Hi, everyone. Thanks for joining us for the Advancements in Psychedelic Therapies corporate panel discussion as part of TD Cowen's NeuroPsych Day. I am senior analyst Ritu Baral. I'm joined by my colleague, Athena Cohen, and with us, we have discussion participants from Atai, GH, and Cybin today to discuss the landscape and their individual programs and strategies. With us from Atai, we have CEO Srini Rao. From GH Research, we have the new CEO, Velichka Valcheva, and she goes by Villi. Thank you for joining us today, Villi, so shortly after assuming your CEO position. And from Cybin, we have CMO Amir Inamdar. Thank you, Amir, for joining us today as well, and thank you, Srini. So I wanna remind everybody, please use the question box on the top right corner of your screen to submit questions.
Athena will be keeping track of that, and we'll be working your questions into our outline discussions. You can email me and Athena, but we've got a few screens going on, so, that question box will get your question, definitively incorporated, as appropriate into the conversation. So thanks. We'll start with some thematic questions. Certainly a lot of investor questions post Lykos for everybody, and I figured we'd start there. You know, after the negative AdCom and the ultimate CRL, people were very concerned about the read-through to the whole development landscape, to all the developers. I will throw it out there. Do you guys think that the agency has changed its approach over the years to reviewing psychedelic therapies? And more specifically, have they changed since issuing guidance?
Is this a real-time thing, or was Lykos a one-off? Srini, maybe we can start with you. What do you think?
Thank you. Yeah, thank you very much for having me, Ritu. There's a lot of idiosyncrasies with the Lykos package, as well as, you know, the entire history here, right? This is something that goes back, I think, till two thousand and one. I think that's when the IND was filed, so it's literally been a generational program at this point. You know, what the agency kind of reiterated was that essentially the bar is not different for psychedelics compared to other compounds. I mean, I think that's the way to think about it. Certainly there was a lot in the guidance document, some of which was specific to psychedelics, I mean, around therapy, et cetera. I think that was mostly in reaction to what they were dealing with, with Lykos.
If you think about kind of the big picture, Compass' phase two trial already addressed many of the things that were brought up in this guidance document, so there's already been precedent here. The package that I and the approval that I think of as the true precedent is actually Spravato, right? So it's certainly a psychedelic adjacent, if you will. They had a breakthrough designation, they had a very successful AdCom, they had a first round review and approval for Spravato. Many of the things were addressed there. Obviously, they didn't go after therapy, and we can obviously talk about that in more detail. But it was a very clean package, got it through in the first go-around. So I think that's where people should really focus rather than on Lykos, which again, was very idiosyncratic.
Villi, maybe we could move to you. What were sort of the takeaways from the whole Lykos precedent and Lykos case study for how you guys are approaching clinical development at GH?
Yeah, so I guess, the first point I wanna make is, to your point, Ritu, I think the Lykos complete response and the outcome helped at least the clarity to evolve. A lot of the issues that were there, the rest of us, psychedelic developers, we were already aware of those and looking to address them in our phase three programs. But what came out of Lykos is more clarity on some of those that are also valid for us. I guess the two things that you probably wanna talk about is, you know, the functional unblinding and the expectation bias, and we can talk about that. But overall, a lot of the issues that came out of the Lykos, I don't see relevant to us, Ritu.
I think the FDA have demonstrated now multiple times, starting from the Spravato outcome, you're right, Srini, but then through all the meetings they've organized to talk about, you know, placebo controls, to talk about outliers, that they're supportive of the psychedelic developers, that they keep an open line of communication, and that they do want to help us get through the regulatory path.
Amir, maybe you can speak to a couple of the points that Villi brought up, the idea of the focus on functional unblinding and the expectation bias. And is there a third takeaway or lesson from Cybin, from the Lykos example, and you know, going to what Srini said, the Spravato example, and the Spravato review, and things that have come up in that?
