Hello, everyone. Josh Sands from Jefferies Healthcare Investment Banking. It is my pleasure to introduce to you today Cybin, a late-stage neuropsychiatry company pioneering the next generation of psychedelic-based therapeutics for unmet needs in mental health. Now it's my pleasure to introduce George Tziras to take away the company presentation. George.
Thanks, Josh.
Good afternoon, everyone. For decades in psychiatry, the treatment of highly prevalent disorders like depression and anxiety has mostly been about managing symptoms with chronic daily antidepressants like SSRIs and SNRIs, which two-thirds of patients do not respond to initially, and which the side effect profile for many can be quite challenging. For example, to name but a few, weight gain, sexual dysfunction, and others. In the last 15 years, we have seen the advent, especially in the U.S., of what is the so-called Interventional Psychiatry practices, by which I mean day clinic intermittent treatments like transcranial magnetic stimulation, ketamine, and esketamine or Spravato. Thus far, there has been a steady growth in these clinics, with there are about 8,000 of them today in the U.S. alone. Access has been somewhat limited due in large part to the administrative burden of the high frequency of those treatments.
At Cybin, our mission is to evolve this new interventional psychiatry paradigm by offering for the first time the potential for rapid and long-lasting relief, and even potentially remission, through as little as two doses a year. We hope to drive greater access, scale, transdiagnostically in mood disorders and beyond in other behavioral disorders by dramatically reducing the administrative burden for both patients and providers. Now, we're seeking to achieve that through two proprietary clinical assets, CYB003 and CYB004, both of which are protected by a robust IP portfolio of over 100 granted patents, and I think now over 250 pending. CYB003 was granted breakthrough therapy designation by FDA and is currently being investigated in a Phase 3 pivotal program for adjunctive Major Depressive Disorder, with the first trial, which we've called APPROACH, currently enrolling and expecting to read out top-line data in the fourth quarter of next year.
EMBRACE is our second phase 3 study, and that has just initiated, with enrollment expected to commence this quarter. CYB004 is our second asset being investigated for Generalized Anxiety Disorder, and that is currently in a phase 2 proof of concept study that has just completed enrollment, and we're expecting top-line data in the first quarter of next year, just around the corner. Both our assets are proprietary analogs based on classical psychedelics. When you think of the psychedelics in development currently, they can be broadly grouped into two categories: those that are orally active, slightly longer in terms of their subjective effects, like psilocybin, LSD, and MDMA, for example, and those that are non-orally active, shorter but more intense in terms of their subjective effects, like N,N-dimethyltryptamine, so DMT, or 5-Methoxy-DMT.
As far as I'm aware, we are the only company that has later-stage assets in both these categories. With CYB003, what we have done is we have taken psilocybin, and we've removed the first metabolic step to the active moiety, psilocin, and then we've deuterated that to stabilize it and also alter the metabolic profile as well. It's an oral capsule where in Phase 2 we saw roughly around four- to six hours on average of acute subjective effects, which we believe fits nicely into an eight-hour interventional psychiatry typical clinical day. Similarly, for CYB004, we have deuterated N,N-dimethyltryptamine, so DMT, and optimized it into an intramuscular injection, smoothing the very intense and short 15- to 30-minute profile of intravenous DMT into a sub-two-hour profile, which we believe is targeting both convenience and scale.
MDD and GAD represent two internalizing disorders of great unmet need with around 20 million patients in each in the U.S. alone, but also they do have significant overlap and comorbidity. We believe by targeting them both, we will have the opportunity to broaden the access addressable market and provide greater access to patients who might benefit from treatment if approved. At the same time, we expect to leverage a common commercialization platform to drive efficiencies both in terms of the sales and distribution network, but also economies of scale in areas like salesforce share of voice and contracting. We believe we've made deliberate choices in our indication selection and protocol design to remove potential barriers for adoption if approved. Firstly, we selected adjunctive MDD as our indication as opposed to monotherapy or treatment-resistant depression.
That is because some studies have shown that around 70% or as much as 70% of treated patients are on background medications, even if they are not adequately managing their depression. Patients have the ability to begin treatment immediately without titrating off their background medications or indeed suffering withdrawal effects that for many patients can be quite challenging. Second, our IP, which I mentioned earlier, provides protection out to at least 2041. This affords us the opportunity to consider expansion into adjacent indications with high unmet need, like other anxiety and addiction disorders, which alone represent around 100 million patients in the U.S., and for which there are early studies with psychedelics showing promise. Thirdly, in our phase two study in depression, we saw durable remission out to 12 months from just two dosing sessions three weeks apart.
