CYB003, that have the potential for really rapid and large reductions in depressive symptoms that are highly durable, lasting many months after just one or two doses. That's a big shift. Finally moving away from treating the signs and symptoms of disease to changing the course of disease. That's what's really exciting, I think, about this whole sector. We have two programs, CYB004, which is our deuterated DMT asset, which is in phase 2 for generalized anxiety disorder, and CYB003, which is about to start phase 3 in MDD.
Great. So, you know, as we look at the psychedelic drug development pipeline, I'm wondering if you can talk about the state of the union for the space. How do you envision the lead compounds progressing in clinical development, both at Cybin and for the field? And importantly, what impact do you think the Lykos Advisory Committee with MDMA-assisted therapy is going to have on the space?
You know, clearly, the CLR that Lykos got has created a bit of an emotional blow, I think in the short term. It's definitely impacting stocks in the sector, and I can understand that. It's to generalists, to retail investors, it's a bit of a red flag. But yeah, we met with FDA in February for our end of phase 2 meeting. And again, just a few weeks ago, we had a Type B Breakthrough Therapy meeting with FDA ahead of the AdCom. So all of this stuff had gotten flushed out already. So first of all, I'd say that's a good thing. Let's have all this, these issues on the table before we go into phase 3. That's good for us. It's beneficial.
But it's very clear to us that the issues there were specific to that submission. You know, an incomplete submission, incomplete data, and surprisingly, didn't follow the guidance, which is quite clear. So we're confident we have clear alignment with FDA on our phase 3 design to address the primary issue, which is functional unblinding. It's not a new issue, and it's not particularly complicated. So clear alignment and clear path to NDA.
Got it. And so, as we move, you know, into discussing CYB003, maybe you could talk a bit about how is this compound similar and different from psilocybin, and what makes it differentiated among the psychedelics at large?
It's purely synthetic. This is a deuterated version of psilocin. So, psilocin is the activation in psilocybin. The psilocybin's inactive and needs to be metabolized to psilocin. So that leads to, obviously, some inefficiency, 'cause it's not all 100% metabolized to psilocin, and we all vary, you know, in terms of our metabolism, so there's likely to be interpatient variability. So the deuteration enables both chemical and metabolic stabilization of psilocin. We're seeing a very rapid onset of action here, 15 minutes, so patients aren't waiting around for their treatment to kick in. And we're using an adjunctive protocol because 70% of depressed patients are taking an antidepressant, and a two-dose regimen.
So far, we're seeing in our phase 2 study really quite spectacular results from that combination.
The lead indication is major depressive disorder.
Yeah
... or MDD. Many of the programs, many of the other psychedelics programs are focusing on treatment-resistant depression. So just first, curious, you know, why, why focusing on MDD rather than TRD, and, how do you envision sort of the product profile? I mean, we've had the phase 2 data, which we'll talk a little bit more about, but how do you envision, CYB003 sort of fitting in that MDD paradigm?
So TRD is a, I mean, a regulatory construct. Physicians, providers don't talk about MDD or TRD. It's simply, from a regulatory point of view, taking more refractory patients, and that obviously is gonna drag down the data. It's about 18% of the depressed population, so we're targeting the other 80-plus% of depressed patients, which we think makes sense. Providers and payers really talk about first, second, and third-line treatments, and even though we're seeing spectacular results, the paradigm's gonna stay the same for a little while. SSRIs first, because they're low cost and safe, to a large extent. Antipsychotics, adjunctive to SSRIs, and then something for third line, and that's where we see CYB003 fitting in ahead of esketamine. And why is it being positioned there by payers?
Because the effects are very rapid, and they're very durable, and the dosing regimen is far less, well, far more convenient. We're looking at maybe two doses a year for some patients, rather than 26 visits to a clinic with esketamine.
So I'd like to talk about the phase 2 data in more detail. First, just what did you see in the phase 2 data that you've shown so far?