Yeah, and maybe I can start with the third question in terms of key takeaways, and I'll echo what, Srini said, that, the FDA is going to apply the same standards that it has applied, and it applies to any other therapy. It will apply the same standard to psychedelics because fundamentally what they need to do is ensure safety, and efficacy of the treatments of medicines. The same thing applies to psychedelics. We know in the case of, the Lykos outcome, and, there are some details now that we know from other meetings that have followed that, like the Reagan-Udall on PTSD more recently-
where it became clear that the psychotherapeutic approaches that were not evidence-based, and I think that's one key takeaway for me as well. So psychotherapeutic approaches that were not evidence-based and put patients at risk of boundary violations, these were being employed.
This was the Lykos-
I think it-
Yeah, this was. So you're saying in the Udall meeting, the Lykos psychotherapeutic support was found to not be evidence-based, what they used?
There was discussion around the psychotherapeutic approach that was employed in the MDMA-assisted therapy, and it was mentioned that the concerns were around that psychotherapeutic approach not being evidence-based and using kind of standard psychotherapeutic terminology for something that was not really standard psychotherapy
... which was being employed in the MDMA-assisted therapy program. You know, things like therapists being told that they could assess patients' needs, including their need to suffer for healing, and that's not a standard psychotherapy approach. So, that's one of the key takeaways for us, which we are already addressing in our EMBARK program, that we have to use evidence-based therapy approaches. Which, by the way, we are not really doing psychedelic-assisted psychotherapy, as I think most of the other companies here as well. That was unique to MDMA, and I keep reminding people that it is virtually impossible to do any psychotherapy during those acute dosing sessions because patients are uninstructable, right?
So you can't really do any psychotherapy.
Yeah.
And using evidence-based measures and treatment wrappers, that's one of the key takeaways for us. So of course we are addressing issues like functional unblinding to the extent that we can. Yeah. So one has to acknowledge.
Yeah. Amir, can you elaborate on that? Because that is a topic that comes up with investors a lot. And feel free to talk about your own program and how you're doing it at this point. I know it's later in my discussion outline, but that's first, that's a suggestion anyway. How do you best address that?
Yeah. Yeah. I mean, so as I said, you, we, you can't really do psychotherapy during the-
... session. And the way I explain it to people is, it's like dropping an atom bomb on the brain, and it disrupts all function in the brain. And one of the key circuitry it disrupts is language. And if you don't have language, you can't understand, and you can't speak. You can't understand any instruction, and you can't really engage in a psychotherapeutic progress.
You can't really do. What's important then, for us as clinicians and as clinical trialists, is to ensure that the patient has a safe environment, and that the clinicians or the monitors who are available in the room are there to ensure patient safety. They are there to guide them. That's the main reason. It's support. It's making sure
... they are safe. But I don't see it any different from clinical practice. And the example I've kind of beaten to death is somebody going for a knee replacement. You wouldn't just throw them into the clinic and just leave them on their own. No, there is a period before your knee replacement where you go to the surgeon, they tell you what it is-
Yeah
... what to expect, what could be the complications, how long it'll take for you to recover. That's exactly what we do with these treatments as well. The pre-dose period is when you're telling the patient what to expect. What is this treatment? What is the surgical intervention in their minds that you're doing? And just like with the knee replacement, the post surgical period is where you do the rehab, you do the recovery, the physical therapy, et cetera. It's exactly the same you do with these treatments as well. The post-dose period is where you debrief. You want to start that mental rehabilitation process-
... and help people help patients make the most of the treatment gains they've achieved during the actual dosing session. That's the framework by and large most of our peers and we are following as well. We have incorporated evidence-based therapeutic methods in our EMBARK framework, which follows that pre- and post-dose paradigm as well.
Understood. Maybe, Villi, we'll pass it to you. Can you talk a little bit about the topic of expectation bias? And, you know, how important is it to have a real number of psychedelic-naive patients, and is there a magic number in there? Villi, go ahead, and I'm gonna have Srini answer this as well.
... Yeah, so that really came out of the Lykos outcome largely, right? So I guess the FDA request is that we co-quantify the impact of the expectation bias. Surely, with psychedelics, to Amir's point, we can manage as to the best extent functional unblinding, but because of their effect, there is the case of functional unblinding. And patients have this expectation bias, so there are now suggested questionnaires. I don't know, Amir, if you're implementing those, and if you're even able to say. Now, we are not yet in our pivotal program, but there are questionnaires that could measure the expectation bias. So you ask the patients before their treatment about their expectations, and then you collect the data and account for the contribution of this expectation bias.