When you look at the growing interventional psychiatry clinical infrastructure in the U.S., and as I mentioned earlier, that represents around 8,000 clinics today across Spravato, ketamine, and TMS, these existing interventional treatments can represent 30 or more treatments annually. We believe if approved, treatments like CYB003 and CYB004 have the potential to significantly reduce the burden on clinics and provide an opportunity to treat more patients. Turning now to CYB003 in more detail, our Phase 2 proof-of-concept study was in 36 patients with Major Depressive Disorder on background antidepressants that were inadequately responding to that medication. Patients were randomized to receive a single dose of CYB003 or placebo with a primary endpoint of change in MADRS score from baseline at three weeks.
All patients then received a second dose of either 12 or 16 milligrams of CYB003 and were followed out 12 months in an open label extension. This followed a phase one ascending dose study in healthy volunteers, which helped us to select those 12 and 16 milligram doses to take into patients after seeing robust PD effects beginning at 10 milligrams. Now, what we saw was that after a single dose of CYB003 at the primary endpoint of three weeks, there was a 13-14 point separation on the MADRS scale as compared to placebo from baseline and an effect size well above two. Now, while this is a small proof of concept study, this is pretty compelling data when you consider that SSRIs separate from placebo only two points in most studies since the 1970s, and the effect size there is around 0.25. Really quite exciting.
Now, what's more, though, after the second dose of CYB003 at three weeks, we saw a clear incremental benefit from the second dose that was around three to five points on the MADRS scale depending on the dose, 12 or 16 milligrams, and durable relief out to 12 months with 71% of patients in remission. This was all in the context of a favorable safety and tolerability profile. All the reported adverse events were mild to moderate. The most common were nausea, headache, a little bit of elevated blood pressure. They were transient and self-resolved on the day of dosing or thereabouts. We saw no AEs of suicidality and no AEs reported in the 12-month follow-up. We are in Phase 3 now in our pivotal PARADIGM program, which seeks to enroll 550 patients across two short-term studies, APPROACH and EMBRACE.
Dosing, as in Phase 2 is two doses three weeks apart in both studies. We've tried to change as little as possible between phase two and Phase 3 given the results I just shared. APPROACH is 220 patients with two arms. The first is 16 milligrams of CYB003, and the second is inert placebo, 110 patients in each arm. It is U.S. only with approximately 45 sites. EMBRACE has three arms. It has, again, inert placebo, 8 milligrams, and 16 milligrams, also 110 patients per arm. This one is an international study with sites in the U.S., U.K., EU, and Australia.
Now, the lower dose 8 milligram arm that you see there in the EMBRACE study is there to address potential concerns around expectancy bias and functional unblinding, as we do expect there to be pharmacodynamic effects enough to confound the patients about which dose they've received and maybe even some therapeutic response, but nothing like the full 16 milligram dose. The primary endpoint in both studies is at six weeks, and there is also a secondary endpoint at 12 weeks. There is a long-term extension to both studies, EXTEND, which follows patients out to a year to better understand both the long-term efficacy, durability, and the redosing regimen for patients that did not respond to the first two studies or relapsed. This also further helps to outlast any expectancy bias or any potential expectancy bias with efficacy data points out to a year.
The PARADIGM design has been discussed and aligned with FDA at an end of phase two meeting last year and subsequent BTD meetings that we've had. Turning last but certainly not least to CYB004, we have the benefit of five early-stage studies with DMT and deuterated DMT. Those studies have allowed us to optimize the PK and PD effects of DMT to arrive at what is now the CYB004 intramuscular formulation. Undeuterated DMT IV is very intense and short, between 15-25 minutes acute effects depending on the rate of infusion.
We saw with that that while demonstrating robust efficacy and safety data in a proof of concept study that we conducted in Major Depressive Disorder, where we saw 46% of patients in remission after three months, and indeed two-thirds of those patients went on to still be in remission at six months, there were in that study some patients who felt that they came out of the experience prematurely because of that brevity. Indeed, they may have benefited from it being slightly longer. What we have looked to do with CYB004 is to smooth the extreme intensity of IV DMT and extend it slightly to allow a longer time for the patients to get the most benefit while still remaining short at around two hours or under two hours.
Furthermore, in our MDD studies, we also saw rapid improvement in anxiety scores, which gave us comfort to pursue Generalized Anxiety Disorder as an indication. Moving now to the design of the CYB004 proof of concept study. In that study, we are evaluating the safety and efficacy of CYB004 in participants with moderate to severe GAD. Those patients are on concomitant antidepressant or anxiolytic treatments, and comorbid depression was allowed. The study ended up recruiting 36 patients who were randomized into two groups. The first group received two intramuscular doses of 20 milligrams of CYB004 three weeks apart, while the second group received two control doses of 2 milligrams of CYB004, which is expected to be a subtherapeutic dose. The primary endpoint is a change in the Hamilton Anxiety Scale from baseline at six weeks with a secondary endpoint at 12 weeks.
