All good? Welcome to the Cantor Global Healthcare Conference. I'm Pete Stavropoulos, a biotech analyst with Cantor. With us, we have Cybin, a company we cover. I'm pleased to introduce Amir Inamdar, the Chief Medical Officer. Welcome. Thank you, Pete. Let's start off with a brief introduction of yourself and a description of the company for those not familiar. Absolutely. Firstly, thank you for inviting me here. It's a pleasure to be here. My name is Amir Inamdar. I'm the Chief Medical Officer at Cybin. I've been with the company for about four years now. My background is in psychiatry. I trained as a physician, psychiatrist, and as a pharmaceutical physician. I've been doing drug development discovery for almost 25 years now, mostly worked in big pharma, but have been more recently with Cybin is an early-stage biopharmaceutical company working on areas of significant unmet medical need in mental health disorders. We've got a range of compounds which are from the psychedelic class, and we are developing them as novel differentiated compounds that can be given intermittently and can result in long-lasting, durable change. These molecules address not just the symptoms, but the underlying maladaptive patterns of thinking that are often at the root of these mental health disorders, which is how we see durability of effect with these compounds. We've got two programs, CYB003, which is a deuterated psilocin. Psilocin, as you know, is the active drug in psilocybin. This is already in phase 3, up and running. It also has breakthrough therapy designation from the FDA and is being developed in major depressive disorder. Closely following that is our CYB004, which is a deuterated dimethyltryptamine or DMT, which is being developed in the treatment of generalized anxiety disorder. We're just about to finish our proof-of-concept study and remain on track for delivery of top-line data early next year. OK. Just your background, I'm just curious, you know, what type of drugs were you developing at these other pharmaceutical companies, the larger ones? Yeah, I've always been in psychiatry and mental health, except for a brief period when I went onto the dark side in respiratory medicine. I absolutely hated it. I have mostly worked in depression, schizophrenia, bipolar disorder. I've worked in all stages, right from identifying new mechanisms to early drug candidates, preclinical discovery, taking them into man. Early phase is what I love doing most. I've got the breadth of experience right up until marketing. Most recently, I worked on an antipsychotic at Takeda, which I was clinical lead for the team that got marketing authorization in Europe. That was Latuda or lurasidone, which is now a billion-dollar molecule. I'm just curious, how are you finding moving into a completely new class of drugs, like psychedelics? I am absolutely thrilled. We've not really had any innovation in mental health for over 70 years now. Since the first discovery or since the first time antipsychotics and antidepressants were administered to patients with mental health disorders, nothing new has happened. We've been recycling the same mechanisms over and over again. It's been just those three monoamines, you know, serotonin, dopamine, norepinephrine, reuptake inhibitors. We've also been tackling the symptoms of an illness. It's like you have an infection and you give them Tylenol to manage fever, but you're not really doing anything about the infection. You need to give them an antibiotic for the infection. That has not been the case in psychiatry. It has been always symptomatic treatment. As a clinician, when I practiced, I saw this in my patients. It was what we used to call revolving-door psychiatry. Patients come in, they get symptomatic relief. It doesn't last for long. They relapse, come back again. It continues over and over again. This is what we saw in the companies that I worked at as well, symptomatic treatments. What psychedelics offer us is a very unique opportunity where you can change the course of illness. I do speak with some trepidation, because when I say that these are literally disease-modifying agents, we've never talked about those in psychiatry and mental health. These will change the way we treat patients with mental health disorders. These will rewrite the textbooks of psychiatry. I'm really thrilled and excited and look forward to potentially bringing these to people who need them most. OK. Moving on, CYB003, this is your deuterated psilocin. What are some of the properties that differentiate it from the non-deuterated form and, more importantly, competitor molecules like the parent before it's metabolized into psilocybin? Yeah. Well. CYB003, as I said, is psilocin. It's not a prodrug. What that does is by giving the active molecule, you take away some of the uncertainty around the conversion of the parent to the active drug. It gives you certainty with dosing. If I'm giving 12 mg, I'm giving 12 mg. If I'm giving 16 mg, I'm giving 16. With deuteration, we've tried to modify some of the physicochemical properties of that drug. More importantly, deuteration gives us intellectual property. It retains all the fundamental pharmacological properties of psilocin, but gives us intellectual property and protection. We are still collecting data on how the impact will be on the duration of the actual experience. We have early data from our phase 2 study, which indicates it'll probably be a slightly shorter experience compared to psilocybin. It may be around four to six hours compared to the longer eight to 10 hours with psilocybin. That remains to be seen in our larger phase 3 trials. You have chosen adjunctive MDD rather than a monotherapy MDD approach