Cybin Inc. — Call Transcript 2025

All right. Great. Good afternoon, everyone. Welcome back to the second annual Guggenheim Healthcare Innovation Conference. My name is Eddie Hickman. I'm one of the biotech analysts here. I'm welcomed today by George Tziras from Cybin. Would love to hear maybe a few minutes just to give an overview of your current clinical programs. Thank you so much for joining us. Thanks, Eddie. Hi, everyone. Yes, we have two programs, two clinical stage programs that are addressing two indications of high unmet need in psychiatry. Depression and anxiety both have high prevalence. I think they're around 20 million patients each in the U.S. alone that suffer from anxiety and depression. We're doing that through psychedelics, which we believe offer a pretty exciting new opportunity within the growing field of, I guess, what's been called now interventional psychiatry. By this, I mean TMS, Spravato, and ketamine. I think there's something like over 8,000 clinics or so in the US and growing in that space. Within that space, we're excited by the opportunity to potentially offer both rapid acting and long-lasting relief through as little as two dosing sessions a year. If you think about psychedelics in development today or in late-stage development, I would say they broadly fall into two categories. The first category is the orally active ones, slightly longer acute psychoactive effects, like psilocybin, LSD, and MDMA. Then you have the shorter acting, non-orally active. By shorter acting, I mean longer duration of the psychoactive effects and more intense, like 5-MeO-DMT and DMT and its analogs. I think Cybin, as far as we're aware, is the only company that has assets in both those different categories. Those are CYB003 and CYB004. They're also novel compounds, so they benefit from robust IP protection. I think we have now over 100 patents granted and something like over 250 pending. Pretty robust patent estate there protecting our programs. CYB003 and CYB004, CYB003 is deuterated psilocin, and CYB004 is deuterated DMT. For CYB003, we were granted Breakthrough Therapy Designation by FDA. That is currently in a phase III program. It is being investigated for the adjunctive treatment of major depressive disorder. There in the phase III program, we plan to enroll 550 patients across two short-term pivotal studies, which are called Approach and Embracing. I am sure we will discuss them more in this discussion. There is also a long-term extension to both, which has been termed, originally, Extend, which follows the patients out to a year. Approach is currently enrolling. Embracing has initiated and is expected to begin enrollment this quarter. CYB004, which is the second asset, deuterated DMT, is being investigated for generalized anxiety disorder. That is currently in a phase II proof of concept study that has completed enrollment as of September. We're expecting that study to read out its top line data in the first quarter of next year. Great. Great overview there. Lots of progress happening this year and some clinical milestones coming next year. Let's start with CYB003. You said this is a deuterated form of psilocin. So not exactly the same as psilocybin. Can you just help us understand what the experience of that is like for the patients in the clinic and how it might differ a little bit from what patients that are taking different forms of psychedelics would be? Yeah, sure. So CYB003, so what we've done is we've taken psilocybin and we've removed that first metabolic step to the active, which is psilocin. And then we've deuterated psilocin, which both stabilizes it and alters the metabolic profile. In early animal studies, what we saw, there was perhaps some suggestion there. Obviously, one has to look at animal data with the necessary caveats, but of potentially better brain penetration. In humans, what we've seen is that lower doses for the same PD effects when compared to psilocybin. For example, the usual high active dose of psilocybin is 25 milligrams, whereas we're seeing very robust effects with 12 and 16 milligrams of CYB003. So far, in terms of the experience in the clinic, what we're seeing is a very relatively rapid onset of effects, perhaps within 15 minutes. The acute subjective effects last between, say, four to six hours in the clinic. In terms of how the patients are treated in the clinic, they are typically reclining. They're wearing an eye shade. They have noise-canceling headphones on for the duration of that experience. There's no interaction with or sort of directed or therapy interaction with the dosing session monitors. Gotcha. No, that's very helpful. You base this robust phase III program on some really compelling phase II results. I don't know if you want to sort of outline or remind us sort of what you saw in phase II in terms of the sort of absolute effect and the remission and response rates and sort of what you used to sort of design the phase III program. Sure, absolutely. In phase II, what we saw was a very robust separation of the primary endpoint. It was two doses three weeks apart. That is something that is following into phase III of CYB003. What we saw at the primary endpoint after just a single dose at three weeks was a 13- to, depending on the dose, 14-point separation from placebo versus active. That is really quite remarkable, I guess, when one puts it into context. I mean, just for context, SSRIs across, I do not know how many studies from the 1970s, separate on average about two points. The effect size was well above two, which again is pretty remarkable in depression and psychiatry. As we scale up to phase III, we would naturally expect going into a larger data set that we would lose some of that effect size. As I said, even if you lose half that effect size, it would still be absolutely remarkable. In terms of the durability, what we saw with our 16 milligram dose and in terms of also response and remission was that 71% of the patients were in remission at 12 months following just two dosing sessions three weeks apart. Really quite remarkable and promising data set in terms of durability, of course, in a smaller study, but a robust and promising signal taking it into phase III. In terms of the phase II design, as a result, what we've tried to do is to change as little as possible between phase II and phase III to try and preserve that integrity of the signal. There are a number of factors in our protocol design, which we believe altogether contribute to driving that durability that we saw in phase II over and above the drug itself. The drug itself is a novel compound. One is the dose selection. I think, again, working with an NCE, we were able to do the dose escalating work in phase II and ultimately landed on the 16 milligram dose, which we believe these drugs have an inherent variability in their PD between patients. What you're really trying to achieve is a threshold effect to get as many patients as possible over the threshold into the full experience, which is purported to ultimately correlate well with therapeutic effects. We believe we pushed the dose to a level that's still tolerable at 16 milligrams that we've taken forward. The two-dose paradigm, three weeks apart, which we're also taking forward, we saw additional benefit from the second dose, incremental benefit of, I think, between three to five points, depending on the dose level, following that second dose in terms of response from baseline. Definitely benefit of the second dose. We think that's also contributing to the durability. Finally, that they're administered adjunctively. That's also differentiation adjunctively in MDD. In one of our early studies with DMT, I know it's a different drug, but you can draw some analogies, we saw that we had a DDI study where essentially there was a comparison between an active arm with SSRIs and one without SSRIs. The SSRIs fared a lot better than the control arm. Yeah, I definitely think the MDD adjunctive approach differentiated you from the competitors as well, having a different patient population. What are your thoughts on the comparator arm or placebo arm and sort of how your thoughts around, did you use a low dose or a placebo in phase II? And sort of what is the sort of company's thinking about how the FDA's guidance around that impacts the design? Right. In phase II, we used the placebo as the control. We've taken that forward into our phase III studies. The placebo is important for safety database, so you can have the comparison versus no drug under the same conditions. In both our phase III studies, you have that placebo. In the second phase III study, we also have a mid-dose arm. This is an 8 milligram arm, as well as the 16 milligram full dose. Really, the rationale there is that that is meant to address some of the issues around functional unblinding and expectancy by demonstrating a dose effect. Great. You have the first phase III study ongoing in the U.S. Can you just talk about what the size and scope of that is again and how the enrollment's going so far? Sure. The first phase III study is, it is two arms, 110 patients per arm. As I said, one is a placebo arm and the other is 16 milligrams. Two doses three weeks apart, primary endpoint at six weeks, secondary endpoint at 12 weeks. All the patients roll into a long-term extension, which are out to a year. That is a U.S.-only study. It initiated enrollment earlier this year, at the beginning of this year. It is expected to read out before the end of next year. How often can they get redosed in that open label extension trial? They have two sort of induction doses over that six-week period. When does that open label extension start? How often would they be permitted from a safety perspective to get a retreatment? It's based on objective criteria. The patients have to relapse and have to have demonstrated relapse based on objective criteria in the protocol. Ultimately, if a patient does relapse or does not respond and they enter into the open label extension, they have the option of getting another two doses. Again, two doses three weeks apart. If they're still relapsing or not responding, they can get a final dose. If you put together the short-term studies and the long-term extension, the maximum number of doses you can get is five. In a year. In a year, correct. Yeah. Great. You have the second study that you're sort of in the early stages of getting started in enrolling patients soon. What is different about that? I know it's going to be XUS as well. Any other changes that you're making to that study? How far behind do you think it will be from a sort of readout perspective? As I said, the key differences are, as you say, it does have international sites as well. It is going to have sites in the U.K., Europe, and Australia. It has also got that middle arm. Again, it is 110 patients per arm, but we have another arm with 8 milligrams. A total of 330 patients in the study. Other than that, the endpoints are the same, six weeks and 12 weeks. Again, the rollover into the long-term extension. Everything else is pretty much identical. Have you spoken to the FDA yet about the sort of use of both of those trials being sufficient to file on completion? Or do you have any sort of details about how you think about the package in full? We think this will be sufficient to submit in its totality across those three studies, the two short-term studies and the long-term extension. Obviously, we have the benefit of Breakthrough Therapy Designation. We had our end of phase II meeting where we ultimately landed on this design. Since then, we've had subsequent meetings as part of that Breakthrough Therapy. That has also added to the. Yeah. I want to ask a little bit about the challenge of functional unblinding. I know every company sort of has a different approach to how they're thinking about doing that. Can you just sort of talk about some of the internal checks that you have with you and your CRO to sort of ensure data integrity in these studies? Sure. The first one is we have centralized, blinded, and remote essentially ratings. They