Yeah, we read out the phase 2 results end of last year. Just spectacular, really. Not really seen anything like this in depression. It's very difficult to find new treatments that deliver remission with patients. We saw after just two doses of CYB003, we saw 75% of patients in remission after just two doses. And we still were seeing 75% remission rates four months later, so two doses and four months of remission. We're starting to see 12-month data coming in. We don't have a complete data set yet, but there are patients coming in at 12 months that are still in remission. That's remarkable.
Wow!
Even one patient would be remarkable. But we're excited for that data, which is coming, you know, in a few weeks' time. But in terms of effect size too, I mean, typically with SSRIs, you see about a two-point reduction in depression score-
Right
... which is pretty minimal. I think we know that they're largely ineffective for most patients. We saw a fourteen-point reduction in depression score, so a massive effect size. So fast, large effect sizes, and very durable, which is, you know, obviously very attractive to payers.
Can you talk about the administration of the drug during the phase 2 trial in terms of, you know, what was the therapy or the support that was provided, before, during, and after treatment?
Hmm. Yeah, so we're not providing any psychotherapy. In fact, with psilocybin, or psilocin, it'd be kind of impossible to do that. So during the dosing session, patients are wearing an eye mask, they're wearing some headphones. They're actually cutting out all external distractions. There's no intentional interaction with the patient. We have monitors in the room for safety. Psilocin creates this ineffable experience because it impacts the language centers, so patients can't describe their experience during their treatment session, so it'd be impossible to do any psychotherapy during treatment. Now, of course, we're doing pre-care and aftercare, as you'd expect with anything new, and especially with psychedelic-naive patients, you want to make sure going into their treatment session, they're well prepared, they have full informed consent, they're educated, they know what to expect. They...
We give them psychosocial tools to help them deal with any anxiety in case they encounter that in the session, and they go into the treatment session with some intent. So they are speaking with their facilitator beforehand about how they feel and what's behind their depression so that they can go into this session with intent. Don't forget, the patient's really doing all the work here. They're taking the treatment, but there's no psychotherapy there. They're all blocked out. So they're doing the internal work, so it's good to them, for them to go in with intent.
Then after the session, we follow up for safety, making sure there are no lingering effects or any lasting side effects, and allowing the patient to unpack, you know, what they experienced in the session. This is really the before and after the session, so we're really mimicking standard clinical practice, as you'd expect any respectable provider to provide, and there's no structured psychotherapy.
Can you discuss what you've seen from a redosing or a second dose perspective? I think this is one of the only datasets where we have that, so or will have that. And maybe you could talk about in the phase 3 data, or phase 3 program, how should we think about redosing or second dose?
Yeah, so interestingly, when we looked at a lot of the academic data going back several decades now, the most interesting studies, the most impactful studies, were those that used the more than one dose, and we think we hypothesize that that's because with psilocin, the experience is a bit wavy. It has peaks and troughs of intensity, and so if patients are a little anxious or skeptical or just not wanting to trust or able to trust the process, they can resist somewhat, and we see that in the data, that the first experience we get some people across the line, and then the second experience, we get far more people across the line, so people kind of dive into the second experience because they've been through it once, and they know what to expect.
So we see an incremental benefit from a second dose, an increase, a further decrease in MADRS scores, and we see an increase in both response rates and remission rates with the second dose. So that second dose, two-dose paradigm, we think, is the right design to get durable effects. I mean, after all, you don't really want to come back for a psychedelic experience on a very frequent basis. So just letting people fail after one dose seems, you know, sort of,
Right
... irresponsible rather than locking it in. As I mentioned, we're starting to get some twelve-month data trickling in at the moment. I can't give you any stats yet. We haven't run that analysis. It's not complete. But we're certainly seeing some patients still in remission and still responding at twelve months. So as we go into the phase 3 program, we'll have two studies, each of which will have primary endpoints at six weeks, aligned with FDA. We'll have secondary endpoints at twelve weeks. But then all of those patients will roll over into a long-term extension, where we'll follow them for a year. And during that year, we'll allow redosing for patients that either didn't respond in the first two studies or relapsed at some point over the course of that year.
