Good morning, everyone. Thanks for joining us for this fireside chat with Cybin Inc. at TD Cowen's fifth annual New Mechanisms in Neuropsych and Epilepsy Conference. I'm a Senior Analyst, Ritu Biral. I am joined by my Associate, Athena Chin, who works with me on all of our neuropsych and CNS names in my universe, as well as management from Cybin Inc. With us from Cybin Inc., we have Chief Medical Officer Dr. Amir Inamdar, as well as Chief Business Officer George Tziras. Thank you guys for joining us this morning. I want to jump in with lead product, CYB003, or your deuterated psilocybin compound, in clinical development for adjunctive major depressive disorder treatment. Can you first walk us through the advantages as you see it, PK, PD, efficacy, safety of deuterated psilocybin over the naturally occurring psilocybin compound, and if you could use it to also touch on your intellectual property? Yeah. Good morning, everyone, and thank you, Ritu, for inviting us here. It's a pleasure to be here. I can take that one, George. CYB003, as you mentioned, is a deuterated psilocybin. What we've done there, as compared to naturally occurring psilocybin, is we've taken away the metabolic step. By deuterating psilocybin, in addition, what we've done is made it a more stable formulation, which, of course, gives us stability with the drug product, but also gives us IP protection. I will hand it over to George to talk about the IP situation with those three, but in terms of advantages, removing the metabolic step naturally would be expected to reduce some of the variability that you typically see when you give somebody naturally occurring psilocybin versus giving actually the active drug. Psilocybin is a pro-drug. It gets converted in the body to the active moiety psilocin. In theory, one would expect that by taking away the metabolic step and reducing variability, you would also expect it to be a slightly shorter duration. We've seen that in animals. To me, that's probably not something we dwell on. What I am concerned about, I wouldn't give too much weight to the PK. I would think more in terms of efficacy and the clinical effects. What we see is essentially with CYB003, an acute effect lasting about four to six hours, which is just about slightly shorter than what you see with the naturally occurring psilocybin. George, maybe you want to talk about the IP situation? Let me just summarize those. You said that it's a deuterated analog. It's a novel compound, and as a result, it has a robust IP. I think currently we have over 100 granted patents and something like over 250 and counting pending. I think we've been able to establish a strong moment around our program and molecule. is the runway for the intellectual property? I think the earliest is 42. Yeah, so. Great. For those on the line, if you guys have any questions as I go through the clinical program and the 003 data, please feel free to email me at ritu.biral@cowen.com or ritu.biral@tdsecurities.com. We'll get those questions incorporated, and that extends for the full day. Now, let's jump to your Paradigm clinical program for 003. Can you walk us through the study designs for your Approach and Embrace trials, and then review for us how enrollment is going? Yeah. The Paradigm is the overall phase 3 program comprising the pivotal studies, Approach and Embrace. As you mentioned, there are the acute efficacy studies. Paradigm also has the long-term extension, which is there to demonstrate durability of effect. Approach is a two-arm study, which compares 16 milligrams of CYB003 with inactive placebo. We have one treatment cycle in Approach, which a treatment cycle is defined as two doses given three weeks apart. Patients will receive either CYB003 16 milligrams or placebo, two doses three weeks apart. The primary endpoint is at six weeks. We also, in line with the FDA guidance, have a secondary endpoint for intermediate durability, which is 12 weeks. That goes out to 12 weeks. Each arm in Approach is about 110 patients randomized. That's a total of 220. Embrace is a three-arm design and exactly the same as Approach, other than the fact that it's got three arms, including an inert placebo, inactive placebo, an intermediate dose of 8 milligrams, and the active dose of 16 milligrams. Across the three arms, you've got 110 patients per arm. That gives you 330. Across the two studies in Paradigm, the acute efficacy studies, we'll enroll a total of 550 patients that roll over into the Extend extension, which goes out to a year. Approach has kicked off enrollment. It's a US-only study. We've got about 45 sites in the US. Recruitment is well underway, and we remain on track to deliver top-line data before the end of 2026. Why did you go straight into the double dose with Approach, rather than trying a single dose arm the way that some of your competitors have? Yeah, so that is replicating what we did in our phase two. The question is, why did you actually do two arms in your phase two? We looked at a number of factors, which we took into consideration at that time. We looked at data that was published with psilocybin, some with our competitors, some in the literature, some based on ritualistic use of psychedelics. What was clear to us was that it wouldn't be a one-and-done paradigm for psychedelics. There would be a need for a second dose, or maybe more. Looking at the data, what appeared clear was that typically with the single dose in the data that was available at that time, we tended to see effects regressing back to the baseline at about four to six weeks. We wanted to preempt that dip or regression to that baseline. We took a calculated guess at that point of time that if we have to do two doses