Good morning again, everyone. We will ask you to take your seats, please, so we can get started again. Just wanted to let people know who are listening on the webcast that the full broadcast will be available at the end of the event for replay. Those who are listening currently from the webcast will also see the event live. We wanted to point out there was a slight technical difficulty at the Yale Club with the internet, so it's now been resolved, and here we can get started again. Thank you. All right. Sorry for the technical difficulties there. So that's the benefits of coming and joining us in person, is not having to deal with technical challenges at home. So, is Dr. Fava ready and available? Let's keep going then with the program. We'll hand over to Dr. Fava to talk about the unmet needs for the current standards of care. Thank you. Thank you so much. It's a pleasure to have the opportunity to speak this morning about the very promising results that Amir just showed you. I think I want to put a kind of a context for the importance of these results. You know, I had the opportunity to serve as one of the three principal investigators for the largest clinical trial ever conducted in depression, called STAR*D. In the study trial, we treated everybody with an SSRI for 12 weeks. With support all kinds of things to help the patients. The outcome was that only one in three patients remitted after 12 weeks. So if you think about it, three months of treatment and one-third of the patients remit. And half of those who remitted, remitted between weeks six and 12. So standard antidepressants, unfortunately, have the significant limitation of limited efficacy. So 1 in 3 patients remit, but also very slow onset of effect. So the efficacy takes time. You know, what we saw in Amir's presentation was a very, very rapid effect on a single administration and remission rates with the 12 mg of 80% at six weeks. So you know, can contrast, if you wish, because there was no randomization, but very, very promising results. The other limitation of the current monoamine based therapies is related to tolerability. That is, you have to take these medicines every day, and they're not devoid of side effects. That is, approximately 20%, 15%-20% of the patients will gain weight on SSRI, SNRI, 20%-25% will have sleep disturbances. There will be 20%-25% of the patients that have cognitive difficulties, problems with memory or executive function as a result of the treatment. In addition, a significant proportion, 15%-20%, may also experience a worsening of anxiety. So if you think about it, daily treatment for three months with you know, efficacy of a 33% remission rate and side effects that can be quite bothersome, versus a model of care of single or maybe two administrations to obtain effects that are rapid and sustainable. So I think that, you know, from my perspective, and this is an important thing to keep in mind. I n STAR*D level two, we tested augmentation. Remember, in this trial, patients were augmented with CYB003, and in STAR*D, we augmented with bupropion and buspirone. And when you look at our Journal of Medicine paper on the outcome of augmentation, at 12 weeks, only 30% of the patients remitted. At 12 weeks. And again, demonstrating how even when you look at augmentation strategies such as, you know, bupropion augmentation of SSRIs, it takes a very long time. Because if you look at that curve in that paper, it's a curve that shows there's no steepness at all. That 30% remission rate at 12 weeks is achieved almost with a linear progression. So, that's the reality, if you wish, the context in which we have to look at the development of compounds such as CYB003. the reality that only one in three patients will remit with the first antidepressant trial. So, with that, I'd like to pass on to the next KOL. Okay, thank you, Dr. Fava. We look forward to having you back for the panel, in just a few minutes. So, with that, I'd like to hand over now to Dr. Knudsen, who will speak about the potential mechanisms for efficacy of psychedelic medications. Thank you. Thank you so much, Doug, and thank you for inviting me to come here along and talk about my favorite topic, which is how these drugs do what they do. It's really remarkable, if you think about it, that just a single dose, a single psychedelic dose of a compound can have such sustainable and long-acting effects. And I can't think of any other drug that has the same effect. But how does it work? That's what I'm trying to talk about, and to give you some impression of what we scientists think is a mode of mechanism. But first, a little about the nomenclature. We talk about hallucinogens, and often people refer to psychedelics very broadly, also including ketamine and NMDA and others that act in a different way. So today, we'll be talking about the serotonergic psychedelics, which are the classic ones. And these psychedelics include LSD, psilocybin, DMT, et cetera. And they all act by stimulating the brain's serotonin 2A receptors. And we know that for a fact, because if you block those receptors, there is no psychedelic experience. So this is a PET study that we have done in my lab, and it shows the distribution of the serotonin 2A receptors. And the positron emission tomography is unprecedented in the way that it can show the target interaction and the blood-brain barrier permeability, et cetera, of drugs such as the psychedelics. And a few years ago, we undertook this study in healthy people, where we PET scanned them before and after they were given different doses of psilocybin. We looked at the association between how the brain's serotonin 2A receptors were occupied with the compound, and the dose that was given, and the plasma psilocin levels, the active metabolite of psilocybin, and also the subjective intensity rating. So we would be asking people while they were being scanned. So on a scale from 1 to 10, or from 0 to 10, what is the intensity of your experience right now? Here are the data. We found that when we measured plasma psilocin levels and brain receptor occupancy, we saw this, a very nice curve that was here composed of data from individual patients or individual people that were given different doses and scanned twice after the dose was