Hello, everyone, and welcome to the fifth annual H.C. Wainwright Virtual Neuro Perspectives Conference. My name is Luis Santos, and I am a healthcare analyst at H.C. Wainwright. We have a robust agenda at the conference this year, with more than 20 companies presenting, with their sessions available on demand through the conference portal. In addition, we are expecting a full day of panels and fireside chats on the day of the conference, June 27th, with a broad neurology focus across many indications, from depression and epilepsy to Alzheimer's disease and ALS, along with novel methods of drug delivery to the CNS. This is by far our strongest agenda ever. And with that, it is my pleasure to introduce our next speaker, Doug Drysdale, CEO of Cybin, a clinical-stage company working to create safe and effective psychedelic-based therapeutics to address unmet need in people suffering from mental health conditions. Hi, Doug, and welcome. Hey, Luis. Thanks for having us. Appreciate the invite. Good to see you. Our pleasure. So to start, can you tell us a little bit more about Cybin, how was it founded, and what differentiates it from others in the mental care healthcare space? Sure. So, Cybin was actually founded right before COVID hit, which was kind of interesting. We've grown the team entirely virtually since then. Despite that, we were still able to go public by the end of 2020. And since then, we've made two different acquisitions to grow the company. Adelia Therapeutics, we acquired at the end of 2020, and late last year, we closed the acquisition of Small Pharma, a U.K.-based company. I mean, collectively, those two acquisitions, combined with our own work, has led to what we think is the most extensive IP portfolio in the sector. We have more than 50 patents granted now and 180 patents or so pending. has led us to be the leading company when it comes to modified psychoactive compounds, these are all, you know, IP protected. Specifically, we're working on modified versions of psilocybin analog and a deuterated version of DMT for major depressive disorder and generalized anxiety disorder, respectively. Our psilocybin analog, CYB003, is heading into phase III program this summer, and our deuterated DMT asset, CYB004, is currently in a phase II study in GAD, reading out around year-end. Thank you for that initial overview, Doug. Very briefly, just, Can you just very briefly say something to why deuterated is the formulation of choice you've decided? Yeah, I mean, the deuteration is quite well known in pharmaceutical development. It's... There's some precedent already. There's at least one asset that's deuterated that's approved and several others in development, you know, across the sector, the broader biotech sector. Deuteration modifies the pharmacokinetics in our case, without affecting the underlying pharmacology. So we're retaining how the drug works, we're just improving how it gets to the site of action in the brain. So that creates a novel molecule. These are new chemical entities, and FDA has confirmed that with us, and of course, it's possible to generate composition about an IP around these new molecules. Fantastic. Thank you for that. And, so going through—we're gonna go through both your programs, CYB003 and CYB004. Starting with CYB003, deuterated psilocybin and 5-HT2A receptor agonists. It's used as an adjunctive therapy in major depressive disorder. Can you tell us more about the unmet need in MDD and why—what makes CYB003 differentiated? Yeah. Well, we know that there are about 300 million people around the world that are impacted by depression. And we also know that current standard of care, SSRIs, leave a lot of people not in remission. So they may be getting some benefit, maybe some blunting of their symptoms, but current treatments don't affect the underlying path of disease or the cause of disease. And for the first time, we may be seeing that being possible with some of these treatments. So, what we see with CYB003 is a very rapid onset of effects. Effects begin within about 15 minutes. We see in a phase II study that we read out at the end of last year, as you say, as an adjunctive treatment in MDD, we gave two doses, three weeks apart. And the purpose for that, the two doses, was to optimize the durability of effects. We think that that's, you know, a major target for us, and payers and providers tell us the same thing, that the fast onset of effects is good, but durability is really what is needed here. And in that study, we can go into details. We saw rapid, large, and sustainable, reduction in depressive symptoms from this protocol. Of course, the adjunctive nature means the patients can be dosed right away after diagnosis or after seeing their physician, and they don't have to wait six or eight weeks to titrate off of their background medications, which of course can be quite challenging sometimes. Excellent. And you've announced that you've reached some alignment with the FDA on a planned phase III program design, patient inclusion, the inclusion criteria, so the target, this target population, and dose regimen. So, can you tell us a little bit more about the plans for that trial? Yeah, we can. So we had our end of phase II meeting with the FDA in February, and we aligned on a phase III program design. The study, the program, will consist of two short-term studies and a long-term extension. So the first short-term study is a two-arm study, 220 patients. These are moderate to severe patients with MDD. They'll be on background medications as we did in phase II, so positioning as adjunctive. We'll give two doses again, three weeks apart, and the primary endpoint will be at six weeks. So two doses of CYB003 compared to two doses of placebo. And then the second study is a three-arm study. It will contain a therapeutic dose, a sub-therapeutic dose of CYB003, and a true placebo. This is to meet the FDA's requirements for some level of dose ranging, number one, but also to provide two-thirds chance of a patient receiving an