I guess when you have a large effect size and you're developing a novel treatment with a plausible mechanism of action and a favorable risk-benefit profile, the expectation bias should be accounted for, but it shouldn't have a huge impact on your efficacy and safety, right? That's how I see it. We just need to collect the data.
Quickly on your second question, it also, I mean, Lykos had large percentage of patients with prior MDMA experience, right?
Yes.
I guess we are excluding patients with prior experience. This is now a requirement by the FDA, so we need to go by it because we need to meet the regulatory requirements and get approvals.
Got it.
Yeah, but we also need to be conscious that the clinical trials we do are reflective of the general population.
Yes, that's why, that's why, Amir, I made this point.
Yeah.
So shining-
There's a difference.
Right? So you need some, but not too many. Is there a magic number or a magic range?
I mean, you know, a lot of trials have sort of implicit in them some assumption of up to maybe 10% of subjects having some previous exposure.
So, you know, just being very explicit about why that's a problem. If you have taken MDMA previously, then you have a sense of what it feels like, and of course, if you're then given placebo in the trial, that can be, you know, that can be problematic, right? So it's, it's interesting because the prep work, as it were, the informed consent around this is a bit of a double-edged sword, right? If you go into a lot of detail of what you could be feeling, that can actually increase expectation bias, right?
So you have to be very judicious with this. It's unclear-
... how Lykos was handling that, obviously, right? So, you know, we don't-- I certainly don't have the details. Maybe others do. But, you know, how are they prepping the patients? You know, if you have a bias that this, this drug works, and that certainly was brought up, you know, a priori, you're just assuming the drug works, then there might be a bias, as it were, to kind of, you know, feed the subjects a more favorable... You know, just giving it a much more descriptive approach, right? Which could also feed into expectation bias. So yeah, there was a couple of things that were problematic here. hat could be one of them-
... but certainly, they had 40% of individuals that had taken the drug before. The other issue here is that the trials are tiny, right? I mean, if you think about it, their two phase III trials were smaller than the phase II trial from Compass, right?
That's a really small subset. One of the ways of getting around some of these issues is to actually be able to do subset analyses post-hoc, right?
Yeah.
This is what it looked like when a patient had previous experience.
Yeah.
This is what it looked like when they didn't. This is what it looked like with high expectation bias. This is what it looked like when they were, the expectation bias was low. You need pretty good end for that to happen. I think one of the major limitations in my mind, and this was always something that bothered me, is how tiny these trials are. First of all, you can't assess safety. You know, there's kind of a rule of three to get a, you know, to get a 1%, you know, an event that occurs at a 1% frequency, you need about 300 subjects. So it's three X.
So putting these two together, they had 200, roughly, say, 100 patients on drug. The lower bound of safety was 3%, right? And so that was the safety side, but on the efficacy side, you had no room to do any kind of post-hoc analyses, right? It's just too small a data set. Again, you know, Compass is around 1,000 patients all in, right? That's a good data set to work with. I think Cybin, you guys are around 500 all in for the phase III, give or take. Again, good-sized data sets actually be able to tease some of these things out.
Okay, and then final question before I turn it over to Athena for some more is, establishing abuse potential and drug liking. That was something that came up in the committee. There wasn't a whole lot of time spent on it, but, you know, between abuse potential and drug liking not being established, and then, you know, the whole question about safety monitoring and oversight, how is that aligning in FDA's minds for development for all of you guys? What are the requirements for safety oversight? You know, who does the safety and oversight? And from the patient perspective, how you've defined abuse potential and drug liking. Amir, we'll kick that to you.
Yeah, it’s interesting because some of these issues we’ve debated quite extensively, especially in some peer groups in the industry.
Yeah
... the ISCTM-
Yeah
... working group on psychedelics, which I chair with Joyce. The bottom line is you need to collect everything. At the end of the day, you are going to have to tell the prescriber what to expect when you give this drug to the patient, and you don't necessarily then, at this point of time, need to differentiate between what is an expected effect, what is an adverse effect, what is an abuse-related effect?