given. What we found was a very tight relationship between how much drug is in the blood and how much reaches the brain and affects those receptors. And moreover, we also were able to see a very nice relationship between the degree to which the drug was sitting on the receptor and the subjective intensity. And the last graph on the right shows the relationship between plasma psilocin concentrations in the blood and the intensity of the experience. Now, the question is, how do these psychedelics work? As I said, it's really remarkable that just one single dose can have such long-lasting effects. And there's been a lot of animal literature that has been trying to tease apart what kind of mode of actions are these. First, this is probably what many psychologists would posit, that these psychedelics induce mystical type of experiences, such as unity, feeling at unity with the universe, and time and space is rolling by in a different way. So they have all these experiences that are quite remarkable and different from what you experience otherwise. It is believed, by this theory at least, that it's those experiences that can facilitate interaction with the therapist and will enable them to gain insight into their own disorder. So that's kind of a more psychological way of explaining it. But when we start to look more into the molecular mechanisms of these compounds, then h ere we can also see that the mystical experience that I was referring to before, this is how people describe the experience they just underwent. That means that if you take those experiences and you look at the long-term effects in healthy individuals, you can see that, the measures of mystical experience that they have in these different subscales also, reflects quite, quite nicely how people perceive it in the long run. Now, another theory is that the psychedelics promote structural and functional neuroplasticity in the prefrontal cortex. That is the front part of the brain, which enable pathological circuits, that are controlling, our emotions, such as mood, fear, and reward, to be repaired. Now we are starting to look into rodent studies, and I'll get back to some human data at the end of my talk. But the idea here is really that you have sprouting of neurons. They make more contacts with each other, and at the left, you can see a nerve cell with the contact points called synapses, that they are interacting through these different modes of mechanism. The serotonin 2A receptor, the brain-derived neurotrophic factor, which is a factor that is known to be involved in the restitution of the brain and growth. And once you give psychedelics to rodents, you can see that they start to sprout and form new synapses with new neurons. So that's called neuroplasticity, which is really the brain's ability to generate new information and to have new ways of working, if you will. So, another model that has been proposed is that they reopen the social reward learning critical period. What does that mean? Well, basically, if you think about a child, you will realize that children are much better at learning new things, and, for instance, with language, if you don't talk another language at the age of 10, you're never going to be able to speak it as your mother tongue. So that's just one example of a critical window, that you need to learn certain things at a certain age, and then after that period, the window is closed. The idea is here, that by taking psychedelics, you can reopen that window, and you can create a neuroplastic transformation that will enable you to get out of these rigid thoughts and iterative thinking like you see in mood disorders, where people often have thoughts that are circulating and ruminating around certain themes. And this is the data here, showing at the left, that you can see at the age of the rodents, that at a certain age, they start to decline. It's getting harder and harder for them to learn new things. But then, if you give them psychedelics, in this case, psilocybin, but it's also been shown with other psychedelics, then you'll be able to kind of reopen that window, and this is another thing that is quite intriguing that we've seen here. And these different psychedelics, they seem to have different effects, and in this group, or this theory, it's been said that that the duration of the psychedelic experience is also related to how long this window is open. Now, I just wanna end up my talk by showing you some human data again, using positron emission tomography. It's possible to measure the amount of synapses in the brain. These are recent data that we showed for escitalopram, another antidepressant, SSRI. And what we can see in these healthy people is that when we treat them with SSRIs, in this case, escitalopram, we can see that those who are on placebo, they don't change their synaptic density, but those who are treated with SSRIs, they have an increase, show an increase in their synaptic density. And we are currently having data acquired and analyzed, and I can see that it seems like we have also similar effects, but much more rapidly occurring with psilocybin. And with that, I'd like to end my talk. Okay. Well, do you want to join us on the table? Great. Well, thank you, Dr. Knudsen. So now we'll move to the panel. Do we have Dr. Fava on the line still? Great. Yes, sir. Okay. Okay, do we have these microphones working as well? Can you hear me? Great. Okay. Well, thank you for that. I'm sure we'll have some more questions around the mechanisms, but maybe we'll start with talking about study design. Maybe, Amir, I'm gonna start with you. You know, what are the key elements or characteristics of a well-designed study involving psychedelic drug candidates? Yeah. I mean, the key elements probably don't change for a psychedelic. I would say the standard randomized double-blind placebo-controlled, which is a gold standard in the industry, which is what the FDA expect. That is also relevant for a psychedelic study. Now, of course, there are challenges with psychedelics, but they are not novel. Maybe give some examples of why I think they are not novel. So key elements like a control group, blinding, you know, using a good rating scale that is fit for purpose. But also, for psychedelics, you have the added requirement