remember, you know, a significant chunk of scripts are never filled in this country.
Mm-hmm. Oh-
... unlike in other countries.
psychiatrist and CVS, and then psychiatrist
Correct.
CVS, and then, okay.
Correct.
Got it.
Is that different from 001? No, it's not. But 001 was both U.S. and ex-U.S., whereas 005-
Mm-hmm.
is just U.S.
Everything centralized, or much more centralized.
Yes, correct. I think the important thing, though, to say is there is no shortage of patients. So the number of patients sadly coming in at the top of the funnel is even larger than it was in the first two years. So we clearly have no shortage of patients. It really is a mechanical process-
Mm-hmm.
of assuring ourselves that we're getting the right patients.
What should we be expecting in terms of effect size from 005?
A very good one.
What's a number that would make you happy?
So what I can guide to is in the IIb, the primary endpoint was at 3 weeks. We have published the 6-week data, which was statistically significant, and depending on which imputation method you use for people who went back on antidepressants, that was a difference of between 4.5 and 5.5. So that certainly should be a threshold to think about.
I think this is the biggest placebo-controlled, certainly only Phase III placebo-controlled psychedelic study that has been conducted to date. We discussed that might have an impact on enrollment-
Yep
... since patients have a 2-to-1, one-
A 1/3 chance, yeah.
Potential of just getting placebo. But that begs the question: what do you expect from the placebo arm? We saw recent data from another psychedelic study where the placebo just didn't go down at all. At all, which was odd, to say the least. Is that a real possibility with...? Can't imagine what happened there with. When we talk about the idea of functional unblinding, I mean, this is, if you're gonna have a trial that's functionally unblinded, it's gonna be a placebo-controlled one.
Sure.
How do you think of that spread for 005?
Yeah. So I mean, there are two or three data sets now-
Mm-hmm.
-that address this. So there is the IIS that was done out of Zurich, where we provided the drug, which was a true placebo. I would argue that the Usona study is effectively an unblinded placebo using niacin. There's also the study you just referred to. And what we do see is that there is a fairly modest effect size on true placebo, and certainly relative to the 1 mg that we use-
Yeah
... as the active control in our Phase IIb. And so I think that's what we can expect to see. Relative to the functional unblinding, yeah, let's be honest, it is gonna be functionally unblinded. We're clearly gonna measure expectancy and what people believe they got. We joke inside Compass. I guarantee there will be at least one person on placebo who gets a full psychedelic subjective experience. But leaving that aside, most people are going to know.
Really? You're sure?
Somebody is.
Pretty sure?
Somebody will get some sort of profound subjective experience of placebo, probably.
May I also add, someone in trial, and they tried to induce full psychedelic experience just with set and setting, and it's actually possible.
Yeah.
What setting?
Setting.
Wow!
Suggestion.
Suggestion.
But, you know, joking apart, we acknowledge that it's functionally unblinded. And again, back to the question around the agency's guidelines. That's why they acknowledge you need the two taken together. You need an active control and a placebo control. And, you know, let's face it, you're damned if you do, damned if you don't. If we didn't have the placebo control, the ad com is gonna be everyone standing up saying you don't have a safety database.
Yes. Yeah.
We will have the placebo control, so it's gonna be everyone standing up saying that this was an unblinded trial, we should discount it, so.
Yeah.
Can I maybe add one aspect to the placebo discussion? Because I don't completely agree that it's so unexpected to see a relatively flat placebo line, and that is because we are working with single-dosing approaches. And placebo effect is really a function of time-
Agreed.
a function of speed dosing, a function of number of interactions with the therapist or with the site staff, and also a function of number of endpoint assessments, even, which also-
Mm-hmm
... influence the placebo effect. If you look even at older studies, so that at single-dosing approaches, and there's the early ketamine trials, for example, also the early esketamine single-dosing studies. There are studies with nitric oxide. Botox was tested for, for depression. All single-dosing approaches, they all had flat placebo lines, right? What you see sometimes is a little, dip at day 1, because then you are in the clinic, right? There are some things happening to you, a lot of activities. But on day 7, you normally bounce back to almost flat. And this is what we see in the psilocin data and the Small Pharma data. I think your Phase IIb study also-
Yeah
... had a very modest-
Yeah
... placebo effect, although there was, of course, psychological interaction. I don't think that we should measure this against the placebo effects that we have seen in conventional depression studies, but rather look at the single-dosing studies.
Okay.
I think that's a very fair point. I agree.
Will you give us more details on the powering of your study once the SAP is locked in and you get closer to data?
In principle, no.