are not at the study site. I guess that is one of the most important ones for dealing with functional unblinding. Another protection that we have put in place is that we have restricted the access of the site staff to patient data. We sort of firewalled that off to reduce the risk of them becoming functionally unblinded. We also try and manage expectations in our protocol as part of the detailed informed consent process. I think there are patients out there that obviously have heard about psychedelics and their effects and have seen some of the study data. We think it is very important that you manage those expectations well ahead of the first dose so that it does not create any untoward expectancy effects. As I mentioned earlier, the other element is also having that mid-dose control there, where it's a level where it's meant to confound the patient ultimately into thinking they've had an active dose, but ultimately, across a large enough data set, it should not have the same therapeutic response. Are you limiting the trial to naive psychedelic users? Or is there sort of a certain percentage that you're allowing to have psychedelic experience previously? What we're doing is there are strict criteria in the protocol about how much prior use there can be. Generally, what we're trying to do is to reflect what's out there in the general population, so in terms of the percentage of patients that we will allow to enroll into the study. Yeah. For the first phase III, what is your current guidance for data? Given your breakthrough, could you sort of initiate accelerated timelines like some of your competitors are doing in terms of enrolling, submission, and things like that once you have that first study? I think typically, I mean, FDA, and I think it's the same across the industry, is going to require two well-controlled studies for submission. We'll have to wait for the data from the second study. Certainly, elements of rolling submission, which are elements that are within, I guess, the purview of Breakthrough Therapy Designation, is certainly something we're going to explore as we get data with FDA. I want to spend a little bit of time on the safety profile so far and what you've seen. I know suicidality is important or suicidal ideation is important across all depression and neuropsych trials. What have you seen so far and sort of how are you mitigating those potential adverse events in your phase III? So far, the safety profile in phase II was actually quite favorable, really favorable, we thought. We did not see any, well, actually, what we saw is we saw some suicidal ideation at screening. After dosing, it resolved. Again, promising to see in this population. I imagine suicidal ideation is unfortunately characteristic of depression. As we go into larger studies, we will have to see. Certainly, that safety profile so far looks promising. On other elements, again, we had no serious adverse events in phase II. We had just transient AEs that resolved quickly on the day of dosing, some elevated heart rate, blood pressure, and nausea, some headaches. Nothing untoward. As I said, all mild to moderate in severity. Very encouraged about that safety profile so far. We're obviously collecting a robust safety data set across those two studies, as well as all our clinical pharmacology studies that we're doing as well in the background as part of that full NDA submission. Confident we'll have that for submission. How does that inform what a potential REMS could look like? Obviously, it's provided with sort of the comp that everyone's using right now in terms of how that sort of two-hour, but yours is going to be a little bit longer than two-hour. Do you see a similar level of observation that needs to be done for that full sort of six-hour period? I'm just sort of wondering how we should think about. Sure. I think what we're doing, I mean, we think that if the guidance that we saw at all from the adcomm for Lykos, for example, about the FDA's views on REMS, it's provided. REMS is a good starting point to think about what it could be like. In terms of the monitoring period, what we're seeing is we're collecting that data in phase III. What we're doing is we have a discharge readiness criteria in phase III that we're collecting after a certain time period has elapsed all the way to the end so that we can exactly characterize what the length of the monitoring period is. Hopefully, that will then inform our discussions with the regulator to establish the REMS. Right. We'll see. Before we get into the 004, I want to just ask you a little bit about sort of from a company-wide perspective when you were designing this program, what the rationale was in going after an adjunctive MDD population versus TRD. I know that TRD is sort of what's seen as where the biggest unmet need is. I'm sort of curious from your perspective what you think you can add to the space by having an adjunctive MDD with a psychedelic. Firstly, MDD allows us to target a broader patient population. Adjunctive means that it will also be a later line of therapy. After initial treatment with SSRIs and SNRIs have failed or are no longer adequate in treating the patient's depression, we think adjunctive treatment makes a lot of sense when you look at the patient population. Amongst treated patients, I think in the U.S., I've seen some studies that have a figure of around 70% of those patients being on some form of SSRI or SNRI, even if it's inadequate in treating their depression. We feel that with going with an adjunctive indication, we remove that bottleneck of having to potentially titrate the patients off their background meds. Also, there are obviously withdrawal effects that are associated with those that can be quite severe with oral antidepressants. It reduces the potential barrier to adoption. So far, I guess in our research with clinics and payers, that approach seems to be getting support. Yeah. Does the bar for success change between should we compare the results or the effect sizes to TRD and Spravato-like studies? Or is there a different sort of benchmark for success with this different population, do you think? I think ultimately, you're treating a later line treatment. I mean, ultimately, TRD, it's not a diagnosis. It's just a failure of the current standard of care to adequately address depression. We think that when we think about that later line population, the adjunctive MDD level gives us more flexibility without necessarily having to do additional studies. Ultimately, we're talking about a third line or later population within depression. I don't think it differentiates. Okay. Great. Yeah, we'll look forward to data next year. Moving quickly, in our last five minutes here to CYB004, this is a derivative DMT that you have in development. Maybe before we get into the 004 study that's ongoing, can you just talk about what we know so far about what DMT can do for neuropsych indications? I know there's some early preclinical work that you guys have done. I'm just sort of curious what led to trying to use this formulation of DMT for anxiety. Sure. We have done, I think, as you say, five studies in total from early phase I and phase II study, actually, in MDD patients as well, seeking to optimize the PK and PD effects of DMT, which ultimately helped us arrive at the CYB004 intramuscular formulation. When you think about DMT IV unduterated, it's very intense and short. As a bolus, it's 10-12 minutes. As a 5-10 minute infusion, it can be anywhere between 15-25 minutes for the acute effects. While that demonstrated robust efficacy and safety data in this MDD proof of concept study we did IV, there were some patients in that study who felt that they came out of the experience prematurely because of the brevity and perhaps a little bit longer. What we've looked to do across all those studies, really, is to smooth the extreme intensity of IV DMT and extend it slightly to allow a bit longer for the patients to get the most benefit out of the treatment while still remaining short under two hours. A little bit gentler, maybe? Is that fair to say? Or higher or lower Cmax, or? We shall see. I think ultimately, with DMT, one of the things that we have learned is that you need it to be relatively rapid on the way up so that they can get into a full experience. Then once they're in the experience, slightly extending that period so that they can get the most benefit out of it. Gotcha. So yeah, intramuscular is the way you've been going. And you have a phase II trial in generalized anxiety disorder. Talk about the size and scope of that study and sort of what the challenges have been enrolling it so far, because I know the data has been pushed a few times. So I'd love to know sort of how that's going and what the challenges have been. With the phase II study, as I said, it's now complete. It's completed enrollment. It was a phase II study that evaluated the safety and efficacy of CYB004 in participants with moderate to severe GAD. That was with concomitant antidepressants and anxiolytics, just like with CYB003. Comorbid depression was allowed into the study. It recruited 36 patients in total who were randomized into two groups. The first group, the active group or the higher dose group, received two intramuscular doses of 20 milligrams of CYB004. The control group was 2 milligrams. It was an active control, which again, two doses intramuscular three weeks apart. The primary endpoint is change in HamA from baseline at six weeks. There's a secondary endpoint at 12 weeks. There's 12 weeks of blinded data. There is an open label extension thereafter. Again, no redosing, just following the patients up. There will also be endpoints with HamD and safety assessments, PD measures, and quality of life. I think we'll have all the data from that study to inform us for, as well as clinical pharmacology studies we're doing in the background, to inform the path into phase II and the phase III design. In terms of recruitment, it was a proof of concept study. We've learned. Now it's recruited. I guess we're just looking forward to the data. To clarify, when you do the top line readout in the first quarter, is that going to be the full 12 weeks of data? Correct. Okay. These are just GAD patients, but is this something that could be used in depression as well? Or do you hope to sort of keep the two assets sort of in separate indications? For now, it's in anxiety. Obviously, we're collecting the data as well in depression. We'll have to see what the data shows. The intention is to take it forward, if successful, into anxiety. Do you have a bar for what would on sort of effect size and what would lead you to pursuing phase III here? I don't think there's a set bar. I mean, generally, what we want to see is that we see within the higher dose arm, robust effects, seeing the patients respond well and some durable effects. I think we'll be very pleased to see that. There's no specific bar. Ultimately, what we're trying to learn from the study as well is a lot of these smaller elements that help us understand and design the phase III program. Is the safety liability for that product similar in terms of what you might expect as 003? Or what are the sort of key things to focus on from an adverse event profile? Indeed, similar. What we saw with IV DMT in our phase II study was, again, a very similar side effect profile. Great. Just our last 30 seconds here, if you could just talk about your financial position. I know you have a lot of ongoing programs. I'm just wondering sort of how well you're capitalized and sort of how you're prioritizing moving forward. Sure. As of our last reported balance sheet, which was Q2, we had $119 million on the balance sheet. Since then, we've actually just completed two weeks ago financing another $175 million in gross proceeds. With that financing, I think we're well capitalized into our two key readouts next year, which are the CYB004 phase II proof of concept data and then the phase III later in the year of the CYB003. Great. Congratulations on the progress. Thanks for being here. Thanks.

