Cybin Inc. (HELP) Earnings Call Transcript & Summary

[Operator Instructions]

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 as 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 with the current standard of care.

Thank you so much. It's a pleasure 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. I had the opportunity to service one of the 3 principal investigators for the largest clinical trial ever conducted in depression cost study. In a study trial, we treated everybody with an SSRI for 12 weeks and with support, all kinds of things to help the patients. And the outcome was that only 1 in 3 patients remitted after 12 weeks. So, if you think about it, 3 months of treatment and 1/3 of the patients remit. And half of those remitted between week 6 and 12. So standard at the presence, unfortunately had a significant limitation or limited efficacy. So 1 in 3 patients remit, but also very slow offset of effect. So, the efficacy, it takes time. What we saw in Amir's presentation was a very, very rapid effect of a single administration and remission rates with the 12 milligrams of 80% at 6 weeks. So, you can't contrast if you wish because those organization, but very, very promising results. The other limitation of the current [indiscernible] based therapies is related to tolerability. It is you have to take these medicines every day. And they're not devoid of side effects. That is approximately 20% of the patients will gain weight on the SSRI. 20-25% will have sleep disturbances. There will be 20%, 25% of the patients that have cognitive difficulties probes with memory or executive function as a result of the treatment. And, in addition, a significant proportion, 15% to 20%, they also experienced a worsening of anxiety. So, if you think about it, daily treatment for 3 months with an efficacy of a 33% remit rate and side effects that could be quite bothersome versus a model of care of single or maybe 2 administrations to obtain effect rapid and sustainable. So, I think that from my perspective, and this is an important thing to keep in mind, [ these are the ] level 2, we tested augmentation. Remember, in this trial, patients were augmented with CYB003. And [indiscernible] paper on the outcome of augmentation and at 12 weeks, only 30% of the patients remitted at 12 weeks. And again, even when you look at augmentation strategy such as proprietary augmentations of SSRI, it takes a very long time. Because if you look at that curve in that paper, it's a curve that show, there's no steepness at all. That 30% remission rate at 12 weeks is achieved almost to the linear progression. So that's the reality; context in which we have to look at the development of compound such as CYB003. And the reality that our only 1 in 3 patients will be to the first under the present 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 so much, Doug, and thank you for inviting me to come here long 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's just a single dose, 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 a sense of what we currently think is the mode of mechanism. But first, a little about the nomenclature. We talk about hallucinogens. And often, people refer to psychedelic very broadly also including Ketamine and NMDA and others that act in a different way. So today, we'll be talking about the [sericogenic] psychedelics, which are the classic ones. And these psychedelics include LSD, psilocybin, and DMT, among others. And they all act by stimulating the brain's serotonin 2A receptors. We know that for a fact because if you block those receptors, there is no psychedelic experience. This is a PET study from my lab and shows the distribution of 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, etc., of drugs such as 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 and we looked at the association between how the brain 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? And here are the data we found: when we measured plasma psilocin levels and brain receptor occupancy, we saw this very nice curve that was 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. 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. 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? And firstly, and this is probably what many psychologists would posit, that these psychedelics induce a mystical type of experiences such as unity feeling, at one 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. And it is believed that, 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 disorders. So that's a more psychological way of explaining it. But when we start to look more into the molecular mechanisms of these compounds, and here, 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 reflect quite nicely how people perceive it in the long run. Now another theory is that the psychedelics promote structural and functional new plasticity in the prefrontal cortex. That is the front part of the brain, which enables 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 on the left, you can see a nerve cell with a contact point 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 new plastic 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. This is the data here showing on the left that you can see at the age of the rodents that are 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 will be able to 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 of this theory, it's been said that the duration of the psychedelic experience is also related to how long this window is open. Now I just want to end 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 could see that. Those are placebos, they don't change their synaptic density. But those who are treated with SSRIs, they 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.

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 going to stop with you. What are the key elements or characteristics of a well-designed study involving psychotic drug candidates?

Yes. 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 expects. That is also relevant for a psychokinetic study. Now of course, there are challenges with psychedelics, but they are not novel. I'll maybe give some examples of why I think they are not novel. So key elements like a control group, blinding, using a good rating scale that is fit for purpose. But also for psychedelics, you have the added requirement of ensuring patient safety and this 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 the defense mechanisms, which are maladaptive. And even if those mechanisms were maladaptive and they were serving to continue their depressive symptoms or symptoms of a 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, these placebo controls, 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. People question the utility of a placebo because with psychedelics, 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 effect. 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 for schizophrenia. We immediately knew on the 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. Sedative, if not give somebody sleep medication, it's quite apparent who's receiving sleep medication and who's not. So, 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 what rating scale to use, how to measure the effect of the psychedelics. Of course, the FDA has 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 psychedelics, there are other effects that they induce which maybe are not captured by these traditional ratings because 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 psilocin 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.