or strictly TRD, like many of your competitors are. Can you just walk us through the key commercial and regulatory rationale behind that choice? Why do you think this is the right indication for the real world? Before that, I'll walk you through the scientific rationale. This was a very conscious decision at the time. When everybody was in this sector going after the more difficult-to-treat indication like TRD, we decided that we will not make it more difficult for ourselves and for our clinical trial. TRD patients are a different class of MDD patients. It's a different severity of MDD patients, and they do not respond to multiple treatments because of certain characteristics in these patients. For example, you see a lot of comorbidity in patients with TRD. They've tried many different drugs, of course, so they have a history of not responding to treatment. On the other hand, if you try to treat patients earlier in the spectrum, they are relatively—no depression is easy—but they're a relatively easier population to treat. We took that active decision to treat patients earlier in their treatment cycle. What will happen in the clinic? Clinicians will pick and choose medications and treat whichever indication they want within the spectrum of MDD. I'm confident that once this gets out into the market, there's no reason why it won't be used, maybe off-label, for the treatment of resistant depression. We also actively decided not to go for monotherapy, unlike what everybody else was doing. The decision to dose as monotherapy has been due to some misplaced skepticism or concerns around the safety of dosing together with ongoing medication. This is largely to do with the perceived threat of patients getting a serotonin syndrome. We looked at the literature. We looked at the science. There was nothing really to suggest that this was even a theoretical risk with SSRIs or SNRIs. The only theoretical risk is with the monoamine oxidase inhibitors. Even then, we've not seen any reports of patients being given psychedelics with monoamine oxidase inhibitors ending up with that condition. We said it doesn't make sense. If you want to give monotherapy, you've got to wean patients off their antidepressant medication. That takes time. It takes almost four weeks in most cases, and then you risk a discontinuation syndrome, which is a well-described entity with antidepressants. There's no reason to complicate. When there's no reason to stop patients taking their antidepressant medications, we decided that this was the best way to move forward and go with adjunctive rather than monotherapy. OK. We held a panel yesterday with two psychiatrists, one of them heavily involved with the development of ketamine and the other one involved with a lot of psychedelic clinical trials. When we asked them about MDD versus TRD, number one, they pointed out that even though the numbers may not seem at the surface as really impressive in terms of the effect in TRD, they note when you look at the STAR study, and you have those patients that are on the third line, response is at least double that for the psychedelics. They stated that as you go earlier in the lines of treatment, you're probably going to see a greater effect. Perhaps. Absolutely. That is one of the things that factored into our decision when we said we'll treat inadequate responders and we'll stay away from TRD patients. It gives us the best chance of showing a positive effect. We all know these drugs work, right? These drugs work, we know, because there's data out there, not just from clinical trials which are being done systematically now, but from historical use in traditional settings. Yes. To me, then all of these clinical trials are confirmatory trials. They're not exploratory trials. Even with the fact that something works, it doesn't necessarily mean you're going to show a positive effect in a study. Of course. You may get an answer you do not like if you ask a question. We give ourselves the best chance of success. We study it in a population that has the opportunity to show the largest effect size. If you want to look for a small effect size, then, of course, you need large clinical trials. That creates challenges in terms of operationalization, you know, doing those phase 3 trials. There's a lot of competition out there. These are difficult trials to do. Why do it when you could do it in an easier manner? Got you. You did conduct a phase 2 study. Just go over the study design and the efficacy outcomes there. Yeah, so we actually did a hybrid study design where we, in part of that study, gradually escalated the doses in healthy volunteers and found a dose that we believed was going to be efficacious. Then we enrolled and administered this drug to patients with MDD. The way the study was designed was at baseline, patients were randomized to either CYB003, an active dose of CYB003, or an inactive placebo. They were followed up for three weeks. At the end of three weeks, which was the primary endpoint, we assessed their response on the MADRS scale. We did something very interesting at three weeks, which is we dosed everybody again. Those who received placebo at baseline actually got an active dose after three weeks, and those who received active got a second dose. In this way, we were able to ask many questions. You know, what's the effect of one dose? What's the effect of two doses? Do patients who receive placebo at baseline, when they get an active dose, do they respond? Those who get a single dose at baseline with a second dose, is there an incremental benefit? We managed to ask quite a few questions in a small number of patients. After the second dose, we followed them up again for three weeks, which