Speaker 2: All right. Great. Good afternoon, everyone. Welcome back to the second annual Guggenheim Healthcare Innovation Conference. My name is Eddie Hickman. I'm one of the biotech analysts here. I'm welcomed today by George Tziras from Cybin. Would love to hear maybe a few minutes just to give an overview of your current clinical programs. Thank you so much for joining us. All right. all right Great. great Good afternoon, everyone. good afternoon everyone Welcome back to the second annual Guggenheim Healthcare Innovation Conference. welcome back to the second annual guggenheim healthcare innovation conference My name is Eddie Hickman. my name is eddie hickman I'm one of the biotech analysts here. i'm one of the biotech analysts here I'm welcomed today by George Tziras from Cybin. i'm welcomed today by george tziras from cybin Would love to hear maybe a few minutes just to give an overview of your current clinical programs. would love to hear maybe a few minutes just to give an overview of your current clinical programs Thank you so much for joining us. thank you so much for joining us

Speaker 1: Thanks, Eddie. Hi, everyone. Yes, we have two programs, two clinical stage programs that are addressing two indications of high unmet need in psychiatry. Depression and anxiety both have high prevalence. I think they're around 20 million patients each in the U.S. alone that suffer from anxiety and depression. We're doing that through psychedelics, which we believe offer a pretty exciting new opportunity within the growing field of, I guess, what's been called now interventional psychiatry. By this, I mean TMS, Spravato, and ketamine. I think there's something like over 8,000 clinics or so in the US and growing in that space. Within that space, we're excited by the opportunity to potentially offer both rapid acting and long-lasting relief through as little as two dosing sessions a year. Thanks, Eddie. thanks eddie Hi, everyone. hi everyone Yes, we have two programs, two clinical stage programs that are addressing two indications of high unmet need in psychiatry. yes we have two programs two clinical stage programs that are addressing two indications of high unmet need in psychiatry Depression and anxiety both have high prevalence. depression and anxiety both have high prevalence I think they're around 20 million patients each in the U.S. alone that suffer from anxiety and depression. i think they're around 20 million patients each in the u.s alone that suffer from anxiety and depression We're doing that through psychedelics, which we believe offer a pretty exciting new opportunity within the growing field of, I guess, what's been called now interventional psychiatry. we're doing that through psychedelics which we believe offer a pretty exciting new opportunity within the growing field of i guess what's been called now interventional psychiatry By this, I mean TMS, Spravato, and ketamine. by this i mean tms spravato and ketamine I think there's something like over 8,000 clinics or so in the US and growing in that space. i think there's something like over 8,000 clinics or so in the us and growing in that space Within that space, we're excited by the opportunity to potentially offer both rapid acting and long-lasting relief through as little as two dosing sessions a year. within that space we're excited by the opportunity to potentially offer both rapid acting and long-lasting relief through as little as two dosing sessions a year If you think about psychedelics in development today or in late-stage development, I would say they broadly fall into two categories. The first category is the orally active ones, slightly longer acute psychoactive effects, like psilocybin, LSD, and MDMA. Then you have the shorter acting, non-orally active. By shorter acting, I mean longer duration of the psychoactive effects and more intense, like 5-MeO-DMT and DMT and its analogs. I think Cybin, as far as we're aware, is the only company that has assets in both those different categories. Those are CYB003 and CYB004. They're also novel compounds, so they benefit from robust IP protection. I think we have now over 100 patents granted and something like over 250 pending. Pretty robust patent estate there protecting our programs. CYB003 and CYB004, CYB003 is deuterated psilocin, and CYB004 is deuterated DMT. If you think about psychedelics in development today or in late-stage development, I would say they broadly fall into two categories. if you think about psychedelics in development today or in late-stage development i would say they broadly fall into two categories The first category is the orally active ones, slightly longer acute psychoactive effects, like psilocybin, LSD, and MDMA. the first category is the orally active ones slightly longer acute psychoactive effects like psilocybin lsd and mdma Then you have the shorter acting, non-orally active. then you have the shorter acting non-orally active By shorter acting, I mean longer duration of the psychoactive effects and more intense, like 5-MeO-DMT and DMT and its analogs. by shorter acting i mean longer duration of the psychoactive effects and more intense like 5-meo-dmt and dmt and its analogs I think Cybin, as far as we're aware, is the only company that has assets in both those different categories. i think cybin as far as we're aware is the only company that has assets in both those different categories Those are CYB003 and CYB004. those are cyb003 and cyb004 They're also novel compounds, so they benefit from robust IP protection. they're also novel compounds so they benefit from robust ip protection I think we have now over 100 patents granted and something like over 250 pending. i think we have now over 100 patents granted and something like over 250 pending Pretty robust patent estate there protecting our programs. pretty robust patent estate there protecting our programs CYB003 and CYB004, CYB003 is deuterated psilocin, and CYB004 is deuterated DMT. cyb003 and cyb004 cyb003 is deuterated psilocin and cyb004 is deuterated dmt For CYB003, we were granted Breakthrough Therapy Designation by FDA. That is currently in a phase III program. It is being investigated for the adjunctive treatment of major depressive disorder. There in the phase III program, we plan to enroll 550 patients across two short-term pivotal studies, which are called Approach and Embracing. I am sure we will discuss them more in this discussion. There is also a long-term extension to both, which has been termed, originally, Extend, which follows the patients out to a year. Approach is currently enrolling. Embracing has initiated and is expected to begin enrollment this quarter. CYB004, which is the second asset, deuterated DMT, is being investigated for generalized anxiety disorder. That is currently in a phase II proof of concept study that has completed enrollment as of September. For CYB003, we were granted Breakthrough Therapy Designation by FDA. for cyb003 we were granted breakthrough therapy designation by fda That is currently in a phase III program. It is being investigated for the adjunctive treatment of major depressive disorder. that is currently in a phase iii program. it is being investigated for the adjunctive treatment of major depressive disorder There in the phase III program, we plan to enroll 550 patients across two short-term pivotal studies, which are called Approach and Embracing. there in the phase iii program we plan to enroll 550 patients across two short-term pivotal studies which are called approach and embracing I am sure we will discuss them more in this discussion. i am sure we will discuss them more in this discussion There is also a long-term extension to both, which has been termed, originally, Extend, which follows the patients out to a year. there is also a long-term extension to both which has been termed originally extend which follows the patients out to a year Approach is currently enrolling. approach is currently enrolling Embracing has initiated and is expected to begin enrollment this quarter. embracing has initiated and is expected to begin enrollment this quarter CYB004, which is the second asset, deuterated DMT, is being investigated for generalized anxiety disorder. cyb004 which is the second asset deuterated dmt is being investigated for generalized anxiety disorder That is currently in a phase II proof of concept study that has completed enrollment as of September. that is currently in a phase ii proof of concept study that has completed enrollment as of september We're expecting that study to read out its top line data in the first quarter of next year. We're expecting that study to read out its top line data in the first quarter of next year. we're expecting that study to read out its top line data in the first quarter of next year

Speaker 2: Great. Great overview there. Lots of progress happening this year and some clinical milestones coming next year. Let's start with CYB003. You said this is a deuterated form of psilocin. So not exactly the same as psilocybin. Can you just help us understand what the experience of that is like for the patients in the clinic and how it might differ a little bit from what patients that are taking different forms of psychedelics would be? Great. great Great overview there. great overview there Lots of progress happening this year and some clinical milestones coming next year. lots of progress happening this year and some clinical milestones coming next year Let's start with CYB003. let's start with cyb003 You said this is a deuterated form of psilocin. you said this is a deuterated form of psilocin So not exactly the same as psilocybin. so not exactly the same as psilocybin Can you just help us understand what the experience of that is like for the patients in the clinic and how it might differ a little bit from what patients that are taking different forms of psychedelics would be? can you just help us understand what the experience of that is like for the patients in the clinic and how it might differ a little bit from what patients that are taking different forms of psychedelics would be