... The unique thing with this class of drugs is that anything that you may feel is an expected effect of the drug and would have confusion about reporting it as an abuse, as an AE or not, an adverse event or not. Those events are all on the FDA list of abuse-related terms. So just close your eyes and report everything, and at the end of the study, you can do an analysis of whether there is a preponderance of abuse-related terms. Traditionally, we've done human abuse potential assessment studies, and what you referred to earlier, like drug liking.
That's a key measure with the in abuse liability studies. Problem with these drugs is people will have bad trips as well. People will have, you know, effects that they don't like, and in fact, there's theory that if you have a really bad effect, you are potentially going to be getting more therapeutic benefit. So, in contrast to what typically drugs of abuse or drugs that are associated-
... with abuse report, which is drug liking, you have this population, or this class of drugs where people report not liking the drug. I think we can get away with some preclinical work in animals, and with-
... collection of abuse-related terms, but there are certainly certain methodological challenges with the human abuse potential studies, things like collecting the liking,
... supratherapeutic dose. You know, that's one big challenge. When you do a human abuse liability study, you give a dose which is far in excess of what typically is a therapeutic dose. Then it becomes a real problem with this class of drugs. How are you going to give heroic doses of psilocybin or, you know, 5-MeO? When, you know, once you've reached the threshold, beyond that, it's only adverse events you are increasing. So some critical issues with respect to methodology, but the FDA is taking the standard approach as far as we are concerned. In our interactions, they're taking the standard approach of giving a list of terms that the sponsors should collect, and we are just following that guidance.
Understood.
Ritu, just one quick point on this, 'cause this kind of threw me for a little while. I was always kind of curious as to why the FDA cared, right?
Yeah.
'Cause if you think about it, these drugs are going to be given only under supervision, right?
Right.
It's not like it's. You're going to get access to the drug outside.
Yeah. Yeah.
And so I was always, you know, initially, I was kind of perplexed, like, "Why do you care?" Because, yeah, sure, there might be likability, there might be a lot of things, but if you can't access a drug, why, you know, why is that an issue? The concern is that, and this came up at the Lykos panel, if someone, quote, unquote, "likes the drug" or got, you know, that can be because of, you know, there was abuse, there were, it was, you know, euphoric, or they got a therapeutic benefit, they could go get the drug.
Yeah.
Right? That was the concern, and in fact, that happened.
They could go get it from street sources, essentially.
Illicit. They could get the illicit drug.
Yeah. Yeah.
I think that was really insightful. That was a really important aha moment for me. You know, because again, it's difficult to envision how this drug could get loose, as it were, but that's the concern. Interestingly, I think it's more of a concern for MDMA than it is for the other compounds, even our MDMA-
... frankly, the drug that we're developing. And the reason for that is that one of the enantiomers, S-MDMA, is basically a stimulant, and we already know stimulants are Schedule II, right? They are drugs of abuse. So at least from the likability perspective, traditional likability perspective, you've got that. Now, all of these drugs, I guess, if the patient got such a big benefit out of it, there is a potential that they would go out and get it. It is what it is, right? Do I think that's a high probability? I don't know. But it's something that all of us will have to keep an eye on, of course.
Understood.
Speaking of bad experiences, the development landscape is building out with different long-acting or long duration and short duration psychedelic therapies. How do their psychedelic experiences differ, and do you anticipate that would also impact the abuse component of these drugs? Maybe we'll start with Villi.
Yeah, indeed. I mean, the, for example, 5-MeO-DMT, especially our formulations inhaled and IV, it's ultra-rapid, right? The patient goes into a psychoactive phase within seconds, and it's up to 30 minutes, sometimes even shorter. And compare it to psilocybin, which is a lot longer and very different. And then, talking about the actual experience, we just had a symposium at ECNP, which was literally a few days ago, and one of our keynotes, Jan Ramaekers, was talking about the difference in psychedelic experiences. It also differs. I wouldn't say nice trip or bad trip. In the case of 5-MeO, it is really very intense experience. But, I guess, you know, that's a good thing from my point of view.