or more than one dose, then approximately four weeks, three to four weeks apart would be the ideal duration between two doses. Now, why three weeks and not four? Three was a choice, based on a number of factors, including logistics in terms of scheduling. We also wanted to give people enough time after the first dose when they've gone through a profound psychedelic experience to work through some of the stuff that emerged during that experience and be ready for a second dose. We didn't want them to be in a situation where, you know, one week after or two weeks after, you call them back and they're like, "Whoa, I don't want it anymore. It's too much. Got it. In phase three, oh, sorry, let's go back to Approach. What guidance are you giving for top-line data from Approach? That'll be before the end of 2026. Got it. Moving to Embrace, when will that study start? Can you talk about the dose selection? You talked about an 8 milligram and the 12 milligram. How did you settle on the 8? Yeah. Yeah. Embrace is, enrollment is imminent, as in first patient in. You may have seen some of the regulatory approvals we published, ex-US, so that study is just about to kick off. It remains on track such that we will end up with filing an NDA by end of 2027. Going back to the choice of doses, 8 milligrams, we wanted an intermediate dose, in line with the FDA guidance. It was selected because we did see some robust psychedelic effects with 8 milligrams in our phase one healthy volunteer portion. We do expect some people to respond to 8 milligrams. Given the natural variability in data, you will see some people respond to 8. That is going to be a very small proportion compared to. This is your subclinical dose, essentially. Not subclinical, but it's an intermediate dose. What we expect to see with Embrace is a sort of dose response. You'll get a smaller proportion responding to 8, then the largest proportion responding to 16 milligrams. I see. Got it. In those studies, I think in both studies, neither of those studies are using an inert placebo. I'm sorry, you were using an inert placebo in both those studies, but neither study has that subtherapeutic dose that the FDA has discussed in its presentations and some of its guidance. Has that guidance evolved? Why not include that subtherapeutic dose? Yeah. As you know, we've got breakthrough therapy with CYB003. It gives us the opportunity to interact with the FDA. I'll just point out that we've been in regular discussions with the FDA, and the study designs have been endorsed by the FDA. What the guidance asks for is an adequate and well-controlled study, and that subperceptual or subtherapeutic dose comes in when you want to select a control arm for psychedelics. That's what they have recommended. They don't necessarily require a placebo arm. What we have done is included placebo for safety, at least in the Approach study, but it also gives us balanced safety information across the two studies. What it also allows us to do is manage some expectations in patients. It's the difference between telling a patient in Embrace, which is the three-arm study, that when you get randomized, your chances of getting the drug are two out of three versus getting the drug three out of three. I know some of our peers, at least one of our peers has a subtherapeutic or subperceptual dose in their dose response study. Another, the LSD study, if you look at that, that study is quite, that design, phase 3 design is quite similar. They've also got a placebo, and I suspect they've had similar discussions with the agency as we've had around expectancy and balancing out the safety across the two studies. What measures are you taking in both those phase threes to maintain blinding then? We are doing the traditional randomized double-blind approach. There will be some functional unblinding, as is expected with CNS drugs in general, not just psychedelics. The impact of functional unblinding on blinding is most relevant on the primary endpoint. In our study, the primary endpoint is MADRS. The primary way we address the impact or reduce the impact of functional unblinding is by employing remote blinded raters who do not know whether the patient is on active or placebo or where they are in their study journey. Is the MADRS, is the MADRS clinician-assessed, though, or a rater-assessed, or is it patient-assessed? It is assessed by an independent rater who is trained in the administration of MADRS. Got it. That's the main approach to reducing the impact of functional unblinding. In addition, we are taking a few other measures to reduce functional unblinding. Also, you know, functional unblinding doesn't occur on its own or in isolation. It is linked to expectations and expectancy bias. We try and reduce expectations by managing that during the informed consent and the pre-dose phase. We also are restricting site staff access to patient data only on a need-to-know basis, because if the site staff knows somebody has gotten a drug, then invariably their expectations translate to the patients. We are also managing the expectation of receiving an active drug by using inert placebo in both the studies. Got it. Do you have a cap of psychedelic experience patients in these studies? Yeah. We have been discussing with the agency about capping prior psychedelic use. It's becoming extremely difficult because these drugs are now being used more frequently. What we are doing is limiting it to a% that is consistent with what we see in the general population. What we will also do is, in our statistical analysis, we have a plan for subgroup analysis based on prior psychedelic use. Got it. Are you, so you have that second dose, but is there any allowance for