was a secondary endpoint. What we saw was something very remarkable. With both the 12 mg and 16 mg doses that were the active doses in that trial, we saw a response, as measured by MADRS, in change from baseline of approximately 14 points. Of course, when you put that into context, SSRIs normally have a response of about two to three points. Esketamine, which is Spravato, which is one of the most effective drugs in TRD, has an effect of about three to four points. This is a substantially large effect, and this effect was maintained. With the second dose, we saw almost six points improvement in symptoms, and this was maintained up to a year. At the request of the FDA and after discussions with the FDA, we put in place a long-term follow-up of those patients who had completed six weeks. We followed up a significant number of them. What we saw at one year, almost 71% of patients who received the 16 mg dose, they were in remission. That's a single-digit MADRS score at one year after just two doses. OK, it looks like it has substantial efficacy in this population. Do you think it actually helps that these patients remain on, or do they remain on their antidepressant? Their standard of care? Yeah, I think it helps. At least as far as clinical trials are considered, you've got a placebo arm where you don't give patients anything. From an ethical point of view, I'm comfortable in the fact that even in the placebo arm, patients are getting some treatment. I mean, those treatments are doing no harm. They may be not as efficacious as we want them to, but they are doing something. That does not leave the patient in a way unattended and not receiving anything. OK. Let's move on. You have a phase 3 Paradigm program that consists of two controlled studies. The two trial designs differ. Can you just sort of discuss their designs and what is each trying to sort of address, including the concerns of the FDA when it comes to psychedelic-based therapies? Yeah. So because CYB003 has BTD, we've been able to engage with the FDA regularly and we've discussed the study designs with them. The agency is on board. We've taken their suggestions, and we've designed the phase 3 program, which, as you said, consists of two short-term studies and a long-term extension. The first short-term study, which is already up and running, is Approach. It's a two-arm study. It compares a 16 mg dose of CYB003, two doses given three weeks apart, with an inactive placebo. Of course, we will get data on efficacy from this study. The placebo arm is also important to get placebo control safety data. This is, again, in line with the agency's guidance that they published a few years ago. The second study is Embrace, which is a three-arm study, which has a 16 mg active dose. We've got an intermediate 8 mg dose and then a placebo arm. That's three arms in Embrace and two in Approach. Altogether, it's about 550 patients across those two studies. What we've also done is all patients that complete these short-term studies are allowed to roll over into a long-term extension up to a year where we'll follow them up. We will assess when patients need retreatment, if they need any retreatment, and how many additional treatments they will need if they do. There is opportunity for patients to receive additional dosing and extend up to three additional doses. OK, the 8 mg dose, I guess, to address functional unblinding, you know, how confident are you that this is a near psychedelic experience? 8 mg is a pretty robust dose. We've known in our phase 1 that it results in reasonably decent psychedelic effects. That's what we need. Some patients will respond to it as well. We know that and expect that that% will be substantially lower than the number that respond to 16 mg. It's a dose-response kind of approach with the 8 and 16. OK. Within Embrace, you also have a placebo? Yes. What are other methods that you're using to mitigate bias? Right. In close collaboration with the agency, we've agreed on certain methodological issues or approaches that address the issue of functional unblinding, which, by the way, I mean, I keep saying this at many different forums. It's nothing new. The most recent example is Spravato. Anybody who's receiving esketamine knows they are receiving esketamine. It's not an issue that's new to CNS drug discovery. In the two and a half decades I've spent doing clinical trials in psychiatry, almost every clinical trial I've seen functional unblinding, whether it be antipsychotic or it's something like Ambien. You know, you take Ambien, you know you're getting Ambien, right? There is functional unblinding. I'm assuming this is more robust. It is more robust, but has the same effect. I mean, functional unblinding is almost, you know, it's binary, whether it happens or it doesn't. When it happens, then you know you're getting the drug. It changes the expectation of the patient. The patient expects to get better. That's why we want to minimize it, because we want to assess the real effect of the drug rather than the effect of expectancy. The simplest and actually the most efficient way of doing it is to take the assessment of symptoms or change in symptoms away from people who may be affected by this bias, which is primarily the investigator. If the investigator sees that the patient is having a psychedelic effect, then they also expect the patient to get better. The way we take this assessment away from them is to employ remote independent blinded raters who have no idea which visit the patient is at, whether they're assigned to placebo or to an active dose. In addition to that, what we do also is firewall the data for the site staff. Another way of knowing whether a patient is