This TRD is huge unmet need, and it's a huge market, right? So we do need more treatment options and different treatment options for the patients. Some patients might want intranasal 5-MeO, others might want psilocybin, you know, it just differs. So I think there's the space for us all with these different, you know, psychoactives, short or long duration, and we need to work together to develop that space.
Srini, would you like to add?
There's-
Oh, yeah. Go ahead, Amir.
No, no. No, I was saying there's no one-size-fits-all, and it's always, as a clinician, I think it's good to have options.
Yes.
That's why you've got so many SSRIs and so many antidepressants.
Sure.
What works for one may not work for another.
Yeah
... so it's good to have that, and there's space for everyone.
... That actually brings up an investor question, so who would be the ideal patient candidates for long-duration, short-duration psychedelic therapies, and what portion of the current market on conventional, conventional SSRIs would benefit from this kind of approach?
I mean, if you're going to be a purist about it, the answer is we don't know yet, right? We don't have the data just yet. We will get more data from the phase III programs that are forthcoming with respect to the long-duration compounds. Short duration is a little bit more nebulous right now. The first data set around that will be BPL-003, which we're working on with our partner, Beckley Psytech. So that's going to be basically the Compass trial, the phase II trial, except replicated with a short duration. So at least some of the preliminary data suggests durability of effect. And I, I do want to emphasize that what Atai's focus is, is short, but not, you know, but basically kind of falling into our window.
So we want to give it once, not too similar to esketamine or Spravato, and then you go home. So it's, you know, it's just a fixed dosing sequence, a fixed timeline. So that's very different. So we kind of have three that are kind of in that bucket. VLS-01, the internal one with DMT, then BPL-003, that in partnership with Beckley and then and an IV psilocin program also partnered with Beckley. So we are looking into that. I think that there's pragmatic considerations there that make that well suited. And even if you do need another dose, it's still, you know, it's much better than esketamine in terms of logistics. So if you think about four weeks, that's eight visits with esketamine.
With a short duration, that could be one or two, that could be that presumably is one with the long duration as well. So that's kind of where our head's at, with this. It's just... Right now, it's very hard to tease out which patient would be particularly you know, well suited to one drug or another, quite frankly.
Understood. So we'll turn it over to company-specific questions now. Gonna continue with you, Srini. So let's start with your TRD candidate, VLS-01, from one of your internal programs. That is slated to enter a phase II study later this year. Can you tell us more about the formulation and treatment protocol, and how does it differ from Spravato?
Yeah. So this program had its genesis like in late 2019, early 2020, and again, it was very much based around Spravato. Now, the, you know, Spravato wasn't selling that much at that time, but, you know, we understood that there was massive muscle behind it, which is J&J. So if anybody could get all these clinics up and running, it was the likes of J&J. So we wanted to have something that could drag and drop, if you will, right into that paradigm. You know, always keep the end in mind, right? That's always, that's a kind of a fundamental mantra in drug development, and I was certainly interested at that time in something that is super simple, that would be patient-friendly, that would be physician-friendly. I've done a lot of work with intranasal in the past.
You know, people generally tolerate it pretty well. There's no doubt about that, but there's a subset of people that really don't like having stuff sprayed up their nose, right? So I wanted to try and avoid that if I could. I'd had some bad experiences, so to speak, with at a previous company with inhaled, having worked closely with a company that did that, so I was rather reticent around that approach as well. So oral transmucosal film is where we netted out, understanding it's a complicated formulation. It's difficult to make that work well, but essentially, the formula. You know, we recently reported about some results of our, you know, second-generation film, and it really exceeded expectations.
I mean, essentially variability, PK variability was equivalent to IV, so we got really good. You know, we got good, repeatable administration, very good, exposures, met our criteria, essentially everything back to baseline within two hours. So that's, that was what we were targeting. So really excited by those results. We were able to actually exceed the dose, in a sense that we actually had a high dose that was causing some, you know, distress, and so we were able to come down one dose level. The tolerability in, you know, from what we've seen in a phase I, and let me caveat with that, it's a, you know, it's a, it's still a small trial, has the potential to be best in class. We didn't have...
