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