Good morning, everyone, and welcome back to H.C. Wainwright's 27th annual Global Investment Conference held on September 8th to September 10th, 2025. My name is Patrick Truchio. I'm a Senior Healthcare Analyst at H.C. Wainwright. It's my pleasure to welcome our next company, an executive at Cybin Inc., a late-stage neuropsychiatry company pioneering next-generation psychedelics and neuromodulators for mental health. Cybin Inc. is currently conducting a phase 3 program, evaluating its lead candidate, CYB003, a deuterated psilocin analog for adjunctive treatment of major depressive disorder, and a phase 2 trial of CYB004, a deuterated DMT compound for generalized anxiety disorder. From the company, it's my pleasure to introduce George Tziras, the CBO. Maybe if we can start just with some background on Cybin Inc. and highlight the progress that's been made over the past year.
Sure, happy to. Just to give you the sort of the mission, I think if you think about the last few, really many decades of psychiatry, the treatment in mood disorders of highly prevalent indication like depression and anxiety have mainly been managed through chronic dosing, daily dosing really, with antidepressants like SSRIs and SNRIs, which we know that two-thirds of patients don't initially respond to. The side effect profile for many can be quite challenging. For example, sexual dysfunction, weight gain. As you then progress on to later treatments, perhaps atypical antipsychotics, again, the side effect profile can also be quite challenging. In the last 15 years or so, we've seen the advent, especially in the U.S., of what's been termed interventional psychiatry. By that, I mean really day clinics where there are intermittent treatments administered.
Things like initially it was TMS, and then most recently we've seen Ketamine and Spravato (S-Ketamine). Those have grown actually quite a bit in the last few years. I think there's over 5,000 centers today that are registered for S-Ketamine and many more also for TMS and many that do combinations there. Thus far, access to those has been somewhat limited and mainly reserved, I guess, for more refractory patients in depressions due to, to a certain extent, the administrative burden. If we look at TMS, for example, there you have typically five days of daily dosing and then that goes on for a month. It's quite a lot of burden on both the practice and the patient. With S-Ketamine for maintenance, you have weekly or biweekly dosing. Again, quite a lot of burden on the practice. What I think we have now with Cybin Inc.
and what we're excited about in terms of the opportunity is how to really evolve that interventional paradigm and give perhaps the opportunity for greater scale access and also transdiagnostically in mood disorders, we think with some of the early data. Beyond that, also into other behavioral disorders potentially. We think that that's going to be possible through reducing and maybe dramatically that administrative burden, both for patients and providers. That is really through short, sort of fast-acting but long-lasting relief through as little as two doses a year or two dosing days a year. In that, we have two late-stage clinical programs, CYB003 and CYB004. CYB003 was granted Breakthrough Therapy Designation by the FDA. It's currently in phase 3, being investigated for adjunctive major depressive disorder. The first trial there launched late last year.
It's called APPROACH, and the second study is soon to start, we hope, it's called EMBRACE. CYB004 is our second asset that is being investigated for generalized anxiety disorder. That's currently in a phase 2 study, which as of this morning, I'm very pleased to say just completed enrollment. We're expecting data for that relatively soon.
It leads into a couple of my next questions. I think maybe the first one just is what are the priorities as you see them in the next 12 months to advance both CYB003 and CYB004?
The priorities, so really, I mean, the priorities for both is really execution, execution, execution. We have a large phase 3 program with Paradigm, you know, ongoing. It's getting to complete enrollment there and also EMBRACE, as I said, that's just about to start. There's plenty to get on with. With the second asset, CYB004, the priority will be to obviously see what our data says and then on the back of that work towards an end of phase 2 meeting with FDA and then determine the path forward for that into registrational studies if the data so merits.
Great. You provide a really thorough background for CYB003. I'm wondering if you could talk a little bit more about the mechanism of action, the indication, why you believe it could be transformative in MDD, and maybe some of this initial data that you've seen from the phase 2 program.
Sure. Mechanism of action, CYB003 is deuterated psilocin. That is an agonist at a range of serotonin receptors. The mechanism, it's at least hypothesized, as we don't know, is that it induces a window of plasticity, allowing the rapid reorganization of aberrant brain circuitry that underlies maladaptive patterns of thinking that are characteristic of internalizing disorders like depression. The onset of effect is within minutes. The subjective effects, the duration for CYB003 is four to six hours really on average. It's simple dosing. It's a 16 milligram oral capsule and one capsule per dosing session. It's a total of two dosing sessions that are three weeks apart. It's delivered adjunctively, on top of background SSRIs, SNRIs.
I think in the phase 2 trial, I think we saw a 71% remission rate at 12 months. What stood out to you as most relevant clinically?
As you said, we're very excited about that durability data. I mean, 100% response rate and 71% remission rate out to 12 months with 16 milligrams. It was a small study, but when it's that, that's pretty compelling. I'd say also actually that if we had put the cutoff point for remission at 12 on MADRS rather than 10, the remission rate would have been even higher. We're very pleased with that. I think the other thing that's clinically relevant is the absolute drop in MADRS, so 23 points on average, which we're quite pleased with. Definitely the separation at the primary endpoint. At three weeks, we had a 14-point separation. There was 13 to 14 points between both 12 milligrams and 16 milligrams. Sixteen is the one we're taking forward, which in our view is really best in class.