You know, we had one case of nausea at the dose we're going to go forward with. We had no vomiting. We had no local tolerability concerns. You know, again, all the, you know, the other formulations can have some of these things. So we're really happy with that. The subjects found that it was very, you know, a meaningful experience, right? So they were able to maneuver within that space. That's something that the FDA was really important, was interested in. You know, we had actually, we had our pre-IND meeting the day after the Lykos panel, which was amusing, you know, kind of time frame, and it was all the same folks that were at the Lykos panel here. Very good meeting, very constructive meeting, and a very different vibe from the day prior.
One of the things that came up is you know they were concerned about it because it's DMT. Are these patients completely snowed? Are they non-arousable during this experience? We're like, "No." I mean, we could wake them up every couple of minutes to see how the depth of their psychedelic experience. We asked it to them. You know, we asked that every couple of minutes. No problem in waking them up, and they were coherent enough to answer the question, but nonetheless, they were you know on the SIRS, which is subjective intensity, they were 7 through 10, 10 being the highest, which is pretty much where psilocybin is, and that's kind of where we were targeting. So again, pretty happy with the way that turned out, kicking the phase II off at the end of the year.
A couple of key points here is we'll have twelve weeks of durability data. We have the Beckley, the BPL-003 trial ongoing, so we can ask a different question with this, which is what happens with two doses? You know, it's kind of like Compass again. So, their phase IIb and their 005 trial are single administration, and then their 006 is two administrations, so we get a chance to ask that question, which is what we're doing. Also getting some dose-ranging data. But the twelve-week durability, I think, is gonna be really important. Going back to the functional and blinding question that came up earlier, durability is important there.
And just walk us through the phase II design for VLS-01, and how involved is the psychological support pre and post-dose? I know we just talked about psychological support before, but if you could just walk us through that and the target number of doses per year, that would be ideal.
Yeah. So the psychological support is probably not that dissimilar to most of the other companies. So it's informed consent plus. I mean, it is an unusual experience to the uninitiated, so we do wanna make sure that they're prepared for that. There's an element of, you know, what you take into it is gonna be what kind of comes up in the psychedelic experience, so obviously making sure that they're not too stressed out, it's not a bad day, a bad week for them is kind of important. We do have, you know, we do meet with the patient the day after. It's really to assess psychological safety, right? So things do come up in these experiences, as we all know, right?
So if something comes up with some prior trauma that they were suppressing, you'd wanna go ahead and deal with that, right? It's, it's not ethical to, let that kind of fester. So, you know, that's an important element. That's what we're doing. We're gonna see, you know, what came up, and how do we best deal with it, right? That's, that's basically the... You know, if I had to summarize the psychological support, that's it. In terms of the trial design, I alluded to bits and pieces of it, so it's a two-arm study. And we're taking the one dose that we found to be well-tolerated, but robustly, robustly psychedelic. It's either placebo versus that. It's true placebo, not the low dose.
Two doses, as I mentioned, because I think that'll be interesting, and a four-week endpoint. It's two weeks apart, four-week endpoint. Then there's a twelve-week endpoint, so twelve weeks post the second dose. We have really nice double-blind, placebo-controlled durability data. And then there's a re-randomization to a lower dose of 60 versus 120 and an additional follow-on period. That'll give us some of the dose-ranging data that we're looking for as well. That's kind of the I mean, that's a summary of the trial. Otherwise, criteria are pretty much as most people look at. We're pretty stringent on prior psychedelic use. So, you know, I think it's six months, but also only two exposures in lifetime. Obviously, it's self-reported, but still, that's what we're looking at.
So we're trying to be very stringent on that, and, yeah, I mean, I think that's a-
Is there a patient cap percentage for prior use?
There is not. There are assumptions made in the stats around what that would look like, and again, I'm not. We haven't guided on this, but if you go back to the Compass phase IIb, they had about 6% of individuals who reported prior use, and so, I mean, it's a good rule of thumb.
Understood.
We'll move to GH now. Villi, you have an ongoing phase IIb for your lead compound. Can you just briefly review the status of that right now, and the status of enrollment? I think we'd all also love any additional refined timelines for top-line data that you can give us at this point.