In principle, no? Oh, that's so disappointing. I'll, I will keep trying.
Srini, let's talk about the new psychedelic additions to your pipeline, BPL-003, intranasal 5-MeO-DMT, and ELE-101, an IV formulation of psilocin for MDD. So how do the two Phase II studies for 003 differ in design, and what are the goals for each of them?
Yeah. So actually, there's a total of three studies that are currently ongoing with BPL-003. There's a smaller open-label study that you, that you've alluded to. That's gonna be reading out. That's in TRD. That's gonna be reading out, the first half of this year. There's an alcohol use disorder trial that's also open-label. That'll be reading out in the middle of this year. And then there's a large Phase IIb trial that will be reading out at the end of the year. That's in TRD. So the, the two TRD studies, again, the first one's open-label. It's looking at one particular dose, 10 mg, single administration, up to three months of follow-up in that one, twelve weeks of follow-up. So that'll be interesting. And then-...
There is the larger TRD study is almost identical in design to the Phase IIb from Compass. So similar ends, and dose controlled, so it's sub-perceptual dose versus 8 mg and 12 mg of 5-methoxy-DMT. One difference is there's no com-- So it's eight weeks of double blind placebo or dose-controlled observation. And then there is a open label extension that follows that, where the patient can get another 12 mg dose and another eight-week observation period. So those are the trials that are coming.
The primary is 4 weeks?
The primary is four weeks, that's a good point. So different than the Compass trial, where the primary is three weeks.
Why did you choose to, like, for four weeks?
Well, 4 weeks, I mean, most regulatory endpoints have been between 4 and 6 weeks, essentially.
Mm-hmm.
So hence, that was one of the motivations to put it at four weeks.
What are you hoping to see in these Phase II, TRD studies in order to advance to Phase III, potentially?
Yeah. So obviously, the open label is, it is what it is.
Mm-hmm.
I mean, one of the things I think will be very interesting from that is looking at the long-term efficacy, you know, the long-term remission rates.
Day 30, day 90?
Day 90. Let's-
Mm.
Let's go all the way out, right?
Mm-hmm.
I mean, it's to the point that we're raised, it's a single administration. If these are all placebo, it should really bounce back at that point. So that's something that we'll be looking at, but obviously, doesn't have a lot of decision, doesn't have a lot of decision impact at the moment. You know, what we're looking for in the Phase IIb, I mean, you can probably surmise. I mean, clearly, a good effect, you know, statistically significant. Ideally across both doses, but we'll see. It could be one of the doses as it was with, with Compass.
Will you release top line, and then the follow-up later, or will we wait?
I mean, we haven't fully
Okay
... discussed that even internally at this point, so.
Are you in control of the data release or Beckley?
Beckley is primarily, right?
Mm-hmm.
there's obviously a discussion between the two of us. It's material to us.
Mm-hmm
... of course. So yeah, that's a discussion.
On to ELE-101 for MDD. So what advantages does IV psilocin have versus oral psilocybin-
Yeah
- or COMP360?
Yeah, good question. So when you take Psilocybin orally, you only end up with Psilocin in your blood. So Psilocybin is basically a prodrug.
Mm-hmm.
I think everybody here knows that if you take psilocybin orally, you get kind of a 4-6-hour psychedelic effect, something in that ballpark. Interestingly, if you infuse psilocin over 10-20 minutes, the modeling suggests that you'll get to serum concentrations which are comparable to 25 mg of psilocybin, but the total duration will be substantially less, and you may even hit sub-perceptual doses, serum concentrations rather, within about 90 minutes. So that's interesting. And again, this is very consistent with our general focus on short-acting agents, right? So, we have an internal asset, which is DMT. This has been something that we've been working on for a while. Oral transmucosal film, then we talked about BPL-003, which is intranasal transmucosal, essentially. This one currently is IV, but same kind of concept, short duration.
What is the monitoring protocol for your healthy volunteers and MDD patients in the ongoing study?
I mean, in general, there is prep work that is done and a small amount of integration work. You know, however you want to define it. There is psychological support. Even in healthy volunteers, things do come up, right? So it is important to really make sure that the subject in this case is safe and well taken care of.
So let's, Theis, let's move to you. Top line data from your Phase IIb TRD study of mebufotenin is expected in 4Q. Can you just review for us the design of the ongoing Phase IIb, this is European, a European site? How enrollment and site activation is going there?
Yeah, exactly. Enrollment is great. As I mentioned, a lot of interest from the sites. We've guided for a Q3 completion, and Q3 or Q4 data is out.
Is this Western Europe alone, or?
No, we have Eastern European countries as well.