Yes. Thank you for that. It's fascinating to me that we see placebo patients scoring high on the visual analog scale. 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 [indiscernible] to the trial that you reported are going to be critical. So, for example, in this trial, we ensured that patients' quality was really excellent because, in addition, the patients had the diagnosis and severity, the treatment history required through what we call the safe prediction view, and the ideology is shown over and over, be to do risk files in Phase III where we're making sure rating into the trial. So, in my mind, it is an important deal to all the other methodologies that Amir has outlined.

Yes, I think that the safer tool has been very helpful, and I assume we'll continue to use that going forward. Dr. Knudsen, and then maybe coming back to your presentation. What are the key differences between how psychiatric drug candidates work versus the current standard of care like SSRIs? I mean, what could be the underlying mechanisms that 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. 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.

Dr. Fava, maybe as you think about the current treatment landscape, what are you think the most pressing issues or the most pressing challenges, the greatest unmet needs only come to treating depression and anxiety today?

To answer your question, I think that in my view, the modest efficacy of standard therapies is a big issue because imagine if you went to the doctor, the doctor said, "Look, I'm going to prescribe this drug that will take 2 weeks to work, and you have a 33% chance of achieving remission." I think you would be very unhappy with that. So, the more tailored approach is needed here. The fact that you have to take pills every day and they have side effects, which are deterrents to treatment, people end up discontinuing, leading to relapses or recurrence, are the main issues we face.

So, would you say that based on the results we're seeing so far, psychedelics have the potential to address some of those unmet needs, some of the challenges?

Yes. I mean, certainly, the remission rate is higher than the 30% we typically see with our existing treatments.

Okay. One for you, Amir. So coming back to study design a bit. Can you go over again why you chose to administer 2 doses of CYB003 rather than just a single dose?

Yes, 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. People, by nature, conditions like depression or relapsing and remitting illnesses. So, to expect that one treatment will cure a patient of their condition is honestly being a bit stupid. 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 wearing off around 4 to 6 weeks. And we wanted to preempt that decline in the benefit that was achieved after a single dose. So, 3 weeks, we said 2 doses, 3 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 6 months. Of course, in this study, we'll evaluate up to 3 months. In our pivotal studies, we are going to look at 6 months for durability, but that second dose was essentially to one to 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 the other drugs which have a similar mechanism of action. So, for example, things like Ketamine. Ketamine is not a psychedelic, but the downstream effects of ketamine are similar to the 5HT2A downstream effects from a biological point of view. And you see about 4 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 the response rates.

I agree. It's clear from these results that the second dose really improved both response and remission, which is the ultimate goal regardless of score changes. 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 we can do for those patients as well. And 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 one of the worst types of headaches you can have. And some patients even have a more chronic version of that, usually comes in attacks. And anecdotally, people have talked about psychedelics as something that has 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.

Yes, it's unusual for molecules to have such broad application, isn't it? One in for you, Amir, and as you're thinking about translating these results, this effect size into Phase III. What are the challenges? What are your expectations?

Yes. I mean, the setup we have for a psychedelic study is different and yet not too different. And it's similar, for example, to 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 an increase 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 you see in this study. Even if you get half of it in our Phase III study, that will be at least 3 to 4 times 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 have to manage expectations with patients with expectations; you see placebo effects. And with the placebo effect, you start losing the difference. Many studies 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 many 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 prefer to work from home and not really commute to the office like 3 hours a day. It's the same for patients. So we are addressing some of those challenges. And yes, 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. And then site selection, sites that are motivated and continue to recruit.

Yes. I mean, your investigator or your site is the single most important factor in the success of the study, and you need people who are, who, 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 challenging to handle some of the symptoms. As I said, they induce non-ordinary states of consciousness, which can sometimes put people off.

Yes. Okay. So moving then maybe from study challenges to more 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 there's going to be a challenge for all health care systems to improve and how the industry, because some of the current settings may not be able to deliver. So there will be some specialized settings but I see there's 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 taking them because again, the sites approved and then say how long we want to be able to strategically already how we integrate them, what spaces we adopt for the delivery of care, how we're organizing.

Yes, 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, 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 specialist clinical setting is needed. So, we thought about some of those things. I think that definitely helps with adoption we have.

Yes. But also we see in medicine that when there is a groundbreaking treatment, the health care 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 health care system will adopt.