Speaker 1: Yeah, sure. So CYB003, so what we've done is we've taken psilocybin and we've removed that first metabolic step to the active, which is psilocin. And then we've deuterated psilocin, which both stabilizes it and alters the metabolic profile. In early animal studies, what we saw, there was perhaps some suggestion there. Obviously, one has to look at animal data with the necessary caveats, but of potentially better brain penetration. In humans, what we've seen is that lower doses for the same PD effects when compared to psilocybin. For example, the usual high active dose of psilocybin is 25 milligrams, whereas we're seeing very robust effects with 12 and 16 milligrams of CYB003. So far, in terms of the experience in the clinic, what we're seeing is a very relatively rapid onset of effects, perhaps within 15 minutes. Yeah, sure. yeah sure So CYB003, so what we've done is we've taken psilocybin and we've removed that first metabolic step to the active, which is psilocin. so cyb003 so what we've done is we've taken psilocybin and we've removed that first metabolic step to the active which is psilocin And then we've deuterated psilocin, which both stabilizes it and alters the metabolic profile. and then we've deuterated psilocin which both stabilizes it and alters the metabolic profile In early animal studies, what we saw, there was perhaps some suggestion there. in early animal studies what we saw there was perhaps some suggestion there Obviously, one has to look at animal data with the necessary caveats, but of potentially better brain penetration. obviously one has to look at animal data with the necessary caveats but of potentially better brain penetration In humans, what we've seen is that lower doses for the same PD effects when compared to psilocybin. in humans what we've seen is that lower doses for the same pd effects when compared to psilocybin For example, the usual high active dose of psilocybin is 25 milligrams, whereas we're seeing very robust effects with 12 and 16 milligrams of CYB003. for example the usual high active dose of psilocybin is 25 milligrams whereas we're seeing very robust effects with 12 and 16 milligrams of cyb003 So far, in terms of the experience in the clinic, what we're seeing is a very relatively rapid onset of effects, perhaps within 15 minutes. so far in terms of the experience in the clinic what we're seeing is a very relatively rapid onset of effects perhaps within 15 minutes The acute subjective effects last between, say, four to six hours in the clinic. In terms of how the patients are treated in the clinic, they are typically reclining. They're wearing an eye shade. They have noise-canceling headphones on for the duration of that experience. There's no interaction with or sort of directed or therapy interaction with the dosing session monitors. The acute subjective effects last between, say, four to six hours in the clinic. the acute subjective effects last between say four to six hours in the clinic In terms of how the patients are treated in the clinic, they are typically reclining. in terms of how the patients are treated in the clinic they are typically reclining They're wearing an eye shade. they're wearing an eye shade They have noise-canceling headphones on for the duration of that experience. they have noise-canceling headphones on for the duration of that experience There's no interaction with or sort of directed or therapy interaction with the dosing session monitors. there's no interaction with or sort of directed or therapy interaction with the dosing session monitors

Speaker 2: Gotcha. No, that's very helpful. You base this robust phase III program on some really compelling phase II results. I don't know if you want to sort of outline or remind us sort of what you saw in phase II in terms of the sort of absolute effect and the remission and response rates and sort of what you used to sort of design the phase III program. Gotcha. gotcha No, that's very helpful. no that's very helpful You base this robust phase III program on some really compelling phase II results. you base this robust phase iii program on some really compelling phase ii results I don't know if you want to sort of outline or remind us sort of what you saw in phase II in terms of the sort of absolute effect and the remission and response rates and sort of what you used to sort of design the phase III program. i don't know if you want to sort of outline or remind us sort of what you saw in phase ii in terms of the sort of absolute effect and the remission and response rates and sort of what you used to sort of design the phase iii program

Speaker 1: Sure, absolutely. In phase II, what we saw was a very robust separation of the primary endpoint. It was two doses three weeks apart. That is something that is following into phase III of CYB003. What we saw at the primary endpoint after just a single dose at three weeks was a 13- to, depending on the dose, 14-point separation from placebo versus active. That is really quite remarkable, I guess, when one puts it into context. I mean, just for context, SSRIs across, I do not know how many studies from the 1970s, separate on average about two points. The effect size was well above two, which again is pretty remarkable in depression and psychiatry. As we scale up to phase III, we would naturally expect going into a larger data set that we would lose some of that effect size. Sure, absolutely. sure absolutely In phase II, what we saw was a very robust separation of the primary endpoint. in phase ii what we saw was a very robust separation of the primary endpoint It was two doses three weeks apart. it was two doses three weeks apart That is something that is following into phase III of CYB003. that is something that is following into phase iii of cyb003 What we saw at the primary endpoint after just a single dose at three weeks was a 13- to, depending on the dose, 14-point separation from placebo versus active. what we saw at the primary endpoint after just a single dose at three weeks was a 13- to depending on the dose 14-point separation from placebo versus active That is really quite remarkable, I guess, when one puts it into context. that is really quite remarkable i guess when one puts it into context I mean, just for context, SSRIs across, I do not know how many studies from the 1970s, separate on average about two points. i mean just for context ssris across i do not know how many studies from the 1970s separate on average about two points The effect size was well above two, which again is pretty remarkable in depression and psychiatry. the effect size was well above two which again is pretty remarkable in depression and psychiatry As we scale up to phase III, we would naturally expect going into a larger data set that we would lose some of that effect size. as we scale up to phase iii we would naturally expect going into a larger data set that we would lose some of that effect size As I said, even if you lose half that effect size, it would still be absolutely remarkable. In terms of the durability, what we saw with our 16 milligram dose and in terms of also response and remission was that 71% of the patients were in remission at 12 months following just two dosing sessions three weeks apart. Really quite remarkable and promising data set in terms of durability, of course, in a smaller study, but a robust and promising signal taking it into phase III. In terms of the phase II design, as a result, what we've tried to do is to change as little as possible between phase II and phase III to try and preserve that integrity of the signal. As I said, even if you lose half that effect size, it would still be absolutely remarkable. as i said even if you lose half that effect size it would still be absolutely remarkable In terms of the durability, what we saw with our 16 milligram dose and in terms of also response and remission was that 71% of the patients were in remission at 12 months following just two dosing sessions three weeks apart. in terms of the durability what we saw with our 16 milligram dose and in terms of also response and remission was that 71% of the patients were in remission at 12 months following just two dosing sessions three weeks apart Really quite remarkable and promising data set in terms of durability, of course, in a smaller study, but a robust and promising signal taking it into phase III. really quite remarkable and promising data set in terms of durability of course in a smaller study but a robust and promising signal taking it into phase iii In terms of the phase II design, as a result, what we've tried to do is to change as little as possible between phase II and phase III to try and preserve that integrity of the signal. in terms of the phase ii design as a result what we've tried to do is to change as little as possible between phase ii and phase iii to try and preserve that integrity of the signal There are a number of factors in our protocol design, which we believe altogether contribute to driving that durability that we saw in phase II over and above the drug itself. The drug itself is a novel compound. One is the dose selection. I think, again, working with an NCE, we were able to do the dose escalating work in phase II and ultimately landed on the 16 milligram dose, which we believe these drugs have an inherent variability in their PD between patients. What you're really trying to achieve is a threshold effect to get as many patients as possible over the threshold into the full experience, which is purported to ultimately correlate well with therapeutic effects. We believe we pushed the dose to a level that's still tolerable at 16 milligrams that we've taken forward. There are a number of factors in our protocol design, which we believe altogether contribute to driving that durability that we saw in phase II over and above the drug itself. there are a number of factors in our protocol design which we believe altogether contribute to driving that durability that we saw in phase ii over and above the drug itself The drug itself is a novel compound. the drug itself is a novel compound One is the dose selection. one is the dose selection I think, again, working with an NCE, we were able to do the dose escalating work in phase II and ultimately landed on the 16 milligram dose, which we believe these drugs have an inherent variability in their PD between patients. i think again working with an nce we were able to do the dose escalating work in phase ii and ultimately landed on the 16 milligram dose which we believe these drugs have an inherent variability in their pd between patients What you're really trying to achieve is a threshold effect to get as many patients as possible over the threshold into the full experience, which is purported to ultimately correlate well with therapeutic effects. what you're really trying to achieve is a threshold effect to get as many patients as possible over the threshold into the full experience which is purported to ultimately correlate well with therapeutic effects We believe we pushed the dose to a level that's still tolerable at 16 milligrams that we've taken forward. we believe we pushed the dose to a level that's still tolerable at 16 milligrams that we've taken forward The two-dose paradigm, three weeks apart, which we're also taking forward, we saw additional benefit from the second dose, incremental benefit of, I think, between three to five points, depending on the dose level, following that second dose in terms of response from baseline. Definitely benefit of the second dose. We think that's also contributing to the durability. Finally, that they're administered adjunctively. That's also differentiation adjunctively in MDD. In one of our early studies with DMT, I know it's a different drug, but you can draw some analogies, we saw that we had a DDI study where essentially there was a comparison between an active arm with SSRIs and one without SSRIs. The SSRIs fared a lot better than the control arm. The two-dose paradigm, three weeks apart, which we're also taking forward, we saw additional benefit from the second dose, incremental benefit of, I think, between three to five points, depending on the dose level, following that second dose in terms of response from baseline. the two-dose paradigm three weeks apart which we're also taking forward we saw additional benefit from the second dose incremental benefit of i think between three to five points depending on the dose level following that second dose in terms of response from baseline Definitely benefit of the second dose. definitely benefit of the second dose We think that's also contributing to the durability. we think that's also contributing to the durability Finally, that they're administered adjunctively. finally that they're administered adjunctively That's also differentiation adjunctively in MDD. that's also differentiation adjunctively in mdd In one of our early studies with DMT, I know it's a different drug, but you can draw some analogies, we saw that we had a DDI study where essentially there was a comparison between an active arm with SSRIs and one without SSRIs. in one of our early studies with dmt i know it's a different drug but you can draw some analogies we saw that we had a ddi study where essentially there was a comparison between an active arm with ssris and one without ssris The SSRIs fared a lot better than the control arm. the ssris fared a lot better than the control arm