Eastern Europe as well.
Seven European countries, about 20 sites. We really see a strong interest in recruitment, and as we've heard, there's certainly a very large patient population. The study is designed in two parts. We have a double-blind, placebo-controlled, randomized part, and then an open-label extension part. The double-blind part is one week, and that aligns with FDA guidance for major depressive disorder-
Mm-hmm
... which cites that for rapid acting antidepressants, you can look at early primary endpoints, and they specifically point out week one. But then, certainly, the guidance also says, and the psychedelic guidance then provides some more color on this, that you should characterize durability. Now, this is a Phase II study. For Phase III, we certainly would have to do a little more characterization work and also look for probably a longer controlled periods. But for the Phase II, we felt it was very important to test this in an open-label fashion, where we have a six months-
Yeah
... open-label follow-up, and we allow for up to five retreatment-
Yeah
in that period. Really assessing, for the first place, the duration of response-
Yeah
... and then assessing the effect of retreatment.
Why, why five?
It's a pragmatic choice, really-
Okay
... based on some anecdotal feedback we had from our initial trials, where we really learned also about relatively prolonged remissions. Really anecdotal, no solid data, but in line with what others have seen with their-
Mm-hmm
... programs, could be as Phase II study. So it is also sort of prolonged efficacy going out to 12 weeks in a large proportion of the patients. So we wanted to offer the flexibility with up to 6 doses. We don't really... We're recruiting now, right? We don't really have an expectation yet on where this would land. But given the simplicity of our approach, where we really have this pure pharmacological approach without any adjacent-
Yeah
... requirements for further visits, we could even support more than single or very infrequent doses with this approach. But we think up to six in a six-month period is certainly, from something like from a commercial perspective, would still work very well. It's still much less than what Spravato requires, and as I said, I think that's our benchmark.
Mm-hmm. So as mentioned, your Phase I, II data was very compelling, patient data on responses, remissions, et cetera. As we think about a broader Phase IIb, complications for, you know, for any neuropsychiatry study that expands the number of sites, how do you- how would you set expectations for effect size, given that very high standard you set with your-
Yeah. No, absolutely. The strong results we've seen in the Phase I, II trial was really from a single center, open-label study.
Mm-hmm.
As you said, normally, effect sizes go down-
Mm-hmm
... once you go into a larger, larger center numbers where you would expect more variability on patient selection, but also on assessment of endpoints and so on, forth.
Mm-hmm.
So that's a normal expectation. I would still say that the individualized dosing approach that we have chosen, where we give up to three doses in a single day, really trying to optimize the outcome on an intra-day, intra-patient basis. We are still very optimistic, of course, that this would deliver strong clinical data. But of course, the final profile will be defined by the study, and we shouldn't speculate about this. Again, the benchmark is Spravato out there, which, as a delta from placebo form, I think it's about 4, roughly. And certainly, that's also a very clinically relevant difference already when you consider that SSRIs normally have a separate separation from placebo of 2 or sometimes cases even less than that.
But of course, our ambitions are much, much higher based on what we've seen in Phase I, II. We have to weigh the data.
So, rounding back to Compass here, can you walk us through your collaboration with Greenbrook, Greenbrook TMS, and Hackensack Meridian Health partnerships? You spoke a little bit about this after your earnings call. But, what do those two different collaborations represent, and are there other sort of modalities of outlet, treatment outlet centers, that are extremely common as you're seeing the-
Sure
... the commercial landscape?
No. So I mean, what we're setting out to do is to address the question that I suspect we get asked more than anything else, which is: how is this commercially viable? Obviously, there are questions around the clinical data and so on, as we've rehearsed here as well, but these are the real questions. So what we set out to do was identify a number of the potential treatment centers, and that clearly builds partly on Spravato, but a lot on our own research, going out, talking to people, and so on. What we've determined was there are clearly gonna be a number of phenotypes or types of setting where psilocybin, and indeed other psychedelic drugs, could be delivered in future.
What we are doing is working with a handful of those that are deliberately chosen to be somewhat differentiated, really to understand a couple of different things. First, who are their patients with TRD? Where are they coming from? How are they accessing care in this particular setting? And then, what will it take in that setting for COMP360 to be made available? How is that gonna be integrated into workflows? How that's gonna be integrated into reimbursement and so on.
So, can I just ask a follow-up? Like, when you said we're gonna go for Greenbrook, and we're gonna go for Hackensack, do you already know the patient that goes to Greenbrook and the patient—like, what is the demographic of the patient that goes to Greenbrook?
So we have a sense of it.
Yep.