Other endpoints in the study include the Hamilton depression scales, safety assessments, and pharmacodynamic and quality of life measures. To recap, looking at the year ahead, we have two key top-line data readouts in 2026. Our phase two readout in Generalized Anxiety Disorder with CYB004 expected next quarter in Q1, and our first Phase 3 APPROACH readout with CYB003 in MDD, which is expected before the end of next year. Plenty to look forward to. With $84 million of cash on balance sheet as of September 30 and a further $175 million just raised last month in gross proceeds in a registered direct offering, we believe we're well capitalized to execute on those milestones. Thank you for your interest and insight in listening today. If there are any questions, happy to take them.
Can I ask you a stupid question?
Sure. No question is stupid.
Your drug, does it take people? How do you handle the high effect? Because this has been the most detrimental side effect for this kind of drugs over the recent years and put the FDA relatively uncomfortable. I'm kind of new to the story. I studied your company in the past, several of the.
Okay. Yeah. No, sure. I would not say, firstly, that the regulator is uncomfortable. It is an in-clinic treatment, and it is always under clinical supervision. We have the dosing sessions, and that is indeed how we expect to commercialize. You have the dosing session monitor in all the clinical studies, both in the room. There are actually two, one in the room, and that is mandated by FDA, both in the room, and now there is one also on video. The sessions are monitored, but indeed, those effects that you mention are at least purported, in this case, we believe, necessary for the effect. So much that we have done in the design that I just discussed with CYB003 and CYB004, where we have tried to, I guess, optimize the profile, is we believe there is a threshold effect here.
What you're trying to do is to get, given the inherent, I guess, variability between patients of the subjective effects, to try and get as many patients as possible into that full-blown psychedelic experience. Because what we've seen across many studies now is that tends to correlate quite well when you look at those PD measures with the therapeutic efficacy if it's there.
How does this compare to Spravato and what's out there, and then what's the economic potential?
We believe Spravato has a much more frequent dosing regimen. That was a little bit what I was covering earlier. If you think about maintenance dosing with Spravato, at least on label, it tends to be biweekly or weekly. You can have anywhere from 30-50, over 50 doses a year, including the induction period. Here, again, we will see what data we collect in Phase 3 in terms of that long-term extension, in terms of the frequency of dosing. In Phase 2 we saw just two doses with CYB003, giving you a very durable remission out to 12 months. We think it compels favorably within that infrastructure, and it will give an opportunity to the clinics to see many more patients.
If you follow up on the commercial potential, so you're going into pretty broad indications like MDD. I think you should talk to payers, how they're going to do pricing, if they're not just going to price against existing MDD, FDA-metered GAD, as opposed to other companies going more into resistant depression versus the universe and so on.
Yeah, sure. Again, I mean, it is adjunctive MDD, not just MDD, broader MDD. I mean, these treatments are not going to be first line. I mean, maybe one day, but at least not initially. I mean, what we're seeing here is a later line of therapy. Yes, in our research with payers, when you look at that later line of therapy, and again, I guess treatment-resistant depression is not a diagnosis. It is ultimately just a later line of treatment where prior treatments have failed. Again, I think when you think about the positioning and where it would be when patients have failed first line, but they're in that later line of therapy, we think there's a broad enough population there that it can be captured quite well and that also it will be reimbursed.
Basically getting step edit through the other therapies, and then you get a good price after that.
Indeed, the step edit will be what they will be, but with a broader label, at least it gives you the opportunity, as the relationship with, and then also there's real-world data to support with payers involved, to be slightly more flexible, we believe, than if we had gone just purely for a treatment-resistant depression indication.
Maybe potential combination use down the road with TMS or other adjunct therapy for real sustained benefit. Have you guys thought about that, or we're really just trying to be monotherapy after they fail these other agents?
Potentially, yeah. I mean, I think there's always benefit of therapy anyway, so psychotherapy. And that works with all drugs. With SSRIs, you do see better data when it's administered with therapy. So certainly, therapy will help. But yes, I mean, some of these other treatments, I guess that hasn't been tested yet in studies. I think there is some early talk or some early studies with combinations with TMS. There's some articles written recently, but yet to be demonstrated. But yeah, in the real world, it's never as clean as this, but at least for the studies, it's proceeding. No? Okay.
The use of proceeds because you are raising much money. What are you going to be? Can you give more details on the use of proceeds?
It's just execution, execution, execution on the Phase 3, really. We have two large, as I mentioned, Phase 3 studies ongoing with CYB003, plus also the long-term extension. It's going to be about getting through those studies and to the milestones, the data readouts next year. Okay. Thank you.