Speaker 2: Yeah, I definitely think the MDD adjunctive approach differentiated you from the competitors as well, having a different patient population. What are your thoughts on the comparator arm or placebo arm and sort of how your thoughts around, did you use a low dose or a placebo in phase II? And sort of what is the sort of company's thinking about how the FDA's guidance around that impacts the design? Yeah, I definitely think the MDD adjunctive approach differentiated you from the competitors as well, having a different patient population. yeah i definitely think the mdd adjunctive approach differentiated you from the competitors as well having a different patient population What are your thoughts on the comparator arm or placebo arm and sort of how your thoughts around, did you use a low dose or a placebo in phase II? what are your thoughts on the comparator arm or placebo arm and sort of how your thoughts around did you use a low dose or a placebo in phase ii And sort of what is the sort of company's thinking about how the FDA's guidance around that impacts the design? and sort of what is the sort of company's thinking about how the fda's guidance around that impacts the design

Speaker 1: Right. In phase II, we used the placebo as the control. We've taken that forward into our phase III studies. The placebo is important for safety database, so you can have the comparison versus no drug under the same conditions. In both our phase III studies, you have that placebo. In the second phase III study, we also have a mid-dose arm. This is an 8 milligram arm, as well as the 16 milligram full dose. Really, the rationale there is that that is meant to address some of the issues around functional unblinding and expectancy by demonstrating a dose effect. Right. right In phase II, we used the placebo as the control. in phase ii we used the placebo as the control We've taken that forward into our phase III studies. we've taken that forward into our phase iii studies The placebo is important for safety database, so you can have the comparison versus no drug under the same conditions. the placebo is important for safety database so you can have the comparison versus no drug under the same conditions In both our phase III studies, you have that placebo. in both our phase iii studies you have that placebo In the second phase III study, we also have a mid-dose arm. in the second phase iii study we also have a mid-dose arm This is an 8 milligram arm, as well as the 16 milligram full dose. this is an 8 milligram arm as well as the 16 milligram full dose Really, the rationale there is that that is meant to address some of the issues around functional unblinding and expectancy by demonstrating a dose effect. really the rationale there is that that is meant to address some of the issues around functional unblinding and expectancy by demonstrating a dose effect

Speaker 2: Great. You have the first phase III study ongoing in the U.S. Can you just talk about what the size and scope of that is again and how the enrollment's going so far? Great. great You have the first phase III study ongoing in the U.S. you have the first phase iii study ongoing in the u.s Can you just talk about what the size and scope of that is again and how the enrollment's going so far? can you just talk about what the size and scope of that is again and how the enrollment's going so far

Speaker 1: Sure. The first phase III study is, it is two arms, 110 patients per arm. As I said, one is a placebo arm and the other is 16 milligrams. Two doses three weeks apart, primary endpoint at six weeks, secondary endpoint at 12 weeks. All the patients roll into a long-term extension, which are out to a year. That is a U.S.-only study. It initiated enrollment earlier this year, at the beginning of this year. It is expected to read out before the end of next year. Sure. sure The first phase III study is, it is two arms, 110 patients per arm. the first phase iii study is it is two arms 110 patients per arm As I said, one is a placebo arm and the other is 16 milligrams. as i said one is a placebo arm and the other is 16 milligrams Two doses three weeks apart, primary endpoint at six weeks, secondary endpoint at 12 weeks. two doses three weeks apart primary endpoint at six weeks secondary endpoint at 12 weeks All the patients roll into a long-term extension, which are out to a year. all the patients roll into a long-term extension which are out to a year That is a U.S.-only study. that is a u.s.-only study It initiated enrollment earlier this year, at the beginning of this year. it initiated enrollment earlier this year at the beginning of this year It is expected to read out before the end of next year. it is expected to read out before the end of next year

Speaker 2: How often can they get redosed in that open label extension trial? They have two sort of induction doses over that six-week period. When does that open label extension start? How often would they be permitted from a safety perspective to get a retreatment? How often can they get redosed in that open label extension trial? how often can they get redosed in that open label extension trial They have two sort of induction doses over that six-week period. they have two sort of induction doses over that six-week period When does that open label extension start? when does that open label extension start How often would they be permitted from a safety perspective to get a retreatment? how often would they be permitted from a safety perspective to get a retreatment

Speaker 1: It's based on objective criteria. The patients have to relapse and have to have demonstrated relapse based on objective criteria in the protocol. Ultimately, if a patient does relapse or does not respond and they enter into the open label extension, they have the option of getting another two doses. Again, two doses three weeks apart. If they're still relapsing or not responding, they can get a final dose. If you put together the short-term studies and the long-term extension, the maximum number of doses you can get is five. It's based on objective criteria. it's based on objective criteria The patients have to relapse and have to have demonstrated relapse based on objective criteria in the protocol. the patients have to relapse and have to have demonstrated relapse based on objective criteria in the protocol Ultimately, if a patient does relapse or does not respond and they enter into the open label extension, they have the option of getting another two doses. ultimately if a patient does relapse or does not respond and they enter into the open label extension they have the option of getting another two doses Again, two doses three weeks apart. again two doses three weeks apart If they're still relapsing or not responding, they can get a final dose. if they're still relapsing or not responding they can get a final dose If you put together the short-term studies and the long-term extension, the maximum number of doses you can get is five. if you put together the short-term studies and the long-term extension the maximum number of doses you can get is five

Speaker 2: In a year. In a year. in a year

Speaker 1: In a year, correct. Yeah. In a year, correct. in a year correct Yeah. yeah

Speaker 2: Great. You have the second study that you're sort of in the early stages of getting started in enrolling patients soon. What is different about that? I know it's going to be XUS as well. Any other changes that you're making to that study? How far behind do you think it will be from a sort of readout perspective? Great. great You have the second study that you're sort of in the early stages of getting started in enrolling patients soon. you have the second study that you're sort of in the early stages of getting started in enrolling patients soon What is different about that? what is different about that I know it's going to be XUS as well. i know it's going to be xus as well Any other changes that you're making to that study? any other changes that you're making to that study How far behind do you think it will be from a sort of readout perspective? how far behind do you think it will be from a sort of readout perspective

Speaker 1: As I said, the key differences are, as you say, it does have international sites as well. It is going to have sites in the U.K., Europe, and Australia. It has also got that middle arm. Again, it is 110 patients per arm, but we have another arm with 8 milligrams. A total of 330 patients in the study. Other than that, the endpoints are the same, six weeks and 12 weeks. Again, the rollover into the long-term extension. Everything else is pretty much identical. As I said, the key differences are, as you say, it does have international sites as well. as i said the key differences are as you say it does have international sites as well It is going to have sites in the U.K., Europe, and Australia. It has also got that middle arm. it is going to have sites in the u.k europe and australia. it has also got that middle arm Again, it is 110 patients per arm, but we have another arm with 8 milligrams. again it is 110 patients per arm but we have another arm with 8 milligrams A total of 330 patients in the study. a total of 330 patients in the study Other than that, the endpoints are the same, six weeks and 12 weeks. other than that the endpoints are the same six weeks and 12 weeks Again, the rollover into the long-term extension. again the rollover into the long-term extension Everything else is pretty much identical. everything else is pretty much identical

Speaker 2: Have you spoken to the FDA yet about the sort of use of both of those trials being sufficient to file on completion? Or do you have any sort of details about how you think about the package in full? Have you spoken to the FDA yet about the sort of use of both of those trials being sufficient to file on completion? have you spoken to the fda yet about the sort of use of both of those trials being sufficient to file on completion Or do you have any sort of details about how you think about the package in full? or do you have any sort of details about how you think about the package in full

Speaker 1: We think this will be sufficient to submit in its totality across those three studies, the two short-term studies and the long-term extension. Obviously, we have the benefit of Breakthrough Therapy Designation. We had our end of phase II meeting where we ultimately landed on this design. Since then, we've had subsequent meetings as part of that Breakthrough Therapy. That has also added to the. We think this will be sufficient to submit in its totality across those three studies, the two short-term studies and the long-term extension. we think this will be sufficient to submit in its totality across those three studies the two short-term studies and the long-term extension Obviously, we have the benefit of Breakthrough Therapy Designation. obviously we have the benefit of breakthrough therapy designation We had our end of phase II meeting where we ultimately landed on this design. we had our end of phase ii meeting where we ultimately landed on this design Since then, we've had subsequent meetings as part of that Breakthrough Therapy. since then we've had subsequent meetings as part of that breakthrough therapy That has also added to the. that has also added to the

Speaker 2: Yeah. I want to ask a little bit about the challenge of functional unblinding. I know every company sort of has a different approach to how they're thinking about doing that. Can you just sort of talk about some of the internal checks that you have with you and your CRO to sort of ensure data integrity in these studies? Yeah. yeah I want to ask a little bit about the challenge of functional unblinding. i want to ask a little bit about the challenge of functional unblinding I know every company sort of has a different approach to how they're thinking about doing that. i know every company sort of has a different approach to how they're thinking about doing that Can you just sort of talk about some of the internal checks that you have with you and your CRO to sort of ensure data integrity in these studies? can you just sort of talk about some of the internal checks that you have with you and your cro to sort of ensure data integrity in these studies