active dose. So it's a way to confound the patients and try to overcome some of the functional unblinding that is natural, you know, with these compounds. So that's a 330-patient study, so 550 patients in total. Also with a 6-week primary endpoint on the MADRS scale. And then from both of these studies, we'll roll over patients into a 12-month long-term extension. That extension will be blinded still, and patients will be able to receive a round of treatment if they did not respond in one of the two arms, one of the two studies, or if they relapse at some point over the course of that, that year. They'll receive one cycle of two doses of CYB003, three weeks apart. So we'll have, a good amount of short-term efficacy data, and then we'll have a, a good picture of what relapse rates look like and time to redosing looks like, with the combination of those three studies. Can you tell us a little bit more about the MADRS score scale, and if this is enough to get potential approval? Yeah. I mean, the MADRS scale is a physician rated scale. It's been used for 50 years and is well tried and tested. But there are some elements of the study here that we are being careful to deploy to overcome some of the, you know, obvious potential unblinding effects of these treatments. So the first is that the raters in the studies will all be independent, remote blinded raters. So they won't know whether the patient received active or placebo or whatever dose, and they also won't be privy to any of the effects that are reported by the patient. So when the patients report any side effects or they report, you know, effects associated with a psychedelic experience, such as euphoria, those go into the report form, but they're in a sectioned report form, and a database that the raters can't see. So they're totally blinded, and that to that, and that independent sort of remote rating using the MADRS scale is tried and tested. Great. Fantastic. And you decided to go with MDD rather than TRD. Why was that? You know, in the real world, when we talk to providers and payers, they don't talk about MDD and TRD. That's a regulatory description. They talk about first line, second line, third line, et cetera. And that's the way we think about it too. We look at the total depressed population, and the bulk of that population is MDD, and then there's a small portion of patients that are treatment resistant. And many of those patients have tried many, many different treatments and may not respond to anything. So the bulk of those MDD patients are also on a background medication. So positioning as adjunctive in MDD, we think addresses the greatest level of unmet need. As I said before, you know, patients not having to titrate off of their background medications is a big plus. It's certainly a big plus for recruiting in phase III. It's one less hurdle for patients, but it also reduces risk for both patient and provider in the real world following approval. Excellent. And, this, this will be the first ever, to our knowledge, a pivotal program evaluating psychedelic compound as adjunctive treatments in MDD. So what data generated to date makes you confident that this will support, potential approval? Yeah. So our phase II study recruited 36 patients with moderate to severe MDD. All of those patients were taking SSRIs or SNRIs, so we've already studied this as an adjunctive treatment. We gave two doses, three weeks apart, and what we saw after the first dose was a very rapid onset of effects, and on average, a 14-point reduction in MADRS score compared to placebo. Highly statistically significant, a massive effect size, frankly, and compares roughly to SSRIs, the standard of care, that deliver about a two-point reduction compared to placebo across many, many studies. So a much, much greater effect size than the current standard of care. And then what we saw from the second dose was an incremental benefit, so a further reduction in depressive scores. We saw an increase in both response rates and remission rates with the second dose, as well. So after just two doses, we saw 75% response and remission rates from patients with moderate to severe MDD. And those were sustained, so far, four months after those just two doses. So, obviously we're very happy with that. In general, it's harder to show incremental benefit with an adjunctive treatment that you're giving on top of the standard of care. But in this case, you know, there's a clearly statistically significant benefit to 75% of those patients. Excellent. That's, that's very promising. Moving to other program, CYB004, a deuterated DMT program in generalized anxiety disorder or GAD. Why this indication? It's a very hard to treat indication. It's a hard to tackle indication. Why did you choose it? It is hard to tackle. In fact, you know, 50% of patients fail in their treatment. 50% of SSRI treatments fail. SSRIs really just aren't the right mechanism for GAD. Then benzodiazepines can really only be used for short periods of time. Buspirone has pretty poor efficacy and the side effects of antipsychotics, which is kind of last line of treatment, are really quite unpleasant. And so there is a massive unmet need here. It's also a massive population. Anxiety disorders collectively have a prevalence of around 18%-19% of the population, so the largest population of any mental health condition. And GAD is kind of the gateway to all of those we think. CYB004 is a short duration treatment from a single administration, which delivers about a 90-minute experience, so would fit very well in those Spravato treatment centers that currently exist today. And it has the potential to provide rapid and sustained benefits, and potentially become best in class if we achieve that. So, we are in a phase II study right now. It's a 36-patient study, two doses of CYB004, three weeks apart, so very similar, protocol, two doses compared to two doses of placebo. And we'll have data right around year-end, the top line phase II data, safety and efficacy. Great. And from the data