We're already seeing that to some extent with SPRAVATO, I think, and 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. So maybe one last question for Dr. Fava, Dr. Knudsen. When you look at this data, we obviously find it very compelling and exciting. 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 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. So I found that very compelling. It was great that you allowed for that.

And then last thing over to you, Dr. Fava, for any final comments.

I agree. I think fundamentally, our patients that had over 30 or more than 30 hours of therapy. So these were typically individuals who had a remarkable improvement. So that was really impressive.

Thank you. Thank you to all of our panelists. Now just towards the end of the session, just going to hand over to questions from the floor.

Couple of questions today. First, for Dr. Fava, I wanted to revisit some of the comments earlier. I wanted to get a sense from you how Envision psychedelics being administered in the real-world setting, specifically with CYB003 based on the data you've seen so far that this data has reconfirmed in Phase III, what proportion of patients with moderate to severe MDD would you envision CYB003 ultimately be appropriate for being prescribed for?

That's a great question. If you say CYB003, the results are confirmed that we have a very robust efficacy but efficacy accompanied by our [indiscernible] with a single or to these patients, this will change dramatically our partner. So normally, let's say, returning to our passion today, you guys are of the main, you're seeing 2 weeks previous player to continue the treatment, and then just then we continue to wish of particularly to have prior efficacy, you may be on definitely for very long periods of time were relative to frequent basis to monitor both facts and efficacy. And sustainability of treatments is very long, how often people would be for that would be a different drastically from the current mess and the, so patients may need to come in once or twice to site and then the [indiscernible] longer medicine. So I think that as a field, we'll have to say how are we going to the different patients like this opportunity because right now for in the fact that our access to care totals, we have a shortage in the United States of over 40,000 psychiatrists, in [indiscernible] according to the government. So with a shortage of providers of their size, the polite or the modesty of the efficacy of the treatment and the fact that they require frequent visits. If you change how we live our care, and we have much efficacy who hopefully will be able to provide a test this to patients.

Yes. That's helpful. And then maybe a few for the company. Just the first is, you understand the patient data, but I'm wondering if you can give us a sense of if the improvements on the 1-milligram cohort with one dose, were those at the second dose for those across all patients were there some patients who were maybe not responding to responders. What do you think about that incremental benefit from the second year?

Yes. 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 is quite clear. A second dose, there is about 3 to 6 points improvement on the MADRS. And 3 to 6 points when you compare that with SSRIs. SSRI is about 2 points, it's at least 2 to 3x more. So we definitely see an incremental benefit of a second dose. Are there specific patients do better than others? Are there some who do not have the benefit of a second dose? It's probably likely, but we have to dig deeper into patient level data for that.

And then just what do you think is necessarily demonstrated at 12 weeks were regulatory but also from payer patients with factor?

I think if we see sustained responses, not traditionally with antidepressants, you see 50% or less response rates. If even we see half of the patients maintaining a responses 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 in our cytological support component, how do you suss out the impact of the therapy. The placebo was actually SSRI. And so how do you think about that and how that go forward? What learnings were Phase III?

So firstly, let's 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 handholding. You give them some reassurance if they become inches, you remind them of some techniques that you would have discussed with them previously. We follow the standard paradigm which is fair. Then during the session, you sit with them and ensure the safety and then 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 follow-up, we briefly say, how 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 very practices for psychological support with psychedelic therapy, we follow up preparation 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-ups, even the follow-up or integration sessions as they are traditionally called, they can be done remotely. Then 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 psychotheraphy model into what we call as EMBARK CT or EMBARK for clinical trials, it's necessary to differentiate between is ideal for clinical practice and what is appropriate for a clinical trial. So, 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.

First one: 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 the buildup of tolerance or [indiscernible] for these psychedelic molecules?

What is the potential for tolerance, buildup tolerance? Oh, yes, we've done also some ideal studies, PET studies where we looked at the downregulation. The 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 5HT2A 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 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, 6 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 of tolerability.

And then for the company, a couple of questions. How would you explain what you saw on the 12 mg and the 16 mg in terms of the scale? Is it simply a statistical quirk because there are 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 works.

Yes. So you probably answered yourself, Sumant, there. We had about 24 on 10 milligrams and 12 on 16. So it's maybe a statistical quirk, but it will be, as Patrick mentioned earlier, maybe 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 milligrams is quite an intense experience. 12 milligrams 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?

Yes. 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 1 of baseline and then switching to active at week 3. 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 psychedelic. So we anticipate no pushback because as of now, our clinical plan for Phase III aligns perfectly with what the FDA has suggested.