on active or placebo is by adverse events. Active has very characteristic adverse events. Psychedelics have very characteristic adverse events. We firewall those data from the rest of the site staff who are involved in assessment of the patient. Between those two measures, it addresses the issue of functional unblinding. Of course, the bigger and the more robust way of addressing some of those methodological issues is to use the two study approach, which are complementary designs. OK. The powering assumptions for the phase threes? Yeah, so we've been skeptical in our powering assumptions. We are not assuming we'll see 14 points in a phase 3. When you scale up from phase 2 to phase 3, you lose the effect. Compass has seen most recently that six points in phase 2 came down to three to four. This is normal in the industry. What we've done is assumed an effect, a difference between active and placebo of about five points. We've assumed variability of about 12 points on the MADRS. We've assumed a dropout rate of about 15%. That gives us 80% power to detect that change. OK. You do have the Paradigm. Yes. With the Extent, it's the open-label extension study. Just give us an overview and how the dosing Paradigm is going to work there. I'm going to correct you and say it's not an open-label extension until. Until? Patients require to be dosed. The blinding remains intact until somebody needs to be dosed, because when they are dosed, then, of course, it's open-label. Everybody who completes 12 weeks in Embrace or Approach is eligible to roll over into Extent. We have defined a set of criteria for relapse of patients. These are agreed with the agency, and these criteria determine who is eligible to receive additional dosing. When patients become eligible to receive additional dosing, it'll be the same thing we did in the short-term studies: two doses, three weeks apart. There's also an opportunity to receive a top-up third dose. In total, between the short-term studies and the long-term Extent, the maximum number of doses anybody could receive is about five. OK. What’s the trigger exactly? It's change in symptoms, so symptoms of depression as assessed by MADRS. If they go back to the threshold that was used for inclusion, we've got 24 as the inclusion for MADRS in the Approach and Embrace program. If their symptoms increase to that threshold, then they become eligible. There's, of course, investigator judgment. We are also using CGI, which is the Clinical Global Impression of severity, to assess whether a patient requires dosing or not. OK. I guess, you know, one important question when it comes to psychedelics is the treatment, is the length of the treatment session. How long is the monitoring session for the phase 3 studies? As I said, in the early phase studies, we've seen about four to six hours. What we've done in our phase 3 is put in place a series of measures which assess readiness to discharge. At the end of their treatment, we will, at a very high frequency, every 15 minutes, assess their mental state and assess their physiological parameters like blood pressure and heart rate to make a determination when the patients are ready to go back home. We want to make sure they are safe when they go back home. These data will be collected in phase 3 and will fine-tune the actual duration of their inpatient stay. I'm not really worried about the duration, really, contrary to popular belief. It doesn't matter if you stay in the clinic for four hours or six hours. Patients will have one of the most powerful experiences in their life. You don't want to go back home if you're not ready. I don't want to send my patients back home when they're not ready. Yeah. How many monitors are there per session, and what are their functions? In line with the FDA guidance, we've got, during the dosing sessions, two session monitors. The lead session monitor is a licensed therapist, and then there's an assistant session monitor who has got a bachelor's degree and is less experienced. Their role during the dosing session is to make sure the patient is safe. They are there to intervene as needed. There is no active psychotherapy taking place, if that is the question you're asking. That's where I was going. Yeah, because, frankly, psychotherapy is not possible during the acute phase of psychedelic experience. What we tell our patients is we give them an eye mask, we give them headphones, which are noise-canceling too, and ask them to direct their attention inwards, because that's where all the work needs to happen. It's that internal work that needs to happen. Even if a therapist wanted to, they couldn't engage in any psychotherapy. They are under strict instructions not to interact with the patient unless somebody becomes anxious or somebody feels nauseous or wants to go and use the restroom. They are there to help if needed, but not actively intervene. OK. I guess we're running out of time, actually. To close, just would like to ask you if we're sitting here a year from now and I ask you, what are the key accomplishments that Cybin has had in the past year? What would you like to say? In the near term, we are expecting to share news about our CYB004 program, which is the deuterated dimethyltryptamine. Early next year, first quarter of next year, we will be releasing top-line data on that generalized anxiety disorder proof-of-concept study with CYB004. We expect to complete enrollment in our first phase 3 study, Approach, with CYB003 by summer next year and expect to release top-line data by the end of next year. All right. Excellent. I look forward to watching the company make progress and the data read-outs. Thank you very much for joining us. Thank you, Pete.