So we'll get an idea of what the average relapse rate or time to retreatment will be.
Right. So noting, you know, the efficacy you've seen is very impressive so far. Maybe you could talk a little bit about the safety profile and tolerability, both on the day of the treatment administration, but then what you're seeing over time.
So yeah, I mean, we have seen no serious adverse events. All of the AEs were mild to moderate in intensity. They all spontaneously resolved without any intervention. Most common side effects were nausea, which you'd expect with 5-HT agonists, headache, and some transient elevated blood pressure. And that also resolved by the end of the session. In fact, for most patients, their blood pressure at the end was lower than when they came in, sort of white coat anxiety or something like that. We're seeing that just transiently during the two dosing sessions, and so far, we're not seeing anything outside of that. But of course, we'll continue to monitor that in phase three.
When is the phase 3 expected to start?
Very soon. Certainly within the next few weeks, we hope. Yeah.
You know, if I guess if all went to plan, when might you have the data from that program? I realize it hasn't even started yet. You know, it's not up and running yet, but you know, just I guess, ballpark timing, what would you expect?
Yeah. So we'll hope to kick off in the next few weeks. The first study will be 220 patients. It's a two-arm study, comparing two doses of CYB003 to two doses of placebo. We've recruited 30 sites already. These are all experienced sites with psychedelic drug trials. They all have Schedule I licenses, so they should be able to get up and running fairly quickly. So 30 sites, 220 patients, seven or eight patients per site, we should be done with recruiting fairly efficiently. So I would hope we'd have a data readout in the first half of 2026.
That's great. And can I just go back to on the phase II trial and as well, the phase III trial, what proportion of the patients are expected to have experience with psychedelics or psilocybin specifically? And can you talk a little bit, you know, about why, why does that matter?
Yeah, it's a good question, actually, and this was a point of discussion in our meeting with the FDA as well. It's important for them that largely, the population is psychedelic naive. They're not too concerned about folks that may have tried microdosing with very low doses. They're really concerned about regular users that can know what to expect. So in the second phase III study, we'll have two active doses as well as a placebo dose, so three arms. Excuse me. We'll have a high-dose therapeutic arm, a mid-dose sub-therapeutic arm, and so patients will be randomized to those, and because they're psychedelic naive, they won't know which is the active, the high dose, and which is the mid dose. So it'll remove some of that expectancy bias.
Got it. So maybe moving on to CYB004, maybe talk about, kind of how this program has evolved over the years, and as well, just sort of next steps for this program, which is targeting, generalized anxiety disorder.
Mm-hmm. We have a very extensive program with DMT, both the work that we've done with Cybin and the work that we acquired from Small Pharma last year, so we've completed five studies, early studies with DMT and deuterated DMT, and from that, we have a very good understanding of the PK/PD relationship. We know what dose we need to use, we know what rate of dosing we want. It's important to get patients into the DMT space quickly and not take too long to do so. And we've developed an intramuscular formulation that we think delivers an ideal PK profile. We also have phase II data with DMT in MDD with anxiety scores as well, so we have good, solid proof of concept.
We know that it's an active agent.
Right.
So with that, we're now dosing in a phase II study in GAD, and we'll have a data readout end of this year or early quarter one.
With CYB003, maybe just remind us what is the, I guess, duration of the drug effect during the treatment? And with CYB004, you know, this being DMT, it's much shorter. Maybe you can frame for us what the duration is for CYB004.
Mm-hmm.
I guess, is there, I don't know, are there relative advantages or disadvantages to having a longer versus shorter, and depression versus anxiety? Maybe you can kind of go through those nuances for us.