of ensuring patient safety. T his is largely psychological safety, so you want some psychological support built in in your clinical trials. And note that I'm saying psychological support. I'm not saying psychotherapy. I know that's an ongoing debate, and probably we won't be solving that here. But by giving psychedelics, you are opening up people's psyches, and you're probably destroying defense mechanisms which are maladaptive. And even if those mechanisms were maladaptive, and they were serving to continue their, depressive symptoms or, symptoms of, mental health condition, they were still protecting the person. When you get rid of all of that, you need to provide some sort of psychological support. I call it psychological chaperoning more than therapy because there's actually no therapy happening. But control groups. Now, is placebo control still a good control group for studies with psychedelics? I would say yes, from a certain perspective. From a safety perspective, at least, a placebo group seems to be appropriate. You know, people question the utility of a placebo because with psychedelics, they introduce, they induce a non-ordinary state of consciousness. You immediately know who's getting a psychedelic and who is not. Having said that, we've observed that even patients with placebo, who are receiving placebo, they tend to get psychedelic effects, and sometimes it's difficult to say who is on active and who is on placebo. So I'd say that element of a traditional design is still relevant for studies with psychedelics. Blinding? Absolutely. Is it possible to blind studies with psychedelics? It is. It's not the problem of unmasking, knowing who's getting a psychedelic and who's not getting a psychedelic. That's not unique to psychedelics. It's not the first time in drug development that we are seeing it. I remember a long time ago, when I was working as an investigator in a study of risperidone, Risperdal, an antipsychotic used for schizophrenia. We immediately knew on the day, next day, who was on the active drug and who was on placebo or control group, because people getting risperidone would have strong extrapyramidal symptoms. They would start having tremors. They would have rigidity in their limbs. They would start drooling. So unmasking happens with other drugs as well. Sedatives, hypnotics. When you give somebody sleep medication, it's quite obvious who's receiving sleep medication, who's not. So a placebo control is relevant there, and a placebo control is relevant for psychedelics as well. I think one challenge we've faced, and I think it's a key consideration for psychedelics, is understanding what rating scale to use, how to measure the effect of the psychedelics. Of course, the FDA have traditional rating scales, like, for example, the MADRS or the Hamilton Depression Rating Scale or the Hamilton Anxiety Scale, for measuring those symptoms. These are regulatory accepted instruments. But for a psychedelic, there are other effects that they induce, which maybe are not captured by these traditional rating scales. I'm happy that Gitte shared earlier the visual analog scale, which, by the way, I love. I think it's a simple and a very efficient scale of measuring who's actually getting the full effect of a psychedelic, and some of the data you showed earlier with respect to serotonin receptor occupancy, and correlations with the visual analog scale. We've used those data in our dose escalation to identify doses at which we felt it was okay now to move into patients with MDD. So those are some of the critical elements, I would say. Yeah, thank you for that. You know, it's fascinating to me that we see placebo patients scoring high on the visual analog scale. Yeah. So to me, that says the placebo is doing its job and is working. So okay, next, I'll move over to Dr. Fava. Dr. Fava, are there best practices or specific methodologies that you believe would be most promising for advancing the understanding and development of psychedelics for treating mental health disorders? Thank you. It's a great question. I think that the, you know, the same methodologies that were applied to the trial that Amir reported are gonna be critical. So, for example, in this trial, we ensure that the quality of the patients was really excellent because had an independent verification, the patients had the diagnosis, the severity, the treatment history required through what we call a SAFER interview. And that methodology has been shown over and over again to, you know, de-risk trials in phase III, where, you know, you're making sure that the right patients get into the trial. So in my mind, this is an important addition to all of the other methodologies that Amir has outlined. Yeah, I think that SAFER tool has been very helpful, and I assume we'll continue to use that going forward. Dr. Knudsen, then maybe coming back to your presentation. Yeah, what are the key differences between how psychedelic drug candidates work versus the current standard of care, like SSRIs? I mean, what could be the underlying mechanisms, do you think? Well, first of all, I think the SSRIs take longer to work. We know that it can take weeks before they work. Even for those compounds that have been in use for more than, I don't know, 50 years or so, we're not really certain about the mode of action. It's generally believed that they work by increasing serotonin levels, but they certainly also increase neuroplasticity, and I just showed you some data that supports that notion. But what is really striking about the psychedelics is the rapid onset and the persisting effects after just a single dose. That is very striking and very different. Thank you. Thank you. So, Dr. Fava, maybe as you think about the current treatment landscape, what do you think are the most pressing issues or the most pressing challenges, the greatest unmet needs when it comes to treating depression and anxiety today? Well, that's a great question. I think that, in my mind, the modest efficacy of standard therapies is a big issue because, imagine if you went to the doctor, and the doctor said, look, I'm going to give you this antibiotic. It will take 12 weeks to work, and you have a 33% chance of actually remitting. I think you would be very unhappy with