But that's what we need to get much more detail into.
Mm-hmm.
So, you know, Greenbrook is a for-profit interventional psychiatry chain, and so they started with TMS.
Mm-hmm.
Their name is Greenbrook TMS, ketamine, Spravato, and they have been talking to us for a long time. They clearly see adding psychedelic drugs, if approved-
Mm-hmm
... as another tool for their practicing psychiatrists.
They use insurance, right? They bill insurance-
Correct.
They know how to do this.
Yes. They are a commercial enterprise that's working with insurers and so on.
Yeah.
Hackensack is an example of a regional health system that actually has a whole network of sites where people with psychiatric illnesses are treated. They, I think they have, I can't remember the exact number of different settings within Hackensack, but there are a fair number. But it includes a major tertiary referral center.
Mm-hmm
... Carrier Clinic outside Belle Mead, which again, is a 300-unit inpatient bed unit for people with all sorts of serious mental illness and so on. So a very different catchment area-
Yeah
... and a very different way in which patients are gonna arrive, shall we say, at the tertiary referral centers-
Mm-hmm
... within Hackensack. Clearly, also offering reimbursement, working with insurers, and so on. So you can imagine that in those two, it's gonna be some very different-
Yeah
... templates for how psychedelics may be offered. Now, both are offering some Spravato today, so there is something to be built on. There's some sense of tying up capital, there's some sense of what's required, but really the purpose is to start to learn both ways, much more what's gonna be needed, and to build what we are calling, if you like, templates-
Yeah
... that then, in a formal pre-launch period, we could take to other examples of that.
How many templates are you thinking on that spectrum of, on one side-
A handful.
Maybe.
A handful. I mean, capacity-wise, it can't be more than, let's say, five or six-
Mm-hmm
... realistically. You can imagine that, you know, we are looking at some other very specific models, ones that might be, let's say, integrated within one of the big healthcare systems.
Mm-hmm.
Or something that might actually be, which you're starting to see, a commercial enterprise that is focused just on psychedelics, which you're also starting to see.
So one of those sort of neuropsychiatric spa, kind of environments versus like-
That, that's not a contradiction in terms.
At least I didn't use the term bougie. Which has been used, but like on the other hand, you'd have like a Kaiser, which would be enormous. So those would be like the two extremes-
Yeah
... with-
We're gonna say, obviously, we can't cover the whole universe.
Yeah.
But the whole point, as I say, is really you know, acknowledging that Spravato is a great tailwind for us and a great, you know, harbinger of what we could do, but there are still significant differences-
Mm.
- between Spravato treatment and what we're offering-
Yeah
or indeed, what any of these different psychedelics they offer.
So are the Greenbrook, the Hackensack, I think you have something with Sheppard Pratt, et cetera. Are those partnerships throwing off data? Going back to the CPT codes for a second, are they throwing off data that's useful for CPT codes?
Potentially, in time, they could.
So not right now?
No.
Okay, got it. What other types of commercial prep, besides this delivery, the various delivery phenotypes, for lack of a better word, are you pursuing that need to be developed before launch?
You know, one that you can argue does or does not fall into commercial is rescheduling, but clearly getting ahead of the state-level rescheduling challenges is critical.
Mm-hmm.
That's an area we're investing significantly from this year. Just as a reminder, federal rescheduling is, in theory, automatic if the FDA-
Yeah
- approves within 90 days, but state-level rescheduling is far from automatic. I think particularly in this environment, the whole question of what would be rescheduled and how that interplays with all these different state movements for legalization-
Mm-hmm
... and decriminalization is really important. So there's a big block of work we're doing around there. There are clearly elements around supply chain that we need to get right. I mean, how are we gonna get product from drug product through packaging into the distribution channel here? Obviously, we don't know what schedule we're likely to arrive on, but we can make some bets around that and actually start to think about that. Because, again, this is non-trivial. We don't yet need to start kind of the downstream elements with SPs and so on, but clearly, we're making our plans around all that and what we will need to do. And once we have data, we've already started to build the kind of, the robust economic models-
Mm-hmm
... but we now definitely need to put data in.
So to go off script for a second, you look at those states that have legalized, not just decriminalized, but legalized psilocybin, and you do have these neuropsych spas popping up, right? They have their own business model. Do you see them as a potential challenger? Just given Oregon requires that it be delivered in a very controlled setting.
Mm-hmm.
They're figuring it out. But I guess I'm asking, like, do those hurt or help? Because they're figuring a lot of things out for you, including cost.
Well, so I, I would say the challenge for those places is they don't have a business model.
Mm-hmm.
