at Water Tower Research. I have the pleasure of hosting Doug Drysdale, CEO of Cybin, in this fireside chat. Cybin is a late-stage breakthrough psych- neuropsychiatry company committed to revolutionizing mental health care by developing novel next-generation treatment options to address the large unmet need for people who suffer from mental health conditions. Cybin trades on the NYSE and CBOE Canada under the ticker CYBN. Cybin's safe harbor statements can be found in its company filings, which are filed with the SEC and Canada's SEDAR. Without further ado, let me welcome Doug. Doug, great to see you again. Hey, Robert. It's great to see you. Thanks for having me on again. Appreciate it. This has already been quite a year for Cybin, notably with the significant advances made in the company's lead developments, CYB003 and CYB004. With several upcoming milestones on the horizon, there's certainly potential for further excitement ahead. Let's begin with the more advanced of these programs, CYB-003. Can you start, for context, by giving us an overview of that program and what has been achieved so far? Yeah, sure. Happy to do that and happy to share the work that we're doing to help advance mental health care. As you say, our lead program is CYB003. This is a synthetic, modified version of psilocin. Psilocin is the active agent in psilocybin. We've modified this molecule through a process called deuteration, where we selectively substitute certain hydrogen atoms on the molecule with deuterium or heavy hydrogen. And the impact of that has been to create a novel molecule, but it also appears to improve the efficiency of psilocin, improves the stability of psilocin, and seems to improve potency, too. We're seeing effects at lower doses than we had anticipated. And what we've seen so far in our work in our phase two studies is, I think, you know, maybe the most impressive depression data we've ever seen in a clinical study. And in our phase two study in major depressive disorder, we used a two-dose regimen of CYB003. So we provided two doses of this. It's an oral capsule. We provided two doses, three weeks apart. And this is on top of patients' background medications. So these were the patients that were moderate to severely depressed, and they were on stable doses of antidepressants, and they were clearly still uncontrolled. So what we're trying to do is have an incremental benefit on top of background medications, and that's obviously a higher hurdle than just using a monotherapy. But it's also much more convenient for patients, too. They don't have to titrate themselves off of these background medications. So just two doses, three weeks apart, and we saw remarkably 75% of patients in remission from their depression. And what that means is that they no longer qualified for the definition of being depressed any longer after just two doses. And then, we're still seeing 75% remission rates four months later after just two doses. So to put that kind of into context, and you think about the current standard of care today, SSRIs or SNRIs, drugs like Prozac and Lexapro, these, and Zoloft that many people have heard of, with those treatments, typically, you see about a third of patients finding remission after about six weeks or so of daily dosing. And of course, patients then end up taking those treatments for every day for weeks, or months, or years, at a time. And they come with them a lot of associated side effects like weight gain, sexual dysfunction, insomnia. So if we can break that cycle and use this more interventional-type treatment and get patients off of their chronic daily medications, and maybe treat them with two doses every several months, a year, we will see as time goes by. This would truly be a really significant paradigm shift in how we treat depression going forward. Right. Thank you for that. So what are the upcoming milestones and expectations you've set for CYB003? So, exciting milestones coming up. We've, as I mentioned, read out this four-month data, so very exciting that these, the CYB003 works very quickly, and is very durable out to four months. But, we have followed patients up now for 12 months, and again, just two doses, so we haven't been dosing them with any more CYB003 in the interim. And pretty soon here, in the next few weeks, we'll be sharing what we're seeing in terms of durability. I mean, just imagine if patients, some patients, obviously, not everyone's gonna respond the same way, but imagine some, for some patients, just having to have two doses a year of a treatment like this is really quite remarkable. So that's coming up, very, very soon. And we're also about to initiate imminently here our phase 3 program. What we're looking to do there, of course, is replicate what we saw in phase 2 on a much larger scale. This will be a multi-site, multinational program, excuse me, recruiting in total about 550 patients, so quite a large program. We've recruited 30 sites so far across the U.S. and Europe, so, and we have a number to go as well. But that's, the preparations for that are well underway, and we should get that started here in the next few weeks. Right.... Okay, great. So similarly, can you give us an overview of your second major program, CYB004, and highlight again the upcoming milestones we should be looking out for and the expectations you have for that program? Sure. So CYB004 is targeting generalized anxiety disorder. So we know that depression affects about 20-21 million people, adults, in the U.S. Anxiety disorders affect maybe almost three times that number. So it's a much larger problem, made up of a range of different anxiety disorders. So CYB004 is a deuterated version again, but of this amount of DMT or dimethyltryptamine. DMT is a compound that naturally occurs in our brains. Actually, it's a neurotransmitter. This is an intramuscular formulation, so it means just a quick shot in the arm. We've all been quite used to that in the last few years. And, as I say, we're underway right now in a phase two study in patients with GAD or generalized anxiety disorder, which is the most prevalent anxiety disorder. And