that. So, the modest efficacy of standard therapies is an issue. The fact that, you know, you have to take them every day, and they have side effects, leads to poor adherence to treatment, people not taking them, and then having relapses or recurrences, even when they do work, are the main issues in my mind. So would you say, Dr. Fava, that CYB003, based on the results we're seeing so far, has the potential to address some of those unmet needs, some of the challenges? Yeah, I mean, certainly, the remission rate is at least at 80% is far different than the 33% chance of sertraline in level one onset. Great. Thank you. Thank you. One for you, Amir. So coming back to study design a bit, can you go over again why you chose to administer two doses of CYB003 rather than just a single dose? Yeah, that's an interesting one as well, and we debated quite a bit, because traditionally, there's been this concept of one and done in the field. Realistically, one cannot expect a patient to receive a single dose of a drug and be done with it. By nature, things like conditions like depression are relapsing and remitting illnesses. So to expect that one treatment will cure a patient of their condition is honestly being a bit stupid. That's definitely ambitious. Yeah. Well, we evaluated quite carefully what should be, the dosing regimen. We looked at the literature, we looked at some of the published data with, psilocybin in this area, and what we saw was in some large, well-controlled studies, you start seeing, the effect sort of wean off around four to six weeks. And we wanted to preempt that decline in, the benefit that was achieved after a single dose. So three weeks, we said two doses, three weeks apart, would ensure that there is an incremental benefit of a second dose, and that would ensure sustained efficacy. Our goal was to sustain efficacy for at least six months. Of course, we'll, in this study, we'll evaluate up to three months. In our pivotal studies, we are going to look at six months for durability. But that second dose was essentially to, one, ensure there is durability of effect, and two, we also thought that some people need a bit of time to do the psychological work that will result in improvement in their symptoms. And maybe if they don't do it at the first treatment session, they could do it at the second one. And then we looked at some of the data with other drugs which have a similar mechanism of action. So, for example, things like ketamine. You know, ketamine is not a psychedelic, but the downstream effects of ketamine are similar to the 5-HT2A downstream effects from a biological point of view. And you see about four weeks, that treatment regimen seems to work for ketamine. So in the absence of any other published, very clear data, we made certain assumptions, and clearly, they paid off. Because you see with a second dose, there is an incremental benefit, and there is a robust improvement in response rates. I agree. It's clear from those results that the second dose really improved both response and remission, which is the ultimate goal. Regardless of score changes. J ust getting patients into remission is what matters. So we're talking about improvements in depression symptoms here, but Dr. Knudsen, do you think beyond depression that there are other indications where psychedelics could have potential therapeutic benefit? Well, yes, I'm a neurologist, so of course, I've been thinking about what can we do for those patients as well. I think there's a number of indications that are very interesting for the purpose of testing psychedelics. We have conducted a small scale study in patients with chronic cluster headache, which, if you know about that, that's the worst type of headache you can have. And some patients even have a more chronic version of that, usually comes in attacks. Anecdotally, people have talked about psychedelics as something that would have been reported to help. So we looked at that, and we actually saw that these patients also benefited from this. I think there are a number of other pain conditions where it could be really interesting also to look into this. But apart from that, conditions such as anorexia, OCD, obsessive compulsive disorder, anxiety, and so on. So I think there are many different disorders where it's worthwhile to try to look into the efficacy of these promising compounds. Yeah, it's unusual for molecules to have such broad application, isn't it? One again for you, Amir. As you're thinking about translating these results, this effect size into phase III, what are the challenges? What are your expectations? Yeah, I mean, the setup we have for a psychedelic study is different, and yet not too different. And it's similar, for example, some of the biologics, where people have to come in and spend an entire day, similar to ketamine administration clinics. But as we go into bigger studies, large multicentric clinical trials, multinational clinical trials, there's bound to be increases in variability of the data. I certainly don't expect the effect to be as huge as we see in this small study. But I'm not worried because there's plenty of room. Even if you get half of the effect that you see in this study, even if you get half of it in our phase III study, that will be at least 3x-4x more than traditional treatments. So I think with the variability, with the number of centers that, we will have in our phase III, we will expect to see some reduction in effect size, but definitely, still be better than, SSRIs and other antidepressants. The other challenge is to manage expectations, I think, at a larger scale. We've trained the small group of sites. We had to manage expectations with patients. With expectations, you see placebo effects, and with placebo effects, you start losing the difference. Many a study have failed because of huge placebo effects. What we are going to try and do, and we've started working on this already, is to try and minimize the contact between the patient and the clinic so as to reduce the placebo response. Most of the assessments we are going to do remotely. Some of the psychological support work we've already piloted in this study that we completed, which we are going to implement in our phase III, where most of the psychological