Speaker 1: Sure. The first one is we have centralized, blinded, and remote essentially ratings. They are not at the study site. I guess that is one of the most important ones for dealing with functional unblinding. Another protection that we have put in place is that we have restricted the access of the site staff to patient data. We sort of firewalled that off to reduce the risk of them becoming functionally unblinded. We also try and manage expectations in our protocol as part of the detailed informed consent process. I think there are patients out there that obviously have heard about psychedelics and their effects and have seen some of the study data. We think it is very important that you manage those expectations well ahead of the first dose so that it does not create any untoward expectancy effects. Sure. sure The first one is we have centralized, blinded, and remote essentially ratings. the first one is we have centralized blinded and remote essentially ratings They are not at the study site. they are not at the study site I guess that is one of the most important ones for dealing with functional unblinding. i guess that is one of the most important ones for dealing with functional unblinding Another protection that we have put in place is that we have restricted the access of the site staff to patient data. another protection that we have put in place is that we have restricted the access of the site staff to patient data We sort of firewalled that off to reduce the risk of them becoming functionally unblinded. we sort of firewalled that off to reduce the risk of them becoming functionally unblinded We also try and manage expectations in our protocol as part of the detailed informed consent process. we also try and manage expectations in our protocol as part of the detailed informed consent process I think there are patients out there that obviously have heard about psychedelics and their effects and have seen some of the study data. i think there are patients out there that obviously have heard about psychedelics and their effects and have seen some of the study data We think it is very important that you manage those expectations well ahead of the first dose so that it does not create any untoward expectancy effects. we think it is very important that you manage those expectations well ahead of the first dose so that it does not create any untoward expectancy effects As I mentioned earlier, the other element is also having that mid-dose control there, where it's a level where it's meant to confound the patient ultimately into thinking they've had an active dose, but ultimately, across a large enough data set, it should not have the same therapeutic response. As I mentioned earlier, the other element is also having that mid-dose control there, where it's a level where it's meant to confound the patient ultimately into thinking they've had an active dose, but ultimately, across a large enough data set, it should not have the same therapeutic response. as i mentioned earlier the other element is also having that mid-dose control there where it's a level where it's meant to confound the patient ultimately into thinking they've had an active dose but ultimately across a large enough data set it should not have the same therapeutic response

Speaker 2: Are you limiting the trial to naive psychedelic users? Or is there sort of a certain percentage that you're allowing to have psychedelic experience previously? Are you limiting the trial to naive psychedelic users? are you limiting the trial to naive psychedelic users Or is there sort of a certain percentage that you're allowing to have psychedelic experience previously? or is there sort of a certain percentage that you're allowing to have psychedelic experience previously

Speaker 1: What we're doing is there are strict criteria in the protocol about how much prior use there can be. Generally, what we're trying to do is to reflect what's out there in the general population, so in terms of the percentage of patients that we will allow to enroll into the study. What we're doing is there are strict criteria in the protocol about how much prior use there can be. what we're doing is there are strict criteria in the protocol about how much prior use there can be Generally, what we're trying to do is to reflect what's out there in the general population, so in terms of the percentage of patients that we will allow to enroll into the study. generally what we're trying to do is to reflect what's out there in the general population so in terms of the percentage of patients that we will allow to enroll into the study

Speaker 2: Yeah. For the first phase III, what is your current guidance for data? Given your breakthrough, could you sort of initiate accelerated timelines like some of your competitors are doing in terms of enrolling, submission, and things like that once you have that first study? Yeah. yeah For the first phase III, what is your current guidance for data? for the first phase iii what is your current guidance for data Given your breakthrough, could you sort of initiate accelerated timelines like some of your competitors are doing in terms of enrolling, submission, and things like that once you have that first study? given your breakthrough could you sort of initiate accelerated timelines like some of your competitors are doing in terms of enrolling submission and things like that once you have that first study

Speaker 1: I think typically, I mean, FDA, and I think it's the same across the industry, is going to require two well-controlled studies for submission. We'll have to wait for the data from the second study. Certainly, elements of rolling submission, which are elements that are within, I guess, the purview of Breakthrough Therapy Designation, is certainly something we're going to explore as we get data with FDA. I think typically, I mean, FDA, and I think it's the same across the industry, is going to require two well-controlled studies for submission. i think typically i mean fda and i think it's the same across the industry is going to require two well-controlled studies for submission We'll have to wait for the data from the second study. we'll have to wait for the data from the second study Certainly, elements of rolling submission, which are elements that are within, I guess, the purview of Breakthrough Therapy Designation, is certainly something we're going to explore as we get data with FDA. certainly elements of rolling submission which are elements that are within i guess the purview of breakthrough therapy designation is certainly something we're going to explore as we get data with fda

Speaker 2: I want to spend a little bit of time on the safety profile so far and what you've seen. I know suicidality is important or suicidal ideation is important across all depression and neuropsych trials. What have you seen so far and sort of how are you mitigating those potential adverse events in your phase III? I want to spend a little bit of time on the safety profile so far and what you've seen. i want to spend a little bit of time on the safety profile so far and what you've seen I know suicidality is important or suicidal ideation is important across all depression and neuropsych trials. i know suicidality is important or suicidal ideation is important across all depression and neuropsych trials What have you seen so far and sort of how are you mitigating those potential adverse events in your phase III? what have you seen so far and sort of how are you mitigating those potential adverse events in your phase iii

Speaker 1: So far, the safety profile in phase II was actually quite favorable, really favorable, we thought. We did not see any, well, actually, what we saw is we saw some suicidal ideation at screening. After dosing, it resolved. Again, promising to see in this population. I imagine suicidal ideation is unfortunately characteristic of depression. As we go into larger studies, we will have to see. Certainly, that safety profile so far looks promising. On other elements, again, we had no serious adverse events in phase II. We had just transient AEs that resolved quickly on the day of dosing, some elevated heart rate, blood pressure, and nausea, some headaches. Nothing untoward. As I said, all mild to moderate in severity. Very encouraged about that safety profile so far. So far, the safety profile in phase II was actually quite favorable, really favorable, we thought. so far the safety profile in phase ii was actually quite favorable really favorable we thought We did not see any, well, actually, what we saw is we saw some suicidal ideation at screening. we did not see any well actually what we saw is we saw some suicidal ideation at screening After dosing, it resolved. after dosing it resolved Again, promising to see in this population. again promising to see in this population I imagine suicidal ideation is unfortunately characteristic of depression. i imagine suicidal ideation is unfortunately characteristic of depression As we go into larger studies, we will have to see. as we go into larger studies we will have to see Certainly, that safety profile so far looks promising. certainly that safety profile so far looks promising On other elements, again, we had no serious adverse events in phase II. on other elements again we had no serious adverse events in phase ii We had just transient AEs that resolved quickly on the day of dosing, some elevated heart rate, blood pressure, and nausea, some headaches. we had just transient aes that resolved quickly on the day of dosing some elevated heart rate blood pressure and nausea some headaches Nothing untoward. nothing untoward As I said, all mild to moderate in severity. as i said all mild to moderate in severity Very encouraged about that safety profile so far. very encouraged about that safety profile so far We're obviously collecting a robust safety data set across those two studies, as well as all our clinical pharmacology studies that we're doing as well in the background as part of that full NDA submission. Confident we'll have that for submission. We're obviously collecting a robust safety data set across those two studies, as well as all our clinical pharmacology studies that we're doing as well in the background as part of that full NDA submission. we're obviously collecting a robust safety data set across those two studies as well as all our clinical pharmacology studies that we're doing as well in the background as part of that full nda submission Confident we'll have that for submission. confident we'll have that for submission

Speaker 2: How does that inform what a potential REMS could look like? Obviously, it's provided with sort of the comp that everyone's using right now in terms of how that sort of two-hour, but yours is going to be a little bit longer than two-hour. Do you see a similar level of observation that needs to be done for that full sort of six-hour period? I'm just sort of wondering how we should think about. How does that inform what a potential REMS could look like? how does that inform what a potential rems could look like Obviously, it's provided with sort of the comp that everyone's using right now in terms of how that sort of two-hour, but yours is going to be a little bit longer than two-hour. obviously it's provided with sort of the comp that everyone's using right now in terms of how that sort of two-hour but yours is going to be a little bit longer than two-hour Do you see a similar level of observation that needs to be done for that full sort of six-hour period? do you see a similar level of observation that needs to be done for that full sort of six-hour period I'm just sort of wondering how we should think about. i'm just sort of wondering how we should think about

Speaker 1: Sure. I think what we're doing, I mean, we think that if the guidance that we saw at all from the adcomm for Lykos, for example, about the FDA's views on REMS, it's provided. REMS is a good starting point to think about what it could be like. In terms of the monitoring period, what we're seeing is we're collecting that data in phase III. What we're doing is we have a discharge readiness criteria in phase III that we're collecting after a certain time period has elapsed all the way to the end so that we can exactly characterize what the length of the monitoring period is. Hopefully, that will then inform our discussions with the regulator to establish the REMS. Sure. sure I think what we're doing, I mean, we think that if the guidance that we saw at all from the adcomm for Lykos, for example, about the FDA's views on REMS, it's provided. i think what we're doing i mean we think that if the guidance that we saw at all from the adcomm for lykos for example about the fda's views on rems it's provided REMS is a good starting point to think about what it could be like. rems is a good starting point to think about what it could be like In terms of the monitoring period, what we're seeing is we're collecting that data in phase III. in terms of the monitoring period what we're seeing is we're collecting that data in phase iii What we're doing is we have a discharge readiness criteria in phase III that we're collecting after a certain time period has elapsed all the way to the end so that we can exactly characterize what the length of the monitoring period is. what we're doing is we have a discharge readiness criteria in phase iii that we're collecting after a certain time period has elapsed all the way to the end so that we can exactly characterize what the length of the monitoring period is Hopefully, that will then inform our discussions with the regulator to establish the REMS. hopefully that will then inform our discussions with the regulator to establish the rems