Yeah, sure, sure, Ritu. So, our guidance is that we complete enrollment by the end of Q3, so today is the twenty-sixth of September. As you can imagine, very exciting times for us, completing enrollment in our phase IIb trial, so that's eighty patients. And, yeah, which really demonstrates the commitment of our team now to execution and really deliver the studies and, present data. The top-line data present by the end of this year or Q1 next year, that relates to our plans to develop comprehensive scientific communication plan, to work with our KOLs. And, you know, when we clean up the database and lock the database, it, it might end up towards the end of the year, which is not an ideal time to come out with the new, new data.
So we've given ourselves, you know, the space to present it at the right moment and to work on the communications. But yeah, very exciting times for GH, for sure.
Got it. And the primary endpoint is MADRS at day seven. Most MDD studies use a six-week, you know, that's the Compass phase III. How does the agency view this early time point, just given what happened with Sage, and honestly, I'm not sure anybody knows what really happened with those early time points, but can you give perspective on that?
... Yeah, for sure. So first, the trial has two phases, right? A double-blind phase with the primary endpoint at day seven, and then an open-label extension for six months, where we're gonna also deliver long-term data. The day seven endpoint is an FDA-defined, a refined endpoint. It's in their guidance for ultrarapid and rapid-acting antidepressants. So, you know, the antidepressants have a much later six-week endpoint because it takes them so long to work. But in our case, as you know, we are ultrarapid, and we start measuring MADRS as soon as two hours, one day, day seven. This is an endpoint that was, at the time when the study was started, also developed with KOL. So it's a KOL-endorsed and advocated endpoint.
I think it's a good point, endpoint for GH001 because it would demonstrate this efficacy where patients can so quickly get out of this depressive episode, and we have very high rates of remission so early. So, yeah, I stand by it, and really, the scientific community is looking forward to the results from that endpoint three, too.
Do you have the option to extend that even further? I think in the FDA guidance, they've said they want follow-up out to a year, or is that something that would be more appropriate in the phase III setting?
Yeah. So obviously, the guidance is, relates primarily to pivotal programs, right? So I think for a phase IIb trial, this is a really good duration of an open-label extension of six months. In addition to that, you know what's good in our trial that after the seven days primary endpoint, all the placebo patients also go on active, and they follow the same treatment paradigm as the double-blind phase. So we would have data from eighty patients, not just safety, but also efficacy data throughout the trial. And what's also good is we allow retreatment of patients. And
That was my next question.
Yeah. Well, I think that's a very, very important paradigm that no other trial is answering. What's happening in the maintenance trial, you know, the maintenance phase-
'Cause you're like-
... and what's the retreatment paradigm?
Yeah, it's not just like twice or, but you're like-
It's as needed.
Yeah.
It's needed based on the depression symptoms. Again, we are in treatment-resistant depression space. It's a chronic disease.
Patients, you know, patients get back to a disrupted network. Some of them might be well for six months. Some of them might relapse. So it's a good opportunity to see what happens with patients, and then they be retreated when they need it. And I think in our case, because we are such a rapid-acting antidepressant, and we are aiming at a very short visiting clinic one day, you know, compared to Spravato, so it could be one to three hours. It allows a simple retreatment paradigm in the future compared to the complex Spravato retreatment paradigm. So that's a good start for us. We'll get to see the data when we're ready, and then plan for the phase III.
Was there a rationale around that five, maximum five retreatments during the six months?
It's the trial duration is six months, so I guess it's up to five. It doesn't mean that patients would have five, and they'll be retreated, you know, every month. I think we would see different patterns, right?
Got it. Amir, we'll move on to you now. CYB003, how is that differentiated from oral psilocybin and IV psilocin? And does the psychedelic experience from the patient perspective differ? And there's a client question that came in about your ongoing study.