CYB004 has been designed to produce very rapid onset of effects. So we see effects beginning within two to three minutes, so patients aren't waiting around for a long time. It's a fairly short treatment duration, about 90 minutes, we're seeing so far. And so that means it's quite an intense and immersive experience, which we expect to get more patients kind of across the line, if you like, than maybe with psilocin. And we'll see what that looks like in terms of outcomes. But we're dosing in that study right now. We expect to see top-line safety and efficacy data in these patients, in quarter one of 2025. Yeah. And this is something that's much needed. You know, 68 million people affected by anxiety disorders, and you know, 50% of them don't respond to current treatments. And then other interventional treatments like benzodiazepines can't be taken over long periods of time. So there's a really huge population here in need and a very large unmet need. So if we're able to rapidly remove someone's anxiety for long periods of time with a couple of doses of CYB004, just like we're seeing with CYB003 in depression, then again, this is a lot of people that that we could be helping in the future. That's amazing. We've seen an explosion of research in recent years investigating much-needed novel clinical approaches to hard-to-treat mental health disorders, and it seems a lot of that research is being drawn to targeting areas of interest that Cybin is homing in on, particularly depression. Mm-hmm. So can I ask you, first, what you believe are the advantages your two lead programs have over other developments targeting the same indications? And second, what gives you confidence that your programs can actually make a real-world impact to the many suffering from depression and anxiety disorders? You know, I've spent the last 35 years involved in building drug development companies of some form or other, and what's clear to me is that for the most part, drug development is incremental. We see small changes, small improvements over previously approved treatments. That's not a criticism, it's just the nature of science. Those small changes are challenging when you come to study psychiatric disorders. So often in depression studies, you see new treatments being looked at that have quite small effect sizes, and so sort of a small improvement in symptoms. The problem is, in these psychiatric disorders, that when you give a patient a placebo, they also react to that placebo because of the psychological effect. So often, one of the challenges with depression studies is that the active agent doesn't separate from placebo because of that placebo effect. So that, I think, inhibits development of new treatments in this area that could be helpful, but often don't make it through rigorous phase 3 studies. So what's very different about these treatments, and we're seeing this with CYB003 in particular so far, is that the effect sizes are very large. And because we are dosing infrequently, just two doses three weeks apart, we're also only giving the placebo infrequently as well, so we're not getting a perpetual placebo effect from daily dosing of placebo. So the risk of separation from placebo is quite small here, and I think we've seen very good separation from placebo in pretty much every larger psychedelic study. So I think that takes a lot of risk out of the development program. We know these treatments work, and what we're seeing is, as compared to other treatments today that are slow to work and have to be taken chronically, we're seeing very rapid onset of effects here, very large effect sizes that are highly durable. So again, if you can move away from this chronic daily treatment of symptoms to these interventional treatments that can remove someone's depressive symptoms for many months at a time, then that has the potential to really change the landscape. And when you think that only 18% of psychiatrists are available to see new patients, they're pretty overwhelmed. The system is overwhelmed. These patients are quite high-touch. They have a lot of visits to their doctor in the course of a year, as you can imagine, because of the nature of their disease. So it's hard for many psychiatrists to fit in new patients. And the average wait time for a new psychiatrist visit is somewhere between 43 and 67 days, depending on whether you want a telemedicine visit or an actual in-person visit. So if we can remove someone's depressive symptoms for many months at a time, and take them out of the system, then that frees up an awful lot of capacity for psychiatrists and mental health workers to see new patients. So we really could be making a difference to the entire system with these treatments. Right. And, I mean, let's you talk about your differentiations with other developments currently happening. You mentioned deuteration already. Why, I mean, why have you gone through to that, down that path? Obviously, you've mentioned the adjunctive benefit. What about the ability to the short duration, which I assume does that give you an advantage in terms of leveraging existing infrastructure rather than having to wait for infrastructure to be built out, to roll out? Yeah, that's a good question. So, we're quite fortunate in that the infrastructure is now kind of in place and continuing to expand. So, there are a number of interventional psychiatric treatments, if you like, that already exist today, and I would include among those, ECT, TMS, esketamine, as examples, and many of these require a lot of visits, 30 to 40 visits a year for some of these treatments. Esketamine, 26 visits a year into a clinic. So those centers though are established. There are about 4,500 of them today, and continuing to grow. So that's an infrastructure where we know our patients can be dosed with our treatments. Esketamine today typically takes about two hours for a dose of treatment. You know, CYB004 is about 90 minutes, CYB003 is four to six hours. But we're talking about two treatments a year, potentially, for many patients, and not 26 visits a year. I mean, can you imagine? I can't imagine the motivation, actually, for