Speaker 2: Right. We'll see. Before we get into the 004, I want to just ask you a little bit about sort of from a company-wide perspective when you were designing this program, what the rationale was in going after an adjunctive MDD population versus TRD. I know that TRD is sort of what's seen as where the biggest unmet need is. I'm sort of curious from your perspective what you think you can add to the space by having an adjunctive MDD with a psychedelic. Right. right We'll see. we'll see Before we get into the 004, I want to just ask you a little bit about sort of from a company-wide perspective when you were designing this program, what the rationale was in going after an adjunctive MDD population versus TRD. before we get into the 004 i want to just ask you a little bit about sort of from a company-wide perspective when you were designing this program what the rationale was in going after an adjunctive mdd population versus trd I know that TRD is sort of what's seen as where the biggest unmet need is. i know that trd is sort of what's seen as where the biggest unmet need is I'm sort of curious from your perspective what you think you can add to the space by having an adjunctive MDD with a psychedelic. i'm sort of curious from your perspective what you think you can add to the space by having an adjunctive mdd with a psychedelic

Speaker 1: Firstly, MDD allows us to target a broader patient population. Adjunctive means that it will also be a later line of therapy. After initial treatment with SSRIs and SNRIs have failed or are no longer adequate in treating the patient's depression, we think adjunctive treatment makes a lot of sense when you look at the patient population. Amongst treated patients, I think in the U.S., I've seen some studies that have a figure of around 70% of those patients being on some form of SSRI or SNRI, even if it's inadequate in treating their depression. We feel that with going with an adjunctive indication, we remove that bottleneck of having to potentially titrate the patients off their background meds. Also, there are obviously withdrawal effects that are associated with those that can be quite severe with oral antidepressants. Firstly, MDD allows us to target a broader patient population. firstly mdd allows us to target a broader patient population Adjunctive means that it will also be a later line of therapy. adjunctive means that it will also be a later line of therapy After initial treatment with SSRIs and SNRIs have failed or are no longer adequate in treating the patient's depression, we think adjunctive treatment makes a lot of sense when you look at the patient population. after initial treatment with ssris and snris have failed or are no longer adequate in treating the patient's depression we think adjunctive treatment makes a lot of sense when you look at the patient population Amongst treated patients, I think in the U.S., I've seen some studies that have a figure of around 70% of those patients being on some form of SSRI or SNRI, even if it's inadequate in treating their depression. amongst treated patients i think in the u.s i've seen some studies that have a figure of around 70% of those patients being on some form of ssri or snri even if it's inadequate in treating their depression We feel that with going with an adjunctive indication, we remove that bottleneck of having to potentially titrate the patients off their background meds. we feel that with going with an adjunctive indication we remove that bottleneck of having to potentially titrate the patients off their background meds Also, there are obviously withdrawal effects that are associated with those that can be quite severe with oral antidepressants. also there are obviously withdrawal effects that are associated with those that can be quite severe with oral antidepressants It reduces the potential barrier to adoption. So far, I guess in our research with clinics and payers, that approach seems to be getting support. It reduces the potential barrier to adoption. it reduces the potential barrier to adoption So far, I guess in our research with clinics and payers, that approach seems to be getting support. so far i guess in our research with clinics and payers that approach seems to be getting support

Speaker 2: Yeah. Does the bar for success change between should we compare the results or the effect sizes to TRD and Spravato-like studies? Or is there a different sort of benchmark for success with this different population, do you think? Yeah. yeah Does the bar for success change between should we compare the results or the effect sizes to TRD and Spravato-like studies? does the bar for success change between should we compare the results or the effect sizes to trd and spravato-like studies Or is there a different sort of benchmark for success with this different population, do you think? or is there a different sort of benchmark for success with this different population do you think

Speaker 1: I think ultimately, you're treating a later line treatment. I mean, ultimately, TRD, it's not a diagnosis. It's just a failure of the current standard of care to adequately address depression. We think that when we think about that later line population, the adjunctive MDD level gives us more flexibility without necessarily having to do additional studies. Ultimately, we're talking about a third line or later population within depression. I don't think it differentiates. I think ultimately, you're treating a later line treatment. i think ultimately you're treating a later line treatment I mean, ultimately, TRD, it's not a diagnosis. i mean ultimately trd it's not a diagnosis It's just a failure of the current standard of care to adequately address depression. it's just a failure of the current standard of care to adequately address depression We think that when we think about that later line population, the adjunctive MDD level gives us more flexibility without necessarily having to do additional studies. we think that when we think about that later line population the adjunctive mdd level gives us more flexibility without necessarily having to do additional studies Ultimately, we're talking about a third line or later population within depression. ultimately we're talking about a third line or later population within depression I don't think it differentiates. i don't think it differentiates

Speaker 2: Okay. Great. Yeah, we'll look forward to data next year. Moving quickly, in our last five minutes here to CYB004, this is a derivative DMT that you have in development. Maybe before we get into the 004 study that's ongoing, can you just talk about what we know so far about what DMT can do for neuropsych indications? I know there's some early preclinical work that you guys have done. I'm just sort of curious what led to trying to use this formulation of DMT for anxiety. Okay. okay Great. great Yeah, we'll look forward to data next year. yeah we'll look forward to data next year Moving quickly, in our last five minutes here to CYB004, this is a derivative DMT that you have in development. moving quickly in our last five minutes here to cyb004 this is a derivative dmt that you have in development Maybe before we get into the 004 study that's ongoing, can you just talk about what we know so far about what DMT can do for neuropsych indications? maybe before we get into the 004 study that's ongoing can you just talk about what we know so far about what dmt can do for neuropsych indications I know there's some early preclinical work that you guys have done. i know there's some early preclinical work that you guys have done I'm just sort of curious what led to trying to use this formulation of DMT for anxiety. i'm just sort of curious what led to trying to use this formulation of dmt for anxiety

Speaker 1: Sure. We have done, I think, as you say, five studies in total from early phase I and phase II study, actually, in MDD patients as well, seeking to optimize the PK and PD effects of DMT, which ultimately helped us arrive at the CYB004 intramuscular formulation. When you think about DMT IV unduterated, it's very intense and short. As a bolus, it's 10-12 minutes. As a 5-10 minute infusion, it can be anywhere between 15-25 minutes for the acute effects. While that demonstrated robust efficacy and safety data in this MDD proof of concept study we did IV, there were some patients in that study who felt that they came out of the experience prematurely because of the brevity and perhaps a little bit longer. Sure. sure We have done, I think, as you say, five studies in total from early phase I and phase II study, actually, in MDD patients as well, seeking to optimize the PK and PD effects of DMT, which ultimately helped us arrive at the CYB004 intramuscular formulation. we have done i think as you say five studies in total from early phase i and phase ii study actually in mdd patients as well seeking to optimize the pk and pd effects of dmt which ultimately helped us arrive at the cyb004 intramuscular formulation When you think about DMT IV unduterated, it's very intense and short. when you think about dmt iv unduterated it's very intense and short As a bolus, it's 10-12 minutes. as a bolus it's 10-12 minutes As a 5-10 minute infusion, it can be anywhere between 15-25 minutes for the acute effects. as a 5-10 minute infusion it can be anywhere between 15-25 minutes for the acute effects While that demonstrated robust efficacy and safety data in this MDD proof of concept study we did IV, there were some patients in that study who felt that they came out of the experience prematurely because of the brevity and perhaps a little bit longer. while that demonstrated robust efficacy and safety data in this mdd proof of concept study we did iv there were some patients in that study who felt that they came out of the experience prematurely because of the brevity and perhaps a little bit longer What we've looked to do across all those studies, really, is to smooth the extreme intensity of IV DMT and extend it slightly to allow a bit longer for the patients to get the most benefit out of the treatment while still remaining short under two hours. What we've looked to do across all those studies, really, is to smooth the extreme intensity of IV DMT and extend it slightly to allow a bit longer for the patients to get the most benefit out of the treatment while still remaining short under two hours. what we've looked to do across all those studies really is to smooth the extreme intensity of iv dmt and extend it slightly to allow a bit longer for the patients to get the most benefit out of the treatment while still remaining short under two hours

Speaker 2: A little bit gentler, maybe? Is that fair to say? Or higher or lower Cmax, or? A little bit gentler, maybe? a little bit gentler maybe Is that fair to say? is that fair to say Or higher or lower Cmax, or? or higher or lower cmax or