support will be done remotely, so patients don't really need to come to the clinic. It also makes sense because m any patients are put off by the number of visits, by the number of assessments that typically they have to do, and if you allow them to be in the comfort of their home and still do the work, they will do it, just like us. I'd prefer to work from home and not really commute to office, like, three hours a day. It's the same for patients. So we are addressing some of those challenges, and yeah, hopefully, we will see similarly robust effect sizes in our phase III studies. It sounds to me like the fundamentals, so robust study design, very good screening processes. Absolutely. And then site selection, sites that are motivated and continue to recruit. Yeah. I mean, that is the, your investigator or your site is the single most important factor in the success of a study. And you need people who are, as you said, motivated, who understand the studies or what to expect from a psychedelic study, because for somebody who's not seen a patient undergoing a psychedelic effect, it can be a bit, you know, challenging to handle some of the symptoms. Like I said, they induce non-ordinary states of consciousness, which can sometimes put people off. Yeah. Okay. So moving then maybe from study challenges to more to challenges of adoption. Dr. Fava, from your perspective, what are the hurdles that we face as developers with providers in terms of getting adoption of these treatments into their protocols? Well, I think that, you know, t here's gonna be a challenge for the healthcare system, I think, through how to deliver these treatments, because in some ways, the current setting may not be suitable to deliver the care. So there'll be some very specialized settings. But, but I see it as an opportunity to really rethink how we deliver care. And so, it's a challenge, but it's an opportunity but we have to start thinking about it because we don't want to be, again, these treatments approved, and then say, now what? We want to be able to start thinking already how we integrate them, you know, what spaces do we adopt for the delivery of care, how we organize it, and so forth. Yeah, I agree, and we've learned a lot from our study. The study rooms, the treatment rooms that we've been using are quite simple. They're comfortable spaces, beds, sofas, lots of pillows, blankets. Patients are wearing an eye mask and wearing a headset. These aren't complex clinical spaces, and also with a simple dosage form, like a capsule or a small volume injectable, no real special specialist clinical setting is needed. So w e thought about some of those things. I think that definitely helps with adoption we have. Yeah. But also, we see in medicine that when there is a groundbreaking treatment, the healthcare system evolves and adapts. We've seen this with ketamine. The infrastructure for delivery of ketamine was not there before, but it evolved, and the system adapted, and now it's commonplace for people to go to a ketamine clinic and get the treatment. And the same thing will happen with psychedelics. Once they are approved, and once people see the profound effects they have and the changes they can make to people's lives, then the healthcare system will adapt. Yeah. We're already seeing that to some extent with Spravato, I think. It's really taking off now, and that doesn't have the most convenient dosing regimen at all, and that's still getting a lot of traction. So I know we're about out of time for this part before we hand over to questions. Maybe one last question for Dr. Fava and then Dr. Knudsen. When you look at this data, we obviously find it very compelling and exciting. What is it, what do you find compelling about the data? Well, I think what I found most compelling is, I mean, you have a large effect size, obviously. But I thought that what I found really compelling was the fact that you saw these large effects also in patients that were on existing SSRI treatment, which I think is great news. There was a big concern within this, the kind of this, among researchers, that this would be a problematic thing that you would need to taper SSRIs before starting psychedelic treatments. But I think it also opens up for the possibility that you can add psychedelic therapy on top of existing SSRIs when people do not have a sufficient response, and you can still have a very, very good response. I found that very compelling. It was great that you allowed for that. Thank you. And then the last, then over to you, Dr. Fava, for any final comments. Yeah, no, I agree. I think that fundamentally, these were patients that had over 30, a score of 30 or more than 30 on average on the MADRS. So these were significantly depressed patients who had a remarkable improvement, so that was really impressive. Thank you. Thank you to all of our panelists. Now, we are just towards the end of the session. Just going to hand over to questions from the floor. We have a couple of microphones if anybody has a question. Hi, good morning. Good morning. Patrick Trucchio, HC Wainwright. A couple of questions. I think first for Dr. Fava, I wanted to revisit some of the comments earlier. I wanted to get a sense from you, how you envision psychedelics being administered in the real-world setting, specifically with CYB003, based on the data you've seen so far. If this data is reconfirmed in phase III, what proportion of patients with moderate to severe MDD would you envision CYB003 ultimately being appropriate for and being prescribed for? Well, it's a great question. I think that if in phase III, the results are confirmed, and we have, as, you know, a very robust efficacy, and. But efficacy accompanied by an immediate response, with a single or two of these patients, this will change dramatically our paradigm. So normally, let's say you come into our depression clinic, you get started on the medicine, an SSRI, SNRI. You're seen maybe two weeks, three weeks later. You continue the treatment, and then you see. But then, you continue, if you wish, often, particularly if you have had prior episodes, you may be on that medicine indefinitely for very long periods of time, with, you know, relatively frequent visits to monitor both side effects and efficacy. You