Yeah. So CYB003, basically, we've taken the metabolic step away. As you know, psilocybin, when it's administered, it gets converted into the body, into psilocin, which is the active molecule. So psilocybin really is the prodrug. So CYB003 is not a prodrug. It is psilocin, which we have deuterated, and we administer it in a convenient oral dosing form as a capsule. The duration of effect is on average between four to six hours. Qualitatively, when you look at it, it's an experience that's similar to what has been reported with psilocybin, though it is more intense with our 60-milligram dose that we administered in the phase IIb.
Because we've taken the metabolic step away, there is expectation that it would take away some of the variability that you would typically see from the conversion of psilocybin to psilocin, which is different-
... in different people. And the other way, I think we are different, at least up until now, is that we've taken the approach of giving two doses, three weeks apart. We started with it. We never started with one dose. Most of the psilocybin paradigms are just a single dose. I think Compass is doing a study with two doses.
Throughout our program, we've been administering two doses, three weeks apart.
A client question that came in, we were talking. The client was speaking about your planned phase III studies. Have you given first dosing in the phase III trials yet? And will Cybin inform investors as to when dosing starts and how that tolerability is looking?
... we will inform investors when the dosing occurs. The phase III start is imminent, is all I can say, to you. We've had some really good discussions with the FDA. We've aligned on our phase III program, on the design of the studies, as well as the overall program. Protocol's final, everything's done. We're just about to start.
Got it.
A little thing.
That's a three-arm study, right? One of your, one of the phase IIIs is a three-arm study. You know-
Yeah.
One with, including a subtherapeutic dose. But can you talk about why you have a subtherapeutic and a placebo arm in that same study?
Yeah, so actually, we are starting with the two-arm study, not the three-arm study.
Okay. Okay.
And the two-arm is active versus placebo. So it's a pure-
Subther-
... placebo, and-
Oh, active dose versus placebo. So the placebo-controlled study, yep.
Versus an inert placebo. Now, with the three-arm design, it's all about managing expectations really, right?
It's the difference between telling a patient that whatever arm you're assigned to, you are going to get the drug, versus you only have a two in three chance of getting the drug.
Yeah
... so in the three-arm design, what we've done is we've included an inert placebo. A mid dose. I'm not. We don't necessarily know whether it's a subtherapeutic, or subpsy- it's not subpsychedelic. We see, you know, reasonably robust, psychedelic effects with that dose. So it's a mid dose rather than a subpsychedelic dose, and then we've got a full therapeutic dose. So those are the three arms. Now, the expectation is, so this is the dose response type of study that the, that the agency has asked of sponsors in this area, and we've agreed the design with the agency for this study.
Expectation is we will show a dose response, as in some patients may respond to the intermediate dose, but not to the same degree, and not to the same proportion as the full therapeutic dose.
I see. Got it, and what have you said about the timing of potential data from these phase IIIs? What general timeframe do you think that top line would be?
Yeah, so from our first phase III, which is imminently starting, we should expect data in 2026.
The second study is staggered by about six months.
Okay.
So we should expect data six months later. Ultimately, we hope that the full NDA will be completed sometime early to mid 2027.
Got it. Great. Athena, any last questions from the channel, from investors?
Yes. It's an interesting one.
Yeah.
To what degree is FDA approval of therapeutic psychedelics dependent on which political party occupies the White House?
Wow, that's an interesting one.
Food for thought.
Yeah, I mean-
Yeah
... it's at least focusing on ibogaine, which we have a development program on, and, you know, it's. And we do support a not-for-profit called VETS, that has been instrumental in getting special operators, you know, SEAL Team, et cetera, folks with severe PTSD and TBI, getting them ibogaine therapy. It's been interesting to see that it's been both, it's, you know, this is one of those places where there's actually consensus across both parties. So you have Rick Perry on the stage with Rick Doblin, and I mean, that literally. So I don't know. I mean, I think this is one place that we should see pretty good consensus. I'm not that concerned about which way the political winds flow this fall with respect to, you know, approvals, etc .
Great. All right. With that, we are at time. Thank you, everybody. Thank you, Villi, Srini, and Amir, for joining us today, and this great conversation. If anybody has any other questions, please shoot them to us by email, Athena and me, and we'll be sure to get them answered.
Thanks.
Thanks.
Thanks a lot, Ritu and Athena. Thank you.
Yeah, thank you.