Yes. So CYB003, the typical experience is four to six hours. We might see longer experience with psilocybin or with LSD, so that's fairly manageable. And with deuterated DMT, CYB004, it's about a ninety-minute experience. So that clearly fits within that esketamine two-hour window, where there's already infrastructure. Patients do tend to get anxious with DMT if you get them up to the peak PK slowly. So our goal is to get them up into that space very quickly. They come down from the peak, and then most of the experience is spent in the tail of the PK curve, where the psychological work appears to happen. So we think it'll be both very scalable and maybe ideal for anxiety patients.
So what's the next steps for CYB004?
CYB004 data readout will be top line safety and efficacy phase II data end of this year or maybe, maybe January.
What do you need to see there to support moving into phase III?
I think if we see anything like we saw in our proof of concept, or anything like we saw with LSD, which is a good indicator as well, then that would help us. That'd provide a very good candidate for phase III. We also now know, because of LSD, that there's a chance for breakthrough therapy designation in GAD, which wasn't clear to us before, so yeah, let's see when January comes around.
Right. Great. And then just, what are investors missing about the Cybin story?
You know, I think this the whole CLR situation has just gotten a few people spooked, especially generalist and retail investors, and that's understandable. I do think it's short term. For us, from a competitive point of view, having one less agent out there ahead of us from a commercial perspective, from a pricing perspective, maybe it's not a bad thing. Having all this news out there, all these issues raised before we start phase III, actually quite useful. We can check those boxes, but I think as we were talking earlier, I think for the sector now, it's a bit of a show me story. Let's deliver the data. We've got Compass with phase III data coming this quarter.
We have our twelve-month MDD data coming in just a matter of weeks, and then that's phase II top line GAD data coming shortly after that.
Right. Great. Are there any additional questions in the audience?
Yeah, just looking into taking account of the qualitative effects of CYB003 and CYB004, and the likability of the drug. I know that was something FDA said to Lykos, that they believed that-
Mm-hmm
...
Yeah, absolutely. So FDA wants us to record all effects of the drug, euphoria, likeability, both within the session and if anything occurs outside of the session, which would be concerning, right, as well. So all of those things matter, and we'll be collecting those as part of the CLRs. Yep. Hey, Steven.
Another phase two in CYB004, or this, depending on the outcome of this, that's enough to go to phase three.
You saw the way we approached CYB003. You know, we know these agents work. We know they're active. We ran a fairly small phase two study for CYB003 and went straight to phase three, and we would intend to do the same with CYB004. The results are what we're expecting. Yeah. Yeah. Yep.
Yeah, so with, like, those, I think we saw them try in one of their phase two trials, this, like, kind of subtherapeutic dose of MDMA, but then taking that away, due to the effect of anxiety in patients. So I'm wondering with your subtherapeutic eight milligram dose in that three-arm trial, is there any adverse events you've seen with that, that could potentially prohibit it in use?
We did dose some patients in our phase one study with eight milligrams. In fact, several doses from one milligrams all the way up to 10, and we didn't see any abnormal side effects there, so we're not expecting that. Very different compound. Yeah. Okay, well.
So for the public to understand more of the measurement used in that, the aspect of, like, how the side effects or what's good and bad for the dose, what I like is one time in and, you know, for not abusive, you know, abuse the drug. And how is your measurements read for just the world, how you're measuring it to what I, I'm trying to say, for the public understanding, more of like for like a retail side of it, how would they look at it as you pronounce, you know, effects of measurement to try to meet, to get to phase three?
The clinical effects?
Yeah.
Yeah. So we're using a standard rating scale, MADRS, the Montgomery-Åsberg Depression Rating Scale. It's a widely used and FDA trusted scale that's been used for fifty years or so. The patients are rated before and after several points after dosing, and they're rated by independent raters. So they're independent from the site, they're remote, and they're blinded. So they never know what the patient's background is. They don't know whether the patient received active or placebo. They don't know if the patient had any euphoric effects or any other kind of effects during the session. So they're completely blinded to that. And that's fairly standard in depression studies. Yeah.
Great. Okay, I think that brings us to the end of our session.
Great.
Doug, thank you so much, and thanks for dialing.