They're searching for a business model, because as long as psilocybin remains federally illegal-
Yeah
... Schedule I, there is actually no business model.
Okay.
Because it's a pure cash business.
Right.
You have no access.
They can't get loans, they can't-
No access to the banking system-
Yeah
... no access to insurance, and so on. So to me, you know, I, I think they neither help nor hinder. It's a kind of parallel world, and I think, again, the best precedent is ketamine. I mean, if you recall, at the time that esketamine was launched, plenty of people said it will fail because you can go to any strip mall in America-
Mm-hmm
... and get someone unqualified to give you a ketamine infusion.
Mm-hmm.
Well, what we see four years later is Spravato is on track for $ billions, and most of those unlicensed small places-
Despite J&J's best efforts.
Yeah.
Sorry.
Those strip mall ketamine clinics are going out of business because there is no business model, and I think actually that's, at least for now, the best analogy.
Mm-hmm. Srini, let's move back to you, and let's move to one of your other programs, RL-007 in cognitive impairment associated with schizophrenia. Can you talk us through the Phase IIb trial design? That trial is ongoing, and the mechanism in this indication for RL-007.
Now for something totally different.
Yes.
Completely non-psychedelic.
Yeah.
So just a caveat-
Back to pure neuropsychiatry.
That's right. So, this is a drug that we're developing for cognitive impairment associated with schizophrenia. It's a compound that was developed by AbbVie, Allergan, actually, quite some time ago. Phenotypically characterized, found to be at low doses for cognitive animal models. At higher doses, it was analgesic. So it was run in total of nine trials, 10 after we started in, you know, mainly in pain studies, though also in, you know, at least one Phase I was focused on cognition. Another one had a secondary endpoint, and actually, one of the pain studies, a larger 180-patient study, had, you know, cognition as a sort of exploratory endpoint.
And what was intriguing to us was there was a consistent pattern of procognitive effects, particularly with respect to verbal memory, both immediate, you know, immediate recall and delayed recall, as well as other things, including attentional elements. Going back to the... So that's, that was the interesting bit. Now, again, I mentioned this compound was phenotypically characterized. Pharmacologically characterizing it turned out to be more challenging than people expected. So it didn't bind the receptors in a normal manner. It has, it has some pharmacology that is, looks a lot like a GABA B PAM.
Mm-hmm
... but a positive, positive allosteric modulator, but it doesn't really behave like one. So when you put it in a human, even at very, you know, just wretched excess, very high doses, you don't see much in the way of sedation, if any sedation. So in the analgesic models, again, it's hundreds of milligrams were given three times a day, not seeing much in the way of sedation. So again, really interesting characteristics of this compound. So we tested initially in a small Phase IIa study that was open label. I mean, there was a sort of a piece that was blinded in there in terms of the patient didn't really know whether they were dosed on placebo first and then transitioned over. And we did look at aspects of the regulatory endpoint for cognitive impairment and schizophrenia.
We looked at things like symbol coding and a couple of verbal memory, of course. We also looked at EEG, which was interesting because, you know, there was a Phase I trial with a so-called scopolamine challenge. It's a cognitive impairment model, and there were changes on EEG that we're seeing with that, that, you know, roughly correlated with pro-cognitive effects. Small study, it was a Phase I. So we did see EEG changes in our study. We did see a pro-cognitive signal within the confines of a very small study, and that was the basis for kicking off our Phase IIb. One of the challenges with cognitive impairment in schizophrenia is you typically require relatively large trials, and that is, of course, what's happening, that's what we're doing. It's a 78-patient, times three, trial.
We have placebo versus 20 mg versus 4 0 mg, 6-week endpoint. We are using the full regulatory endpoint, which is the MATRICS consensus cognitive battery or MCCB.
Yeah.
Um-
That is accepted by FDA?
Mm-hmm.
In the guidelines? Okay.
Yeah, that is accepted. I mean, it was developed in conjunction with the FDA a long time ago.
Mm-hmm.
You know, I ran a CIAS trial a very long time ago, and it was, you know, the MCCB and other things were more in development. This is over 10 years ago.
Mm-hmm.
You know, one of the concerns that the FDA had was, you know, there were companies that were lobbing in compounds and saying, "This is what I'm gonna measure to assess cognitive impairment in schizophrenia." The FDA's concern was: I don't know if that measures anything. How is this relevant to cognition writ large? And what happens if it improves this one thing but makes a mess of something else?
Mm-hmm.
Those are all the concerns that the FDA had. So this was an NIH academic, industry consortium, and they basically identified seven domains of cognition. I think it's a total of ten instruments to actually measure those seven domains.
