Cybin Inc. (HELP) Earnings Call Transcript & Summary

Good morning, and welcome to the Cybin R&D Day. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Cybin website following the conclusion of the event. I'd now like to turn the call over to your host, Doug Drysdale, Chief Executive Officer at Cybin. Please go ahead, Doug.

Good morning, everyone, and welcome to Cybin's R&D Day. Thank you for joining us today. I am Doug Drysdale, I'm the CEO of Cybin, and I'll be your host this morning. So we have an exciting and an informative program today, highlighting progress on 2 key clinical programs, CYB003 or generated psilocybin analog for major depressive disorder and CYB004, deuterated dimethyltryptamine or DMT for generalized anxiety disorder. Following a brief company overview, Amir Inamdar, Cybin's Chief Medical Officer will dive into our CYB003 program and share an interim readout from our Phase I/IIa CYB003 trial. Very excited about this. And it's worth noting that CYB003 is the first ever generated psilocybin analog to enter clinical development. After Amir, we will hear from the distinguished Dr. Maurizio Fava, who will provide insight on the current data landscape for psychedelic-based therapeutics and what we can expect in the near-term and the mid-term. Following Dr. Fava, Pradeep Nathan, our Vice President of Clinical Development will discuss the excellent progress that we're making with CYB004. And we will then open up the call for questions. A few housekeeping reminders today, the webcast is scheduled to end at 11:30 Eastern. In addition to following along, today's presentation is now available on our website in the Events and Presentations section for download. Excuse me, we'll have a moderated Q&A session after the prepared remarks and to submit a written question, please fill out the form on the webcast front page. A webcast replay will be available later today on Cybin's website in the Investors section under Events and Presentations. Quickly turning to the cautionary statements. For a full disclosure of risks associated with our business, please visit our website. So let's begin. What do we mean when we say we're revolutionized in mental health care? Cybin takes the patient-first approach to everything that we do. We're building upon decades of research that validates the potential of psychedelics to improve treatment options and outcomes. And through our rigorous and differentiated approach, we're harnessing the potential of psychedelic molecules and modifying them to optimize their profiles for the treatment of mental health conditions. Frankly, the need has never been greater. Today's standard of care for patients with anxiety and depression often fall short and individuals are often left with ongoing symptoms as well as life altering side effects. What we're aiming to do at Cybin is to develop treatments that have a fast onset and a short duration. So less timing in the clinic and fewer resources. We're looking for low variability for more predictable patient responses. And we're looking for low dosing, which means efficacy with a favorable side effect profile. And the potential at the end of the day to deliver faster therapeutic benefits when compared to the current standards of care or SSRIs. Now these may seem like lofty goals, but I think we're well positioned for the challenge and to execute on our strategy. We have a highly committed, talented and experienced team for whom this work is, frankly, personal. And collectively, we have decades of experience in drug development and commercialization, both within the psychiatric and psychedelic sectors. We're supported by a strong and growing IP portfolio with strategic partnerships and a robust pipeline. We're looking at a range of treatments, routes of administration to give patients and provide us thoughtful options with support for our development efforts through world-class partners and institutions. All with the goal of developing differentiated compounds that complement our R&D strategy and support our position as an innovator in the psychedelic therapeutic space that will build shareholder value. Most notably, we quickly become a multi-program clinical stage company with the financial stability and access to capital to support our strategy and our clinical milestones. So let's get into the programs themselves. CYB003 is our proprietary deuterated psilocybin analog being evaluated for the treatment of major depressive disorder or MDD. The numbers and the impact of MDD are staggering. MDD has been ranked as the leading cause of disability due to mental illness, with an economic burden of over $200 billion in the U.S. alone. More sadly is that the suicide rate of people who die by depression stay is staggering and only about 1/3 of those treated for MDD drive benefit from existing treatments. So there is clearly an opportunity for improvement here. Turning now to CYB004, proprietary deuterated DMT molecule, which we recently announced that we plan to evaluate for generalized anxiety disorder or GAD. Like depression, anxiety disorders are a leading contributor to disability worldwide. By estimates, anxiety disorders affect 18% of the