This is Elaine on for Charles Duncan at Cantor Fitzgerald. As you've shown earlier, C360 achieved a placebo-adjusted difference in MADRS score about 7 points for 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 COM 360 and CYB003. COM360 was studied in treatment-resistant depression patients. At the beginning of the program, we made that decision not pursue treatment-resistant depression. That's, to me, is a different type of depression. Maybe Dr. Fava has different views about it. But certainly, the fact that we started with inadequate responders, these were not first episode depression patients who were already on an antireso 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 2 doses rather than one to give patients the best chance of improving. That is probably a differentiating factor as well.

Yes, I can just add to that. I think obviously, the 14-point reduction was at the single dose, of course. But preclinically, with the deterred compound compared to the non-generative compound, we did see an increase in bioavailability, and we saw an increase in the brain concentration ratio [for into] plasma. So it was clear to us that more of the molecule is getting into the brain and out of the periphery. We also, of course, saw robust psychomimetic effects at 8 milligrams. And we pushed the dose up to 12 and 16. So it may just be that we pushed the dose higher, and we've got more of it getting into the brain. And it's hard to tell at this point exactly which of those elements is playing into it. Is something along those lines.

Dr. Fava, you mentioned that in the [indiscernible] trial, you've seen a 30% remission rate. When you look at the package insert of recently approved antidepressants, they don't talk about revision rates. Why do you think that is?

Because the higher it is, the response is easier to achieve the remission. I think about the, for example, in the CYB003 trial, patients have an average of 30-33 to get to 10 or less, you need to go down by 20, 25 points, and it's much higher than response is a 50% reduction from 30 response by decreasing the score and points. So in general, I would say, most part of users don't really focus our mission, which is the optimal treatment but focus for resource because it's, of course, an easier clinical outcome to achieve.

Right, right. So what do you see as a key difference between the clinical trials that examine the daily pill regimen like Trintellix or [ Ovality ] versus a psychedelic clinical trial and big impaired 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 low tariffs are right because one thing that we know from trials [we have seen] the questions is the series that to recur in the first hospitals of trial regardless of its creation. Most of, like 80%, of the growth in placebo is in the first half. So if you do a 6-week trial, most of improvements, it's in the first week. But then also made on the fact that you take a medicine every day. So you have to think about you do something every day to get better. So taking a pill is in 6 weeks, placebo pill, many of the different effects that you may have had the same level of improvement. And so that's something that we need to understand. That said, we have seen robust improvements with placebo, even with deteriorating like in the case of [Indiscernible]. So you always want to be explored that you try to minimize. But thus far, I think at the day has a more predictable robust improvement than internet.

I had a question for the company. First of all, congratulations on the clinical trial. I just wanted to dig more into that 6-week endpoint. And I know in control is the consumer. You guys gave a dose of CYB003 to the placebo group at the 3-week mark. And then I just want to know how that affected the placebo group by the site endpoint, and I wanted to confirm my assumption that compared to the placebo group, it's an active group anymore because you gave them a…

Yes. So at 3 weeks, it essentially becomes an open label. And what you are looking at 6 weeks is in those patients who received an active dose at baseline, what is the effect of a second dose? Does improves the response which we obviously saw? There's an incremental benefit of a second dose. What we also did was look at the cation 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 3 and 6, 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 mattress. So that's the improvement we saw.

Okay. Got it. And then I just had another question about the SSRIs. So you guys have the SPL006 trial, where you had some patients with SSRIs, few didn't have the right end, you saw a much greater improvement as well as building of remission, meaning the SSRI presence? 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 is [indiscernible]?

Yes. I mean everybody in the CYB003 study was either on an SNRI, the SPL-026 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 blend the response or 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 SPL on top of SSRIs. When we dig into patient level data, we will obviously for CB3, 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 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 of 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 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 in only approved patients on SSRI or SNRI already, but addition Phase II?

Yes.

Maybe one final question over here.

Just a question for Dr. Knudsen. Since the patients in this trial are on a 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 patients?

Yes. If I understand you correctly, you're asking about receptor occupancy with on 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 the downregulation of 5G 2A receptor some 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 affects you have a more pronounced psychedelic experience, which may be 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. So I think actually, that could be one of the explanations why those individuals, those patients who are necessaries 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 and what happens.

Just a very quick one for Amir. You mentioned that even half of the excise in 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 those?

Yes. So, it's a small sample size, 12 participants per cohort, 3 cohorts, so that's 36. And you're bound to see limited variability in such a small sample size, there were 2 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 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 to 12 points of standard deviation on the mattress. We took that into account. We take into account what effect we've seen in our Phase III. 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.

Great. Thanks, everybody. Thanks all of you for your engagement this morning, and 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 for Cybin, and we look forward to sharing future progress across our programs and 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.