An effect size above two, we think that, and really what's important there is we think that that sets us up nicely into phase 3, i.e. that one would expect as you go into larger studies that the effect size will naturally come down. There's plenty of room to play there.
Can you talk more about the design objectives of the phase 3 Paradigm program? You sort of talked about, you know, some aspects of this design in the program at the outset, but maybe you can talk about how this program is structured to support regulatory approval.
Sure, absolutely. Paradigm is 550 patients in total across two short-term studies, APPROACH and EMBRACE that I mentioned earlier. There is a long-term extension to both called EXTEND, which follows the patients out to a year. Dosing is exactly the same as phase 2. It is two doses three weeks apart in both of those studies. The first one, APPROACH, is 220 patients with two arms. The first is 16 milligram CYB003 and the second is placebo, so inert placebo. There are 110 patients, so it's randomized one to one, 110 patients in each arm. That study is U.S. only, about 45 sites across the U.S., and it's ongoing now. EMBRACE is going to be three arms, a placebo arm, a mid-dose arm at 8 milligrams, and then again a 16 milligram arm, each one 110 patients.
It is international this time, so there are going to be sites in the U.S., in the UK, EU, and Australia. The primary endpoint for both short-term studies is at six weeks with a secondary endpoint at 12. It is a sort of embedded design, so both of those studies will then roll on into EXTEND, and the patients will be followed out into a year.
What role does FDA Breakthrough Therapy Designation play in shaping these timelines and regulatory interactions?
There are a few things. Firstly, we have the benefit of regular meetings with FDA. We've met a number of times since even our end of phase 2 meeting. That helps us align along the way and to ensure that alignment continues. The second is rolling review, so rolling submission of the NDA. That's helpful too. Finally, there's priority review at the end. We've got that sort of six-month priority review as well. I think there's quite a few benefits there.
You have APPROACH, you have EMBRACE, and then you have EXTEND that will build on those two trials. I'm wondering, can you talk about just which of these studies you need in order to submit for approval? How does the EXTEND trial build on those other trials? What do you hope to learn from that long-term extension?
I think we, you know, obviously we'll have to determine with the regulator ultimately as we go what we're going to need to submit. You know, we will need the data from those two studies, I think it's safe to say, and then longer-term data as well. What was your second question?
How would that long-term data, what do you hope to learn from that long-term extension?
Okay. For the long-term extension, what we're really trying to understand is, one, the efficacy, longer-term efficacy, durability. I think it's also going to be important for any potential expectancy bias. If you're following the patients out to 12 months, it should outlast any potential expectancy bias. Also, it's important to understand the redosing profile. If patients don't respond or relapse, they will be given the opportunity in that long-term extension to have another course of treatment.
Right.
We'll really understand, you know, what redosing looks like.
We talked about the efficacy data. I think the safety and tolerability has also looked very compelling. I'm wondering if you can talk about how you see CYB003 fitting in this current MDD treatment landscape if approved. Maybe you can talk about both from the efficacy, but also the safety and tolerability side.
I mean, there's certainly, you know, as I mentioned earlier, within that sort of interventional psychiatry framework, these are going to be at least initially, you know, in clinic treatments. That's the intent. They're going to be administered by a clinician in probably, in most parts, you know, daycare or a day clinic.
Right.
In terms of the paradigm of MDD, we'd see them certainly coming in later line therapy. It's going to be after, if SSRIs or SNRIs are no longer working, and there've been a few trials of treatment, and either they were working or no longer working or adequately managing the patient's depression. You could see how, at least initially, there could be from, I guess, also the access side, certain step aids that's put in place. Perhaps there might be trials with other agents or other adjunctive treatments required at least initially before. That's certainly the idea, that it will come in at that adjunctive, as an adjunctive treatment after those primary ones have failed.
Great. Moving on to CYB004, this is the deuterated DMT in GAD. Can you provide here as well more of an overview over the mechanism design and the unmet need that you believe this drug addresses in GAD?
Sure. CYB004 is deuterated DMT. It's delivered via an intramuscular injection, so jabbing the arm. The duration of the experience is shorter. I would say sub two hours, maybe on average 19 minutes or so, but obviously we'll see when we get the phase 2 data how it performed in patients. The phase 2 design was, as I said, it's 36 patients now enrolled. It's evaluating safety and efficacy for CYB004 in moderate to severe GAD patients that are currently taking concomitant antidepressants or anxiolytic treatments. It's blinded through 12 weeks with an optional follow-up to assess efficacy at 12 months. The patients, those 36, are randomized into two groups. It's randomized two to one.