demonstrated, shown to date, what makes you confident that CYB004 will succeed in this indication? Well, we know that DMT has positive benefits in depression. We have data from our phase II DMT study in MDD patients. We saw there 40% remission rates six months after one or two doses. And we also saw meaningful reductions in anxiety scores in those studies, a number of studies, as well. So we've got good proof of concept. We believe that we have created quite a valuable and interesting PK profile. Typically, DMT is quite aggressive in the sense that patients get up into that breakthrough space very quickly, and then they come down very quickly, five or 10 minutes or so. What we have here from our single administration is we get... are able to get patients across that line and into the breakthrough space very rapidly, which is important. You don't want to take too long, they get anxious. So we get them there quickly, and then once the patient comes down from peak, they're then in a long tail of the PK curve for the bulk of that 90 minutes. So and that's where the, the psychological work appears to be, to be done. So we, we think that that PK profile could be useful, and of course, this treatment very, very scalable, and very high unmet needs in GAD. That's really interesting, those snippets of data you gave. So let me just try to clarify something here. For GAD, is durability also key, or... And are you expecting a massive effect size like you saw with CYB003? What are the differences here? You talked about the read-through that existed from MDD, from CYB004 in MDD, but can you speak to the endpoints and what you're expecting to see from this trial? Yeah, look, I think there's been a number of trials now with psychoactive compounds, and they all appear to deliver rapid effects and very large effect sizes as well. Of course, durability, whether it's MDD or GAD, remains important. You know, people don't want to have a DMT experience or a psilocybin experience or an LSD experience. They don't want to have that every week or month. You know, that's just not something that's practical. So, this is why we're studying a two-dose regimen. We definitely see with our psilocybin analog that the second dose has incremental benefit. And we also see that all patients report a more intensive experience with the second dose because they're fully immersing themselves and letting themselves go. Yeah, that said, DMT, deuterated DMT, is highly immersive and intense. There's no real fighting the experience. Patients are in that space pretty quickly. And so two doses may not be necessary. One dose may be just fine. We saw that in our regular DMT study in MDD, that there wasn't really much difference between one dose and two doses. That's the purpose of our phase II here, is to show proof of concept with efficacy, but also to determine what the protocol for phase III will be. And when can we expect data? Yeah, we're already started that study. We're running the study at the same sites that we ran our CYB003 phase II, so they're very experienced, and we'll have data right around year-end 2024. Great. Shifting gears, we'd like to know how you're thinking about the outcome from the FDA's Advisory Committee meeting on Lykos recently for MDMA-assisted psychotherapy in PTSD, which was not positive. If there are any read-throughs to your programs, what are they? How does this impact your lead programs? I mean, first of all, obviously, the outcome's quite disappointing, I think, for anyone following the sector and especially for patients. So hopefully these issues can be resolved in a, you know, a practical way. Yeah, I will say that, aside from some very clear things that FDA had asked for that weren't provided to them in the application, there are some elements of the protocol that are quite unique, I would say. I'd say that the MDMA-assisted therapy protocol is an outlier in the sector. Whereas it combines talk therapy with the drug, so patients are receiving talk therapy while they are under the influence of MDMA. That's quite different than what anyone else, any other companies are doing in the sector, including us. We're not providing psychotherapy. That combination, that interaction with the patient for an extended period of time while the patient is intoxicated, for want of a better word, with MDMA, provides, you know... It creates risk. It creates risk to the patient. As we've seen, it creates risk to the therapist, frankly, because MDMA is pro-social, it's a challenge for the therapist. It creates some potential for bias because, you know, you have a therapist that is guiding a discussion with the for many hours, with the knowledge that the patient is taking the drug. So it's a challenging protocol. I'm sure that they'll find a way to overcome some of those challenges. But what we're doing at Cybin is quite different. Patients are not receiving the psychotherapy. In fact, during dosing, patients are wearing an eye mask, and they're wearing a headset with a playlist. They're actually intentionally cutting out external distractions, so there's no intentional interaction with the patient. But interestingly, psilocybin's a different has a different effect than MDMA. MDMA, as I said, is pro-social, psilocybin is not. During psilocybin treatment, patients often describe or experience ego dissolution or this ineffability. And ineffability literally means an inability to describe the experience. And the reason the patients can't describe the experience is because the language centers are disrupted during the treatment protocol. So it's interestingly, psilocybin is completely incompatible with psychotherapy. It just would be not possible to get the two together. That's one unique part of the protocol, I think, that separates what we're doing from what was, you know, reviewed there by the AdCom. That is really useful. Thanks for that. What is Cybin doing to prevent functional unblinding? You've already mentioned that, there are some advantages to psilocybin. So, is there anything