Within the MCCB?
Yeah.
Okay.
Yeah, so there's 10 instruments, and there's 7 domains, you know-
Okay
... social processing speed, you know, verbal memory, et cetera. So it's quite, you know, there's a long list. And the idea is that, you know, you'll take the drug, and you'll see what, you know, the... Either it'll move the entire thing, seems a little unlikely, but nonetheless, or you'll at least move some things, but you'll be able to demonstrate other things did get worse.
What about things like ADL? When we talk about cognition in terms of-
Yeah
- Huntington's or Alzheimer's-
Yeah
- usually they want, or agencies want, like, a complementary activity of daily-
Absolutely
- living improvement. In this case, is there a scale that you're looking at or an obvious complementary ADL scale?
Yeah, this is exactly right. They wanted to see that.
Mm-hmm.
They wanted to make sure that regardless of what's being measured, there's nothing adverse happening.
Yeah.
So the one that we're using is something called VRFCAT, and it's a virtual reality based task. And-
Is that the same one Sage is using for Huntington's?
I don't know.
Or does that sound familiar?
I don't know.
Okay.
Yeah, I can't tell you. But the way it works is you basically put together a shopping list, and then you have to go to a grocery store, in a virtual environment, pick up those items, then come back home.
Mm-hmm.
So that's the task. So you can see it's got, you know, it's face validity to a real activity of daily living. It kind of encompasses everything, right?
Mm-hmm.
So you've got to have memory, you've got to have executive function, et cetera. So it is a nice task. That's what we're currently looking at. One of the questions around these functional measures is: What duration do you need of drug therapy?
Yeah.
What duration of cognitive remedial therapy, et cetera, do you need to really see changes there? And I think that's an open question at this point. I'm not entirely sure.
Okay. When is the data... When is that data coming out, and what does good data look like to push it forward?
Middle of next year is what we're looking at.
Mm-hmm.
You know, there's certainly some data that's out there. Boehringer Ingelheim had a positive trial with that, so that's, you know, the sort of data that we're looking for as well.
Um-
They're in Phase III at this point.
Okay.
Different drug, very different pharmacology.
But using the MCCB-
Mm-hmm
- as well?
Yeah, yeah.
And any, the ADL, the VRFCAT or something?
They're either using SCoRS or the VRFCAT.
Okay.
I'm not sure which one they're using as their functional measure.
Got it. Thank you. Back to you, Theis. The IND for your GH001 proprietary aerosol device is on clinical hold. Can you remind us of FDA's main concerns, with the device and what they asked to lift the clinical hold?
Yeah, sure. So this IND, as you mentioned, related to GH001, not administered with the current device that we use in our clinical trials, but with our proprietary aerosol delivery device that we have developed since 2021. In November, we announced that this IND was put on clinical hold, the FDA citing as reasons for the clinical hold insufficient information to assess human risk, and that's pretty important because they could have cited an actual safety concern. That's another 21 CFR ground for clinical hold. They quoted insufficient information, and they were now asking for two additional non-clinical studies. That's a study, inhalation toxicology study in a non-human species and in a human species and in a rodent.
Then they were also asking for some additional information regarding our device design verification information that we've already submitted, and that is primarily around some clarifications, I would say, on data that we've already provided. Then there's one aspect of discussion around the FDA now, so that is related to an aspect that we could describe as contact duration classifications, where we basically classify how long is that device in contact with human tissue. We've made one assumption based on our clinical model. The FDA wanted to put it in a bit of a more conservative assumption that leads to assessment of different endpoints, and we are now in discussion with them on how to assess this.
But the device aspect probably is not gating with regard to timing of the resubmission, and also not risk-wise. I would say those questions were rather limited. The timeline is more a cumbersome aspect is the non-clinical work where we are now doing and have started those two additional studies that the FDA requested. Again, an inhalation toxicology study in rats and one in non-rodents. We have started those, and as we've said in our most recent release, we'll provide an update in the second quarter.
The toxicology studies and the non-rodents, are they being studied in dogs?
Exactly. It's a dog species.
Why did you select dogs?
So most ideal would be non-human primates from a metabolism perspective-
Mm-hmm.
For sure, but that's notoriously difficult to execute with inhalation drugs, which have these kind of effects, because you would require for a solid inhalation administration that you use neck restraints, and that's not possible in drugs that induce at least a severely altered state of consciousness, because that's for animal welfare reasons you could suffocate the animals.
Mm-hmm.
That's why we couldn't use a non-human primates, and the second most appropriate species is probably the dog, also commonly tested with those models as well.