know, if the sustainability of treatments is very long, you know, how often people would default out would be, you know, may differ drastically from the current treatments. You know, so patients may need to come in once or twice through a single treatment, and then that monitoring of tolerability, side effects, and efficacy, the tolerability no longer need, they're no longer on a medicine. So I think that we'll, as a field, we'll have to think h ow are we going to deliver agents like this? And I really think it's an opportunity because right now, apart from the fact that access to care is still challenged, we have a shortage in the United States of over 14,000 psychiatrists and over thousands psychologists, according to, you know, the government. So with a shortage of providers of that size, and partly it derives from the modesty of the efficacy of the treatments and the fact that they require frequent, you know, visits. If we change how we deliver care and, and we have much greater efficacy, we hopefully will be able to provide much greater access to patients. Yeah, that's helpful. And then, maybe a few for the company. Just the first is, you know, I understand the patient data remains blinded, but I'm wondering if you can give us a sense of if the improvements on the 12 mg cohort with one dose were those at the second dose, were those across all patients, or were there some patients who were maybe not responders who then became responders? How do we think about that incremental benefit from the second dose? Yeah, maybe I'll take that one, and actually, I'd like to know the same. As you said, the data is still blinded, so we haven't gone into a patient-level detail. What I can say is summary data, it's quite clear. A second dose, there is about 3 points-6 points improvement on the MADRS. And 3 points-6 points, when you compare that with SSRIs, SSRIs is about 2 points. It's at least 2x-3x more. So we definitely see an incremental benefit of a second dose. Are there specific patients who do better than others? Are there some who do not have a benefit of a second dose? It's probably likely, but we have to dig deeper into patient-level data for that. Got it. And then, just what do you think is necessary to be demonstrated at 12 weeks from a regulatory but also from a payer and patient perspective? I think if we see sustained responses, not traditionally with the antidepressants, you see 50% or less response rates. If even we see half of the patients maintaining a response up to 12 weeks, I think that will be robust data, and that would be acceptable. Maybe one last one. Just, if you can discuss the therapy component or psychological support component. Yeah. You know, how do you kind of suss out the impact of the therapy? You know, the placebo was actually the SSRI, and so how do we kinda think about that, and how will that kind of go forward? What learnings emerge in the phase III? So firstly, I'd say we did not do therapy. We did psychological support. I'm very careful about saying what we did because when a patient is receiving or under, experiencing a psychedelic effect, they are in the clinic. No therapy is possible. All you do is hand-holding. You know, you give them some reassurance. If they become anxious, you remind them of some techniques that you would have discussed with them previously. We follow the standard paradigm, which is prepare. Then, during the session, you sit with them and ensure their safety, and then follow up with, in follow-up, you debrief, which is actually not very different from what you do in clinical practice. If I am prescribing somebody an antipsychotic, before I prescribe them that medication, I tell them what to expect, what will happen with the drug, how to manage those effects, and once they've taken the medication, they come back for a follow-up. We debrief. We say, h ow did you do? What could you do better? So what we've done with our psychological support model, which is EMBARK, and this EMBARK was developed after a very careful review of what was existing out there in the community, and the varied practices for psychological support with psychedelic therapy. We follow a preparation up session, which can be done remotely. That's one of the efficiencies we've developed in the trial, that this can be done remotely. The only time that a patient needs to be with the therapist is when they are receiving the drug, so that reduces the resource burden. Even the follow-up or integration sessions, as they are traditionally called, they can be done remotely. We are going to carry this forward in our phase III as well. We have worked with an external partner called Fluence to adapt or rather evolve the EMBARK psychotherapy model into what we call as EMBARK CT or EMBARK for Clinical Trials. It's necessary to differentiate between what is ideal for clinical practice and what is appropriate for a clinical trial. We've taken that EMBARK model, and we have evolved it into something that is more scalable, can be deployed very easily, and does not place an undue burden on the resources at the site, which is what we are going to use in our phase III. Wonderful. Thank you very much. Sumanth Kulkarni from Canaccord. Thanks for hosting this event. First one for Dr. Knudsen. You've done some really interesting work on receptor occupancy and effect studies. With that as a backdrop, what do you think the potential is for buildup of tolerance or tachyphylaxis for these psychedelic molecules? Oh, what is the potential for? For tolerance buildup. Tolerance buildup. Oh, tolerance. Oh, yes. We've done also some longitudinal studies, PET studies, where we've looked at the downregulation. So expectation is that if you stimulate a receptor, you will downregulate. And we've actually seen, some of our data have indicated that the degree to which the 5-HT2A receptor downregulates is associated with the long-term beneficial effects in mindfulness in healthy individuals. So it seems to be actually a good thing that you have some sort of downregulation, but it's very minor. It's not a major downregulation we see. And, my guess is that with such a brief exposure, then after, say, six weeks, I think you'll be back to normal. But that is, of course, something that can be investigated, but I'm not