In the first one, it's two doses of intramuscular CYB004 three weeks apart, very similar to the design of our CYB003 phase 2, and at a dose that's predicted to be therapeutic, and that's 20 milligrams. The second arm is again two doses intramuscular of CYB004, but it's at a lower dose, again three weeks apart, a lower dose that's predicted to be subtherapeutic, so two milligrams. Primary endpoint is the change in the HAMA, Hamilton Anxiety Scores, from the baseline at six weeks. The 12 weeks is a secondary endpoint. We're also taking depression and quality of life scales to see how it performs there.
Where do things stand now with enrollment in this phase 2 trial and the expected timing for the top line data and any expectations you can give around that?
As of today, we announced that enrollment is complete. We would expect now we have, you know, it's essentially 12 weeks plus time to analyze and collect data. I think what we're guiding to is Q1 of next year for top line data.
Maybe you can talk a bit about how CYB004 is differentiated from the other short-acting psychedelic compounds in development.
Sure. With CYB004, we have really the benefit of five studies now optimizing the PK and PD effects of DMT, which ultimately arrived at the CYB004 intramuscular formulation. We saw in MDD patients with IV DMT, when we administered it, that actually for some of them, the very rapid IV DMT, which was essentially between 15 and 30 minutes, was a little bit too short. We sought to extend a little bit of that experience and allow them a little bit more time to do psychological work, but to still keep it quite short and differentiated from the longer orally active psychedelics like psilocybin and LSD. That's what that intramuscular deuterated formulation delivers. Again, I said it's around a sub two-hour experience, and we think we're happy, we're very happy with the profile there.
If the data were positive in the first quarter next year, you know, what does this program look like into phase 3 and beyond?
I think we'd progress to an end of phase 2 meeting and then finalize the design of the phase 3 next year, obviously see what learnings we have from the data and the study, and then move forward.
For CYB004, do you see potential for expansion beyond GAD? Actually, same question for CYB003, is there potential to expand beyond MDD?
Obviously, with generalized anxiety disorder, there are further anxiety, broader anxiety indications. Indications such as social anxiety disorder, OCD, phobias, they all together have quite a high prevalence. I think GAD is about 7 million in the U.S., and I think anxiety disorders all together represent about 60 million patients. There is quite a lot to expand into there, at least in anxiety. More broadly, to answer your question and also thinking about CYB003, there's certainly potential, we believe, transdiagnostically in other mood disorders here for both assets. Then also you think in broader sort of behavioral disorders, also addiction disorders. That's quite a high prevalence, 50 million patients, I think, in the U.S. with addiction disorders. You can certainly see, you've seen at least some early data with other psychedelic agents where that is quite promising in smaller studies.
Certainly an area that we're keen to explore at some point.
I'd like to look a little bit further ahead. You've announced recently the OZMINE collaboration with its 800 clinic network. How is this collaboration and maybe any others that are to come, how will this support clinical and commercial readiness?
We're quite excited about the OZMINE collaboration. OZMINE, just so you understand, if you are unaware of them, they're an EHR software business essentially that serves those, those exactly interventional psychiatry day clinics that I spoke about. They're currently administering Spravato, Ketamine, and TMS. They're likely to be, you know, frankly important part of the infrastructure, you know, if approved at launch. This partnership really allows us to better understand and work with those sites now to understand things like their clinical workflows, any logistical challenges, as well as opportunities that we might have of adapting to what they're doing today for a treatment like CYB003 or CYB004. Also, you know, obviously reimbursement and specialty distribution processes, how they work and how they could be adapted. It's really about better understanding their needs so that we can be ready at launch.
A question we often get from investors just around market, you know, how do we size this market? I'm wondering, how do you see the opportunity for CYB003 in MDD and CYB004 in GAD?
If you think about it, I mean, if you just take a step back and think, in terms of potentially the U.S. population, I think this, I read somewhere about 15% are on some form of SSRI or SNRI, even if it's not adequately managing their symptoms. That's a very large market. Just looking at, I guess, the analog that's often quoted here, just Spravato. Spravato has, well, it's delivering currently what, run rate $1.6 billion sales. That's off what they, I think they've disclosed, you know, 100,000 or just over 100,000 patients treated. If you think about that number and in the context of the much larger opportunity, we think there's actually plenty of room there.
Right.
To establish quite a compelling market.
Just stepping back, what excites you most about the broader psychedelic neuropsychiatry landscape today? There's been, I think, a lot of compelling data released more recently. I think there's high hopes and high expectations for Cybin's data coming. I'm just curious, how are you viewing this, the landscape broadly and then how Cybin's going to navigate that?
I think, in terms of excitement, I'd say I'm excited, first and foremost, about the potential, I guess, if approved, to bring these new treatment options to patients. I think what you mentioned, there is increasing validation now in the space of this mechanism through robust data from multiple different drugs in now quite much larger studies. To see that certainly evolve out is very exciting.
As you look ahead, what are the key milestones investors should be watching for over the next year?
Q1, as I said, next year, the CYB004 top line data. Before the end of the year also, we hope to be able to provide top line data for the first of those two phase 3 studies, APPROACH. There's plenty to look forward to.
Terrific. Thank you so much, George, and thank you to Cybin. Thank you everyone for attending the conference. Have a great rest of your day and conference.
Thank you.