Speaker 1: We shall see. I think ultimately, with DMT, one of the things that we have learned is that you need it to be relatively rapid on the way up so that they can get into a full experience. Then once they're in the experience, slightly extending that period so that they can get the most benefit out of it. We shall see. we shall see I think ultimately, with DMT, one of the things that we have learned is that you need it to be relatively rapid on the way up so that they can get into a full experience. i think ultimately with dmt one of the things that we have learned is that you need it to be relatively rapid on the way up so that they can get into a full experience Then once they're in the experience, slightly extending that period so that they can get the most benefit out of it. then once they're in the experience slightly extending that period so that they can get the most benefit out of it

Speaker 2: Gotcha. So yeah, intramuscular is the way you've been going. And you have a phase II trial in generalized anxiety disorder. Talk about the size and scope of that study and sort of what the challenges have been enrolling it so far, because I know the data has been pushed a few times. So I'd love to know sort of how that's going and what the challenges have been. Gotcha. gotcha So yeah, intramuscular is the way you've been going. so yeah intramuscular is the way you've been going And you have a phase II trial in generalized anxiety disorder. and you have a phase ii trial in generalized anxiety disorder Talk about the size and scope of that study and sort of what the challenges have been enrolling it so far, because I know the data has been pushed a few times. talk about the size and scope of that study and sort of what the challenges have been enrolling it so far because i know the data has been pushed a few times So I'd love to know sort of how that's going and what the challenges have been. so i'd love to know sort of how that's going and what the challenges have been

Speaker 1: With the phase II study, as I said, it's now complete. It's completed enrollment. It was a phase II study that evaluated the safety and efficacy of CYB004 in participants with moderate to severe GAD. That was with concomitant antidepressants and anxiolytics, just like with CYB003. Comorbid depression was allowed into the study. It recruited 36 patients in total who were randomized into two groups. The first group, the active group or the higher dose group, received two intramuscular doses of 20 milligrams of CYB004. The control group was 2 milligrams. It was an active control, which again, two doses intramuscular three weeks apart. The primary endpoint is change in HamA from baseline at six weeks. There's a secondary endpoint at 12 weeks. There's 12 weeks of blinded data. With the phase II study, as I said, it's now complete. with the phase ii study as i said it's now complete It's completed enrollment. it's completed enrollment It was a phase II study that evaluated the safety and efficacy of CYB004 in participants with moderate to severe GAD. it was a phase ii study that evaluated the safety and efficacy of cyb004 in participants with moderate to severe gad That was with concomitant antidepressants and anxiolytics, just like with CYB003. that was with concomitant antidepressants and anxiolytics just like with cyb003 Comorbid depression was allowed into the study. comorbid depression was allowed into the study It recruited 36 patients in total who were randomized into two groups. it recruited 36 patients in total who were randomized into two groups The first group, the active group or the higher dose group, received two intramuscular doses of 20 milligrams of CYB004. the first group the active group or the higher dose group received two intramuscular doses of 20 milligrams of cyb004 The control group was 2 milligrams. the control group was 2 milligrams It was an active control, which again, two doses intramuscular three weeks apart. it was an active control which again two doses intramuscular three weeks apart The primary endpoint is change in HamA from baseline at six weeks. the primary endpoint is change in hama from baseline at six weeks There's a secondary endpoint at 12 weeks. there's a secondary endpoint at 12 weeks There's 12 weeks of blinded data. there's 12 weeks of blinded data There is an open label extension thereafter. Again, no redosing, just following the patients up. There will also be endpoints with HamD and safety assessments, PD measures, and quality of life. I think we'll have all the data from that study to inform us for, as well as clinical pharmacology studies we're doing in the background, to inform the path into phase II and the phase III design. In terms of recruitment, it was a proof of concept study. We've learned. Now it's recruited. I guess we're just looking forward to the data. There is an open label extension thereafter. there is an open label extension thereafter Again, no redosing, just following the patients up. again no redosing just following the patients up There will also be endpoints with HamD and safety assessments, PD measures, and quality of life. there will also be endpoints with hamd and safety assessments pd measures and quality of life I think we'll have all the data from that study to inform us for, as well as clinical pharmacology studies we're doing in the background, to inform the path into phase II and the phase III design. i think we'll have all the data from that study to inform us for as well as clinical pharmacology studies we're doing in the background to inform the path into phase ii and the phase iii design In terms of recruitment, it was a proof of concept study. in terms of recruitment it was a proof of concept study We've learned. we've learned Now it's recruited. now it's recruited I guess we're just looking forward to the data. i guess we're just looking forward to the data

Speaker 2: To clarify, when you do the top line readout in the first quarter, is that going to be the full 12 weeks of data? To clarify, when you do the top line readout in the first quarter, is that going to be the full 12 weeks of data? to clarify when you do the top line readout in the first quarter is that going to be the full 12 weeks of data

Speaker 1: Correct. Correct. correct

Speaker 2: Okay. These are just GAD patients, but is this something that could be used in depression as well? Or do you hope to sort of keep the two assets sort of in separate indications? Okay. okay These are just GAD patients, but is this something that could be used in depression as well? these are just gad patients but is this something that could be used in depression as well Or do you hope to sort of keep the two assets sort of in separate indications? or do you hope to sort of keep the two assets sort of in separate indications

Speaker 1: For now, it's in anxiety. Obviously, we're collecting the data as well in depression. We'll have to see what the data shows. The intention is to take it forward, if successful, into anxiety. For now, it's in anxiety. for now it's in anxiety Obviously, we're collecting the data as well in depression. obviously we're collecting the data as well in depression We'll have to see what the data shows. we'll have to see what the data shows The intention is to take it forward, if successful, into anxiety. the intention is to take it forward if successful into anxiety

Speaker 2: Do you have a bar for what would on sort of effect size and what would lead you to pursuing phase III here? Do you have a bar for what would on sort of effect size and what would lead you to pursuing phase III here? do you have a bar for what would on sort of effect size and what would lead you to pursuing phase iii here

Speaker 1: I don't think there's a set bar. I mean, generally, what we want to see is that we see within the higher dose arm, robust effects, seeing the patients respond well and some durable effects. I think we'll be very pleased to see that. There's no specific bar. Ultimately, what we're trying to learn from the study as well is a lot of these smaller elements that help us understand and design the phase III program. I don't think there's a set bar. i don't think there's a set bar I mean, generally, what we want to see is that we see within the higher dose arm, robust effects, seeing the patients respond well and some durable effects. i mean generally what we want to see is that we see within the higher dose arm robust effects seeing the patients respond well and some durable effects I think we'll be very pleased to see that. i think we'll be very pleased to see that There's no specific bar. there's no specific bar Ultimately, what we're trying to learn from the study as well is a lot of these smaller elements that help us understand and design the phase III program. ultimately what we're trying to learn from the study as well is a lot of these smaller elements that help us understand and design the phase iii program

Speaker 2: Is the safety liability for that product similar in terms of what you might expect as 003? Or what are the sort of key things to focus on from an adverse event profile? Is the safety liability for that product similar in terms of what you might expect as 003? is the safety liability for that product similar in terms of what you might expect as 003 Or what are the sort of key things to focus on from an adverse event profile? or what are the sort of key things to focus on from an adverse event profile

Speaker 1: Indeed, similar. What we saw with IV DMT in our phase II study was, again, a very similar side effect profile. Indeed, similar. indeed similar What we saw with IV DMT in our phase II study was, again, a very similar side effect profile. what we saw with iv dmt in our phase ii study was again a very similar side effect profile

Speaker 2: Great. Just our last 30 seconds here, if you could just talk about your financial position. I know you have a lot of ongoing programs. I'm just wondering sort of how well you're capitalized and sort of how you're prioritizing moving forward. Great. great Just our last 30 seconds here, if you could just talk about your financial position. just our last 30 seconds here if you could just talk about your financial position I know you have a lot of ongoing programs. i know you have a lot of ongoing programs I'm just wondering sort of how well you're capitalized and sort of how you're prioritizing moving forward. i'm just wondering sort of how well you're capitalized and sort of how you're prioritizing moving forward

Speaker 1: Sure. As of our last reported balance sheet, which was Q2, we had $119 million on the balance sheet. Since then, we've actually just completed two weeks ago financing another $175 million in gross proceeds. With that financing, I think we're well capitalized into our two key readouts next year, which are the CYB004 phase II proof of concept data and then the phase III later in the year of the CYB003. Sure. sure As of our last reported balance sheet, which was Q2, we had $119 million on the balance sheet. as of our last reported balance sheet which was q2 we had $119 million on the balance sheet Since then, we've actually just completed two weeks ago financing another $175 million in gross proceeds. since then we've actually just completed two weeks ago financing another $175 million in gross proceeds With that financing, I think we're well capitalized into our two key readouts next year, which are the CYB004 phase II proof of concept data and then the phase III later in the year of the CYB003. with that financing i think we're well capitalized into our two key readouts next year which are the cyb004 phase ii proof of concept data and then the phase iii later in the year of the cyb003

Speaker 2: Great. Congratulations on the progress. Thanks for being here. Great. great Congratulations on the progress. congratulations on the progress Thanks for being here. thanks for being here

Speaker 1: Thanks. Thanks. thanks