expecting to see any major downregulation or tolerability. Then for the company, a couple of questions. How do you explain what you saw on the 12 mg and the 16 mg in terms of the scales? Is it simply a statistical quirk because there were too few patients in this trial? Or could it be something else, like the differences in background medication that people on 12 mg versus 16 mg were? Yeah. So you probably answered yourself, Sumanth, there. We had about 24 on 12 mg and 12 on 16 mg, so it's maybe a statistical quirk, but it will be, as Patrick mentioned earlier, it may be it will be actually interesting to go down to patient level and see what background SSRIs or SNRIs those patients were on and whether that modulated their response to treatment. What I can say is that 16 mg is quite an intense experience, 12 mg is intense, but is the preferred dose, which is what we are planning to take into our phase III. As you go to the FDA next, interaction with the FDA, what are some of the, I guess, places where you think there could be pushback from the agency, given what you've seen in terms of your trial design? Is there any potential for the FDA coming back and saying, this is something you need to do differently? Yeah. So one thing that we will do differently is, we will keep the placebo arm as a pure placebo arm. So right now, we have, the placebo group receiving placebo at day one or baseline, and then switching to active at week three. That is not something we will do in our phase III, which actually aligns very well with what the FDA have recommended in their draft guidance on psychedelics. So we anticipate no pushback because, as of now, our clinical plan for phase III aligns perfectly with what the FDA have suggested. This is Elaine on for Charles Duncan at Cantor Fitzgerald. As you've shown earlier, COMP360 achieved a placebo-adjusted difference in MADRS score of about 7 points, whereas CYB003 showed 14 points. Would you attribute this to patient selection, like MDD versus TRD, the implementation of a second dose, or differentiated PK profile or bioavailability? So maybe I can make a few comments on that. Obviously, patient population is different between COMP360 and CYB003. COMP360 was studied in treatment-resistant depression patients. At the beginning of the program, we made that decision not to pursue treatment-resistant depression. That, to me, is a different type of depression. Maybe Dr. Fava has different views about it. But certainly, t he fact that we started with inadequate responders, these were not first-episode depression patients. They were patients who were already on an antidepressant medication. Despite that, they had scores of, on an average, 30, 33, which is moderately severe depression. That's one key aspect. And again, the strategic decision we took in the beginning to administer two doses rather than one, to make to give patients the best chance of improving, that is probably a differentiating factor as well. Yeah, I can just add to that. I think obviously the 14-point reduction was at a single dose, of course. Yeah. But preclinically, with the deuterated compound compared to non-deuterated compound, we did see an increase in bioavailability, and we saw an increase in brain concentration ratio, brain to plasma. So it was clear to us that more of the molecule was getting into the brain and out of the periphery. We also, of course, saw robust psychedelic effects at 8 mg, and we pushed the dose all the way up to 12 mg and 16 mg. So it may just be that we pushed the dose higher, and we got more of it getting into the brain. It's hard to tell at this point exactly which of those elements is playing into it, but it's something along those lines. One for Amir over here. Hi, Amir Tirosh from Stockbox Securities. For Dr. Fava. Dr. Fava, you mentioned that in the STAR*D trial, you've seen a 30% remission rate. When you look at the package insert of, recently approved, antidepressants, they don't talk about remission rates. Why do you think that is? That's a great question. Because it's a higher bar. It is. You know, the response is easier to achieve the remission. Think about the, for example, in the the CYB003 trial, patients had an average of 30, 33 on the MADRS. To get to 10 or less, you need to go down by 20, 25 points, and that's much harder than a response, which is a 50% reduction. From 30, you achieve response by decreasing the score by 15 points. So in general, I would say, most pharmacists don't really focus on remission, which is the ultimate goal of treatment, but focus more on response because, you know, it's, of course, a easier clinical outcome to achieve. Right. Right. So what do you see as a key difference between, clinical trials that examine a daily pill regimen, like Trintellix or Auvelity, versus, a psychedelic, clinical trial, and we compare drug effect to placebo? The placebo effect in conventional trials seems to be much higher. Why do you think that might be? Well, this is something kind of it's a new territory, right? Because, you know, one thing that we know from trials of standard antidepressants is that the placebo response tends to occur in the first half of the trial, regardless of its duration. Most of it, like 80% of the improvement of placebo, is in the first half. So if you do a six-week trial, most of the improvement, it's in the first three weeks. But that's also based on the fact that you take a medicine every day. So you have to think about that you're doing something every day to get better. So, taking a pill twice in six weeks, a placebo pill, may have a different effect. That is that you may not have the same level of improvement, and so that's something that we need to understand. You know, that said, you know, we have seen robust improvements with placebo, even with intermittent dosing, like in the case of esketamine. You can never underestimate the placebo, because you always want to make sure that you're trying to minimize. But thus far, I think that the daily placebo has a more predictable, robust improvement than intermittent. Thank you. Thank you very much. Okay. Hi, Matt Vanessa here for Jim Molloy at AGP. I just had a question for the company. First of all, congratulations on the clinical trial readout. I just wanted to dig