retreatment in the main study, or is that something for the extension? That is, in the main study, there is no retreatment. There's just one treatment cycle, which is two doses three weeks apart. In Extend, there is opportunity for retreatment. Okay, and we'll get to that in a second. With data by the end of the year, what will you feature with your top-line Approach data? With some of your competitors, there has been this sort of back and forth about that sort of top-line data release versus preserving equipoise through a longer time frame. What will we get with top-line at this point if you guys have alignment with the agency? What do you hope to see on that MADRS to be commercially differentiated? Yeah. Sure. I mean, maybe I'll say I don't think we've guided yet to exactly what we'll be releasing as part of that top-line. What I can say is you can expect at a minimum to see the primary endpoint at six weeks. Amir, maybe you want to comment on the MADRS expectations. Yeah. In our phase two, we saw roughly about 14 points differentiation from placebo on the active. As you scale up to phase three, you naturally lose some of that effect because of the additional variability that is introduced with the larger data sets. Even if we cut it by half, it would still be spectacular. If you've seen some of the meta-analysis, if you look at the data, the FDA themselves reviewed all the clinical trials for SSRIs that were submitted to them from 1970 onwards. The average improvement on MADRS in terms of difference from placebo is about 1.8 points. Even if we have about half of what we saw in phase three, that would be pretty spectacular still. To me, the effect size isn't as great, even though it is great, it is not as exciting as the durability. Not two doses of CYB003, we saw durability, as Ramesh said, out to 12 months. What will be differentiating, I think, will be the durability of those data. If we can replicate that to a large extent, then that would differentiate us from others. Can you walk us through the open label design now and how the protocol differs for responders, non-responders, and what sort of data will that generate beyond just durability? Yeah. Firstly, it's a long-term extension rather than open-label extension. The distinction here is I am making because the study remains blinded. The long-term extension remains blinded until somebody requires a treatment. As soon as they require a treatment, then it becomes open-label. What happens is all patients from Approach and Embrace are eligible to roll over into the long-term extension, Extend, where, based on predetermined criteria, which have been agreed with the agency, if somebody relapses or is a non-responder, then they are eligible to receive at least one cycle of CYB003, which is two doses of 16 milligrams, three weeks. We then assess response. There is, of course, an opportunity to get one more top-up dose before the end of the year. When you consider the logistics in terms of time frame, etc., they'll probably only have time in that one year to get one more top-up dose if needed. In the phase two data where to hold, we expect people who have not received any active drug in the short-term studies to maybe improve with one treatment cycle. Those who have improved in the short-term study, they are unlikely to respond. What that Extend study will give us, of course, is durability of data. Those who have responded, how long they remain in response or in remission, it will also give us data on whether additional treatments are required. If they are required, how many additional treatments are required over a one-year period. In terms of long-term safety, those are crucial data as well that we'll acquire from the study. How frequently are the DSMBs looking at the trial for safety and signals? That's on a quarterly basis. Got it. Before I turn it over to Athena for some commercial questions, maybe you can talk sort of top line on clinical differentiation between CYB003 and what's on the market now. We talked about other psilocybin-based therapies, but if we think about Spravato, as well as other actives, how do you see CYB003 differentiating itself there? I'll let Athena take the commercial follow-ups. Yeah. Maybe, George, you want to take the first piece. Yeah. I think first is, as with Spravato, I think it's the frequency of the treatment, really. I mean, if you look within that interventional psychiatric setting that I'm sure we'll discuss more in detail with Athena, the difference here is you're getting dosed, you know, ultimately perhaps weekly or biweekly as a maintenance with Spravato, whereas here, potentially with just one cycle of treatment, you're getting to 12-month durability. We think that's really the key differentiator. Got it. What would you say is your commercial strategy for CYB003 if it is approved as adjunctive MDD treatment? How do you envision it fitting within that interventional psychiatry infrastructure? Right. There are certain features that CYB003 has, with its controlled substance. It's administered in an in-clinic setting, and it's a day treatment, an outpatient setting. That has certain features and implications in the commercial infrastructure, controlled distribution REMS that we know already from Spravato. The natural point of focus for the commercial launch strategy, if approved, will be that infrastructure. Currently, I think there are at least 5,000 interventional psychiatry centers, and that's just for Spravato, not counting TMS and others with just Ketamine. They're growing, and they've grown substantially over the last couple of years. What we've done is really focused on that infrastructure. Earlier this year, we announced, to that end, a