the patients that put themselves into that setting 26 times a year, and then, you know, can't drive a car afterwards, can't go to work afterwards. So, yes, I think these are relatively short-acting. They can fit within the existing infrastructure. But at the end of the day, I think the durability of response is really going to make a difference. Mm-hmm. As patients don't have to keep coming back so frequently. Great, great. So it's moving on to another area, probably an area that we wouldn't have considered at the beginning of the year, but you've probably had discussions with the FDA post the regulator's issue of a complete response letter to Lykos's MDMA-assisted therapy NDA submission. So can you share with us... I've got this is a three-part question. Firstly, what questions did you initiate to ask the FDA in light of that NDA rejection? Yeah, it's had a lot of press, this, this, this situation, and disappointing for PTSD patients that are gonna have to wait quite a bit longer now. Look, we had our end of phase two meeting in February of this year, so we already had a good sense of what the FDA was looking for from our phase three design. We're then very fortunate, because of our breakthrough therapy designation with FDA, to have a follow-up type B meeting with them in August. So this was after the Lykos Ad Com, and so all of that discussion, all those issues were public and available to us, which is perfect timing ahead of starting phase three. It gives a great opportunity for us to ask pertinent questions and to reconfirm expectations, making sure nothing has changed from our February discussion. And we discussed, as you'd expect, study design, patient population—which was quite an interesting topic—and the definitions of various endpoints. You know, I can't say there's any really significant major changes that came out of those discussions because we've been fortunate enough to have previous conversations with the FDA. We've seen their guidance. Nothing much, honestly. The Ad Com was particularly new or surprising to us, but valuable to have that meeting with the FDA at that point in time and ahead of our phase three beginning. I think that's actually quite an advantage for us. On that basis, were there any lessons you actually learned from these post-Lykos discussions that you may not have been that apparent from your prior consultation with the FDA, and on that basis, is there anything at all that you have to adjust or at least tinker in even the smallest way with your approach to the upcoming CYB003 phase 3 trial in order to maximize its chances for it to pass muster with the FDA? Not really. Any of the issues that were raised at the Ad Com were not new, and not a surprise, and definitely not a surprise to the FDA. But, you know, good, good to have that chance for, for alignment with them. Yeah, I think there is a disconnect between what we're seeing from the FDA's communication and behavior and what you saw at the Ad Com. We're seeing FDA being quite supportive, positive. I think my personal opinion is that they are genuinely looking for a way to safely approve these treatments because they see the potential. Obviously, we've got to go through all the rigorous work of, you know, phase 3, phase 3 trials, but I'm not seeing the FDA purposefully stand in the way. I think what you saw at the Ad Com was a number of issues that, you know, where people were somewhat outraged by some events that had happened, and then a lot of focus on functional unblinding. So which, again, is not a new thing for FDA. So if there's anything we've had to do differently following the Ad Com, is to reassure investors and stakeholders that we're tackling this issue of functional unblinding. It's not a new issue. It is an issue that's been seen with every CNS drug. If you are taking a benzodiazepine, you know you are. If you're taking an antipsychotic, you know you are, so this isn't a new issue. But it was an opportunity for us to confirm with FDA what they are looking for to address that issue, and that is, for the most part, they want a three-arm study, where there's two active arms, a therapeutic level dose and a sub-therapeutic level dose, where patients still feel some kind of psychedelic effects or PD effects. So it confuses the patients, and it removes kind of sort of expectancy bias. Not a new thing, not a new element of design, but good to have a chance to communicate that with them. But other things that we've had to share with our investors to reassure them is, "Yes, we are following FDA guidance. Yes, we're doing a 3-arm study. Yes, we're using independent raters that are remote and don't have any visibility to the patient's experience or what dose they received. And we're using auditing of various sessions, so we know what's going on in the room between any facilitators and the patients for safety. And this is also... I think the last thing is, this is also a psychedelic-naive population for the most part. Right. And I think that was a concern in the AdCom, that a number of, a large number of patients in one of the studies had had a lot of experience with MDMA, and so may have had some expectancy. So I think we've covered all the bases. There weren't any really material changes following the AdCom or the FDA discussions. But you know, as I've mentioned, it's a really good opportunity for us to align, make sure we are 100% aligned with FDA and then sharing that with our investors. Great. Thanks. I think we'll wrap it up there. Thank you, Doug, for all your thoughts and insights on the development programs that you have at Cybin. Just addressing the audience, if you have any more questions for Doug, please send them to me, and I'll pass them on to him. For our analysis of the company, please refer to our open access website at www.watertowerresearch.com. The views expressed in this fireside chat may not necessarily reflect the views of Water Tower Research and are provided for informational purposes only. Finally, I'd like to thank Doug again for his, for your participation, and thank you everyone for joining us, and have a great day. Thanks, Robert.