In your recent press release, I believe you also may be pursuing this study in the EU instead.
Yeah.
Could you give us a bit more color on that?
Exactly. So the purpose of the IND then was, of course, to perform a clinical pharmacology bridging study to support the use of this device, because we've generated all the data so far with the third-party device that we acquired on the market in Europe. So we want to perform some bridging, and that's a clinical pharmacology trial. It was supposed to be the IND opening study. Now, due to the delay of the IND, because that study is required for our initiation of Phase III, where we want to, of course, use our proprietary device. To mitigate that IND delay, we are currently preparing for moving that study potentially into Europe, but we haven't yet really guided on the final conclusion, which really depends on the specific regulatory timelines and also on the clinical execution timelines.
But in that scenario, we would have the three aspects running in parallel. That's the non-clinical works towards the IND, and that we, of course, then need to initiate then the Phase II and Phase III trials. That is the end, the Phase II study, where we've guided for a Q3, Q4 completion, and then in parallel, we could run the clinical pharmacology study in Europe, really aiming to mitigate any impact of this IND delay-
Mm-hmm.
So that hopefully this situation is primarily a delay on the IND, but not necessarily a delay on the overall clinical program.
Have you requested a meeting with the FDA yet to remove-
Exactly. We have requested a meeting to discuss certain aspects of the response and our recent strategy.
Got it. You also recently released some healthy volunteer data from GH002. When can we expect more detailed secondary endpoint data from that study, and what are you thinking in terms of clinical development strategy forward?
Yeah, so we already announced, I think, the majority of the at least top-level data. So, it is, as you kind of expect, similarly rapid acting as the inhaled version and some intravenous administration, as it was a relatively rapid infusion. We saw a very significant psychedelic effect. Again, I would say in line with, what we've seen with the, with the inhaled, formulation, so a very potent, potent molecule for sure. We've seen good safety, so in that sense, it's, it's really, yeah, a strong contender here in our, in our pipeline. We will have to assess really the PK and, PD modeling in detail to see, how we want to progress this. That's not done yet, and, probably also with our next update in the second quarter, we'll provide further color.
Kabir, your next data readout is gonna be PTSD, correct? Can you help frame that data for us? What have you said on timing, and, I'm assuming this is CAPS-5, primary, the accepted pipeline. What effect size do you need to see in order to say this is a compelling treatment, COMP360's a compelling treatment for PTSD? And, actually, I'll just let you start there. Of course, I have a follow-up.
So we've said spring, and as a reminder, just before Christmas, we did publish the kind of 24-hour safety data because that was the original purpose of the study. So this is 22 patients across, I think, 4 or 5 sites. Yeah. Open label, single arm, so it's not a controlled study. CAPS-5 as the primary efficacy measure. So obviously, you know, the benchmark is out there as Lykos, and while, you know, we will not directly be drawing comparisons, everyone else will. So we can assume that that is the benchmark at least, and that's what people will compare it to. But obviously, the other benchmark is our own data in TRD.
Mm-hmm.
Yes, so we need to see something that is somewhere in those ballparks. I think-
Is there a point? I guess, is there a delta on points of the CAPS-5 that you're looking for, or is this gonna be in terms of effect size?
So I think what people have in their minds-
Mm-hmm.
is what MAPS are claiming for remission.
Okay.
Yes. I mean, that's what people are benchmarking to now. We will have an effect size and so on, but I think, you know, what MAPS are hooking, Lykos, sorry, Lykos are hooking things on-
Yeah
... this is the percentage of patients who are in remission, yes, after this treatment.
Mm-hmm.
So I'm not saying that we have to be in the same number, but I think, you know, that we have to understand that just effect size may not actually resonate with the audiences out there.
Okay.
I think that the second critical thing to say is the Lykos protocol is intensive.
Right.
It's 3 sessions with 2 therapists with MDMA, plus an additional 12 sessions.
It's exposure therapy, where you have to relive the-
It's... Yes.
Which is-
They don't mandate a specific type of therapy, but essentially that it is, and very-
That's the standard of care for PTSD-
Yes
... which is, which sounds horrible.
Well, while the sessions typically are 8 hours, we've heard of sessions that go 12, 14 hours.
... and, you know, remember, that's gonna be in contrast to what we studied, a single session with PTSD, with kind of the nature of the sit of the therapist in the room. That was exactly the same training as for TRD. So again, it's non-interventional. It's essentially there to help the patient work through their issues for psychological-
Yeah
-support, psychological safety. So I think, you know, that contrast and comparison with Lykos is really what's gonna be upfront, both from an efficacy but also a protocol perspective. And that's also because, remember, there is actually nothing else approved in PTSD.