extra that Cybin needs to do also for expectation bias or selection bias? Yeah, look, I mean, functional unblinding is not new to FDA, not at all. In fact, they've approved many drugs that have a clear functional unblinding, esketamine is a good analog for that, but most trials are not fully blinded. Patients better feel something, some side effect or something. So, yeah, FDA is fully aware of that. You know, they provided guidance on how to design clinical trials, and one of those being this three-arm study there to confound the patients, which we're doing. As I mentioned, we're using remote independent raters as well, so it'll be arm's length, and it'll be blind to the patient's experience and to the dose that they received. You know, expectation bias, we are trying, as we did in our phase II, to recruit... We are aiming to recruit psychedelic-naive patients. So patients will not have been able to have had any recent psychedelic experiences. So for the most part, naive. I mean, if someone maybe experienced LSD or mushrooms in college 20 years ago, we probably wouldn't exclude that. But for the most part, we, you know, don't want experienced users in the protocol. And then as for expectancy bias, you know, I think you're less likely to have expectancy bias with inexperienced users because they just don't know what to expect. But the real test for expectancy bias is long-term data. So it's hard to see how an expectancy effect or a placebo-type effect could persist over weeks and months of these trials. In fact, we saw that in our phase II study, that we did see a placebo reaction after the first dose of CYB003. But by three weeks after dosing, after the first dose, that placebo effect had pretty much regress back towards baseline. So expectancy bias placebo effects are unsustainable over time. That makes sense. Did you already, do you already have an idea of the proportion of patients that would have experience, previous experience? So within the lines that you've described, no recent experience, is the, is the goal to ex- Yeah. So none. The answer is zero. Okay. Zero will have recent experience. But as I've said, you know, there's a point, a cutoff in time where we'll allow some patients in, but heavy users or even heavy past users would not meet the criteria for psychedelic-naive. Mm-hmm. And not just for the effect size, but also for the safety database that the FDA, the FDA seems to be requiring, do you expect that your phase two and three trials will cover that? Yeah, we have no reason to think it wouldn't. At this stage, and 550 patients is what we've discussed with FDA. They are happy with the endpoints and the design and the sample sizes. So no reason to think that won't be large enough at this point. I will say that, you know, the durability of effect plays into this somewhat as well. We had an interesting discussion with FDA at our end of phase II meeting, around relapse. And, you know, if you're able to deliver benefits to patients for many months at a time, and they're in remission, free from depression for many months, at some point, the next episode of depression, if it occurs, is an acute episode and not a relapse from the previous episode. Then they start to look at these treatments then as acute treatments, and not intermittent treatments, and that changes the, you know, mindset when it comes to safety database and redosing schedule. We think that that threshold is six months. That's our guesstimate, for want of a better word, based upon discussions with FDA. And so far we're seeing tremendously robust benefits out to at least four months. And we didn't really see any regression in that data at four months, so there's no reason to believe that the six-month data won't be great, as well. And so that's, again, another reason why we've gone from the beginning with this two-dose regimen aimed at extending durability, because it might also have an impact on the overall safety database that we need. That was really useful, Doug. Thank you. And on the proposed REMS program, do you think there's gonna be any read-through about the program that was proposed for MDA-assisted, MDMA-assisted therapy and CYB003 and CYB004, or is it actually? Is it? Yeah, is it- are there any similarities and differences? You know, so far we're not seeing any real surprises. You know, from the REMS, you know, a requirement for a patient registry, that's fairly normal. Dosing under supervision, well, that's to be expected. SOPs for handling controlled substance, that's, you know, normal. So pretty much along the lines of esketamine. I don't know if the MDMA REMS will end up being different from any other psychedelic REMS. I expect more likely that they'll have to address those issues in some way because the REMS doesn't really address them. So we're not expecting anything too surprising. I would be surprised if it wasn't pretty much a copy-paste of esketamine, frankly. Makes sense. Okay, so that would include the qualifications or certifications of the supervisors during the supervision during dosing? I don't know, that's possible, and that FDA doesn't have a mandate over revision of clinical care. And when we visited esketamine centers, they have a very good setup. You know, the rooms are all private. They have an intake system and an informed consent system that is performed by a technician or a nurse practitioner or a prescribing assistant. The patients are in a room with an emergency call button. They're monitored with cameras, their blood pressure is checked several... From what we saw, and we've seen as we've gone out to the centers, it's pretty easy to see how CYB003 or CYB004 would drop pretty much right into that very similar protocol. So I'd say that the infrastructure already exists for what we're trying to do. Excellent. Doug, this was really useful. Thank you so much for this overview. Really appreciate it, and thank you to our, all our participants for joining us today, and enjoy the rest of your conference. Thanks, Luis. Thanks for having us.