partnership with Osmind. Osmind is a software business, ultimately a services business. It can go over 800 at this stage of exactly those interventional psychiatry centers. What that is allowing us to better understand is important features that will be relevant for commercialization, like what is the patient experience and journey, what are the clinical workflows, what are the reimbursement pathways, what is the specialty distribution channel, and how that could be adapted or how it's relevant for a treatment like CYB003. Following up on that treatment journey for patients, how long do you think those clinical days will take for these patients from start to finish? We see it as an in-day. If you think of a typical day as, say, perhaps an eight-hour shift, so to speak, obviously, some clinics may vary, but typically, it's an eight-hour shift in a clinic. We see it as fitting comfortably as a day treatment within that. Honestly, we think that's fine because ultimately, we're talking about very infrequent treatments here. As we said, perhaps as few as one cycle of treatment for a year's worth of durability if the phase 2 results replicate in phase 3, and maybe there's one cycle more. Ultimately, within that day, there's a comfortable period for the patient to be able to come in, to be prepared, to be dosed, and then to leave without requiring any additional resources from the clinic or its staff. Given that, you know, day treatment, who do you believe is your ideal patient? I think the ideal patient ultimately is one that, or at least the patient that we have identified and we're ultimately targeting here, is one that is getting an inadequate response on traditional first-line or later-line treatments with SSRIs and SNRIs. They may have responded in the past, be no longer responding now, or they may not have responded at all. They're looking for another solution. Got it. Before we wrap, I do want to touch on CYB004 for your deuterated DMT for generalized anxiety disorder. Can you walk us through the biological rationale of this compound in GAD? Yeah, maybe I can take that one. The choice of GAD was based, of course, partly on biological rationale, but also on the significant amount of GAD has a prevalence of approximately 300 million patients globally, almost 7 million patients in the US. There is space in the market also because there are only limited treatments. Clinicians, GAD patients take a lot of time. They are almost 50% of patients in the clinic. What we did when we selected this indication was look at data from the literature as well as the biology of CYB004 versus other psychedelics. You know, 5-HT2A/1A agonism, it seems to be sort of a unifying mechanism for psychedelic effects, though there is some contribution from 5-HT1A. Both seem to have, they seem to have both antidepressant as well as anxiolytic effects. As you know, there's significant comorbidity between depression and anxiety. Almost 80% of patients with generalized anxiety will have depressive symptoms as well. At that time, there was some emerging data as well with another 5-HT2A agonist, LSD. This group in Switzerland, Frederica Holzer and a group published some data with LSD in anxiety up to 16 weeks. As you know, LSD is a 5-HT2A and 1A agonist. Deuterated DMT has similar 5-HT2A and 1A agonistic properties. All of those kind of created a perfect song. We believe that GAD would be the appropriate indication for CYB004. Can you walk us through that phase two study design and remind us of when we should expect top-line data? Yeah. That phase two study is a two-arm study, a low-dose control, which is a subpsychedelic dose, and an active dose, so 2 milligrams versus 20 milligrams. It employs intramuscular administration of deuterated DMT, 12 patients on the control arm versus 24 on the active arm. Similar to the 03 in the sense two doses given three weeks apart. Primary endpoint is at six weeks. We've got a 12-week second. What is the primary endpoint? What scale? It's the HAM-A. We've got a secondary endpoint at 12 weeks. We also allow patients to enroll in an optional 12-month observational follow-up. That study, of course, is complete. We are expecting the follow-up of patients to complete before the end of the year, and we are on track to deliver top-line data first quarter of 2026. What do you hope to show on the HAM-A that would support advancement to pivotal trial? Also, this is a proof-of-concept study, right? This is the phase where you learn about what you need, the information that you need for larger phase 3 studies. We are defining our inclusion and exclusion. We are looking at how do we need to tweak the patient population. Is the dosing regimen appropriate? This is the first time intramuscular DMT, deuterated DMT, has been administered to patients with generalized anxiety disorder. We're looking at what thresholds on the HAM-A, the GAD-7, should we have in our phase 3. We are going to use all of that information to design our phase 3 program. We also expect to see a differentiation between the control group and the active group. I would be most interested in looking at a within-subject improvement as well. It's a kind of a dose response study with a low 2 milligram dose versus a high 20 milligram dose. Within-subject improvement becomes really important as well. It is not powered like a traditional study, but we are still going to do the same statistical analysis that one would do for a properly powered study. Understood. With that, we are over time. Thank you, Amir and George, for joining us today. For those who tuned in, we will be having our next fireside chat with Atai at 10:00 A.M. Hope to see you there. Thanks, everyone. Thank you both. Bye-bye.