Right.
There's no other benchmark with, I think, one of the illnesses arise. That's it.
Yeah, correct. I think, yeah.
So, I mean, it just sounds like there's room for a potentially smaller remission for a therapy that's just less emotionally and psychically commanding.
Potentially.
Nice way of putting it, anyway. On the safety side, again, just having Lykos show this emotional lability at ACNP, which is what people are talking about, do you expect the safety profile for PTSD patients to be different than what has emerged from TRD patients?
We wouldn't expect so.
Mm-hmm.
But again, remember, you know, if we find the data compelling, you know, then it will be incumbent on us to do a much larger controlled study, really, to answer that question. This is 22 patients over label, so, you know, if we'd seen something different, we'd know by now. But obviously, we'd have to do a larger study to really determine that.
Srini, in the couple of minutes that we do have left, what other key data readouts can we expect from the rest of Atai's pipeline?
So let's see. We've got—we talked a little bit about, I mean, BPL-003. So we've got those three readouts, the Phase IIb being the large one. ELE-101, we have something in the middle of this year. It's a Phase I, II. So, looking at the PK parameters and seeing if this hypothesis around getting PK, you know, C-maxes that are in line with oral psilocybin, but then dropping back down by 90 minutes to 2 hours. We'll see if that's validated, and then it goes into an open-label study of 12 subjects or 12 patients with MDD. We just kicked off and announced this morning our Phase I for our VLS-01. So that's an oral transmucosal film formulation of DMT.
We had had some results late last year with a prototype formulation. So this is with something that's suitable for a Phase II, so we want to confirm the results that we saw there. So, you know, those results will be the latter part of this year. And there's other things that we'll be kicking off over the course of the year, but in terms of results, those are the main things.
What's the status of your GAD study?
I'm sorry?
The general anxiety disorder-
So that's-
... tension.
Still something we're looking into at this point.
Mm-hmm.
You know, we've also kicked off a process there and talked about that a little bit in terms of being additional.
Got it.
Theis, last question for you. You're also pursuing bipolar two and PPD. Can you talk about the rationale for pursuing those two indications versus the many you've had to choose from?
Yeah, certainly. I mean, the opportunities in mood disorders is certainly much broader than that even, right? And we've heard PTSD-
Yeah
and there are other studies looking at anorexia and OCD and other kind of indications.
Mm-hmm.
We felt postpartum and bipolar. But certainly, we talk about bipolar, the depressive episode, so that's somewhat related to what we've already shown, and the same is true for postpartum. So in that sense, there may be a bit of lower-hanging fruit than some of the other indications.
Mm-hmm.
And still a very significant unmet need, where in the postpartum context, we have a clear regulatory pathway in front of us that has been shown by Sage. And FDA seems to think a bit differently about the postpartum indication than they think about MDD.
Mm-hmm.
Right or not, but they see this MDD as really chronic. While it's not really chronic, it's intermittent.
Mm-hmm.
But postpartum being more-
Episode
... a short term.
Yeah.
Shorter-term episodic indication. That's why that threshold appears to be somewhat lower if you look at the Zurzuvae-
Okay, yeah
... approval package, two relatively small studies with a 60-hour primary endpoint and then just 30-day follow-up, where they even missed in one of the studies, the significance at day 30. So it seems a bit of low. So it's a bit of a strategic aspect as well to look at postpartum. But of course, the unmet need is huge. We will now clearly follow the launch of Zuranolone-
Mm-hmm
... and see how well that does, and see what the market potential there is. But with our approach, again, we have a single dose a day. We do nothing around it. We see very rapid effects, and we have a drug which has a very short half-life. So in that context, it could be very interesting and relevant for the postpartum population, where a major concern has always been breastfeeding.
Mm-hmm.
In our case, the drug has gone out of your system after one hour, and we're currently assessing this in our postpartum Phase IIh trial, how this appears in breast milk. Likely, we will have a profile where you can even basically continue breastfeeding throughout, with the exception probably of the short clinic visit, and that is probably very attractive here. Bipolar, of course, we all know how large the unmet need-
Yeah
... there is, and we are optimistic that we see good results there as well. Those studies... I mean, the postpartum study is already on track for Q3 completion-
Mm-hmm
... and top-line data as well. For bipolar, we have added also further centers to the trial, but we have to assess recruitment through those centers before we can provide an updated timeline on readout for that study.
Great. Well, thank you, guys.
Thank you.
We're at time, and really appreciate all the insight. Thank you.
Thank you.