more into that six-week endpoint, and I know in the control versus the placebo group, you guys gave a dose of CYB003 to the placebo group at the three-week mark, and then I just wanted to know how that affected the placebo group by the six-week endpoint, and I wanted to confirm my assumption that you couldn't compare the placebo group to the active group anymore because you gave them a dose of CYB003. Yeah. So at three weeks, it essentially becomes an open label, and what you are looking at, at 6 weeks, is in those patients who received an active dose at baseline, what is the effect of a second dose? Does it improve, the response which we obviously saw? There's an incremental benefit of a second dose. What we also did was look at the patients who received placebo at baseline and an active at, week 3, and that was by design. We planned to use, placebo patients as their own control. And when we do that, between week three and week six, there's roughly about a 14-point improvement in patients who, were assigned placebo at baseline. So I say this, to folks in the company, that one dose of CYB003 is worth about 14 points on the MADRS. That's the improvement we saw. Okay, got it. And then I just had another question about the SSRIs. So, you guys have the SPL026 trial, where you had some patients with SSRIs, and a few didn't have SSRIs. And you saw a much greater improvement as well as a durability of remission in the SSRI versus the non-SSRI group. And are you going to take this into account for your phase III trial design, and do you expect to see similar results when the patient data from CYB003 gets unblinded from the phase III? Yeah, I mean, everybody in the CYB003 study was either on an SSRI or an SNRI. The SPL026 came as a surprise to us. I think that was the question that Dr. Knudsen was alluding to earlier in the industry or in the sector, that do SSRIs blunt the response of psychedelics? Is there any interaction between a psychedelic and SSRI? That was the main reason that study was done, and we also looked at efficacy, and we were quite pleasantly surprised to see such a robust response for SPL026 on top of SSRIs. When we dig into patient level data, we will obviously, for CYB003, separate them into SSRIs and SNRIs by drug class and see if there's any difference, and we plan to do the same for phase III. In phase III, we will allow patients to remain on stable doses of their antidepressant medications. There will, of course, be some exclusions, like monoamine oxidase inhibitors. We don't want that. But otherwise they'll stay on their treatment. It just doesn't make sense to take people off their drugs, off their medication. The discontinuation syndrome with SSRIs probably may dampen or reduce some of the benefits we see, so we don't want to do that either, and practically, it just makes sense. And clearly we see from the results that those who are on SSRI, there is no impact or no dampening of the effect, so we plan to continue that in phase III. Okay, and just finally, for the phase III, do you plan to only recruit patients on SSRIs or SNRIs already, like you did for phase II? Yes. Okay, awesome. Thank you, guys. Thank you. Maybe one final question over here. Hi. Dan Tangone, Oppenheimer. Just a question for Dr. Knudsen. Since the patients in this trial are on background SSRI, in the light of this data from the 12 mg and 16 mg, could you talk about how you think about receptor occupancy and particularly the potential for individualized dosing in patients? Yeah, if I understand you correctly, you're asking about receptor occupancy with o n SSRIs, and to the best of my knowledge, it hasn't really been examined in people. We haven't certainly done it. It's been done in rodents, and what you see there is a downregulation of the 5-HT2A receptors, which is modest. It's not very large. But we also have some interesting data suggesting that a slight downregulation can actually be beneficial for the effects. You have a more pronounced psychedelic experience, which may be sort of counterintuitive, but that's actually what we've seen in a fairly large sample of individuals that we have PET scanned and also given psychedelics. So there are some interesting aspects here that we need to understand even better. But I think actually that could be one of the explanations why those individuals, those patients who are on SSRIs, actually also benefit quite well from the psychedelic interventions, and that's why I think it could be interesting to look at a combination therapy, and we'll see for the phase III trial what happens. Thank you. Just a very quick one for Amir. You mentioned that even half of the effect size seen here would be a win in phase III. Could you just help us understand some of the variability from this data set that makes you consider this? Yeah, so it's a small sample size, like 12 participants per cohort, three cohorts, so that's 36. And you're bound to see limited variability in such a small sample size. There were two sites. When we go to phase III, we'll be expanding to multicentric, multinational clinical trials, and that adds to the variability as well. When designing our phase III, what we have done, so we are in the process of finalizing that protocol right now. What we did was go into the literature and look at what sort of variability has been seen in the past with other clinical trials in depression. So the standard measure for that is standard deviation of the effect, and we see about 10 points-12 points of standard deviation on the MADRS. We took that into account. We take into account what effect we've seen in our phase II-B. We cut it by half, and that's how conservatively we design our phase III. So we've taken that into account, and we believe that it will give us the results that we are expecting. Thank you. Great. Thanks, everybody. Thanks, all of you, for your engagement this morning. And, of course, thank you to our panelists, Dr. Fava and Dr. Knudsen, for your insights. Thank you very much. We appreciate all of your interest and your support of Cybin, and we look forward to sharing future progress across our programs and the development pipeline. More to come in just the next few weeks. So thank you all very much for attending, and have a wonderful day. Thank you.