U.S. population and over 300 million people globally. What's most unfortunate in these patients is the prevalence of substance abuse and risk of suicide in people suffering. Like MDD, there are limited treatment options available for anxiety and relapse rates are very high. And the prevalence of depression in this population is also higher. So let's move on to the key updates for today. On our CYB003 and our CYB004 programs. I'll provide a quick overview of the information that we'll be sharing today, and then I'll leave it to the experts to take over for the deep dive. We are very excited by the progress that we've made on both of these programs. And through an interim data readout, which you'll hear much more about shortly, we've learned that CYB003 has so far confirmed what we saw in our preclinical studies, including a rapid onset of action and a short duration. We've seen low plasma variability among subjects and all of this at low dose levels of CYB003. In fact, we saw robust psychedelic effects at low dose ranges, and there were no safety concerns. So very encouraging, and we certainly gained deeper understanding of dosing dynamics that will further support our pivotal trials. And looking ahead, we expect Phase I/IIa top line data readout, including the look and efficacy in late quarter 3 of this year. So very exciting and gratifying to see robust and rapid psychedelic effects confirmed in these first subjects, which provide a strong indication that CYB003 has the potential to be efficacious and well tolerated, and you will hear more about this from Amir. This data also supports the completion of our Phase IIa portion of the study and our preparation for pivotal trials, some more to come on CYB003. For CYB004, in Part A of the study, and this is the part of the study that we acquired, which is now complete. The initial cohort showed no safety or tolerability issues with IV DMT. And we saw dose-related increases in both DNT exposure and behavioral effects. So there's a correlation between dose and effects that we're seeing. Most notably for this program, as we announced a couple of weeks ago, the initial study design has been expanded to include first-in-human dosing with CYB004, and we expect that to commence in early quarter 2. We continue to leverage the benefits of duration, in other words, improved by availability, brain penetration and half-life. To work on formulation development of CYB004 and to explore less innovative and more convenient dosing methods for CYB004, as compared to IV infusion and bolus. And we expect to complete this combination work in parallel to this current ongoing stay. Our Phase I top line data readout, including both DMT and CYB004 is expected in quarter 3 of calendar 2023. So our team continues to rapidly accelerate this program towards developing a highly competitive short acting and convenient treatment option for providers and for patients. So that's a quick overview, and we're going to go into much more detail. But let me introduce you now to the featured speakers. Firstly, Amir Inamdar, Cybin's Chief Medical Officer. Amir is a qualified psychiatrist and pharmaceutical physician with over 20 years of clinical and drug development experience. Amir has successfully led global teams and has overseen the development of novel medications across a range of psychiatric conditions, including treatment resistant depression, narcolepsy, anxiety, schizophrenia, bipolar disorder and substance use disorders. We're also thrilled today to have Dr. Maurizio Fava join us. Dr. Fava, as many of you in the audience will likely know is a world leader in the field of depression. Among his many accomplishments, Dr. Fava founded Boston Mass General Hospital's Depression Clinical and Research Program, which became one of the most highly regarded depression programs in the country. He is now the Executive Director of Mass General's Psychiatry Clinical Trials Network and Institute, the first CRO specialized in the coordination of multi-center clinical trials in psychiatry. As well as associate dean clinical and translational research and professor of psychiatry at Harvard Medical School. A big thank you, Dr. Fava for joining us today. And lastly to discuss CYB004, we're joined by a very owned professor Pradeep Nathan, Cybin's Vice President of Clinical Development. Pradeep is a neuroscientist with research interest in the molecular and neural substrates of psychiatric and neurological disease phenotypes. Pradeep's specialties include drug discovery and developments, experimental medicine, neuroscience, brain imaging, behavioral neuroscience, neuropharmacology and clinical trials in neurology and psychiatry. So thank you all for joining us today. And with that, I'll turn the program over to Amir. Thank you.

Okay. Thank you, Doug. Happy to be here today to share our progress and interim readout on CYB003, proprietary deuterated psilocybin analog, which is currently in Phase I/IIa development. Now Doug has already spoken about the significant unmet need in this area. When I joined Cybin, it was after almost 2 decades spent in the industry, developing treatments for mental illnesses where there really hasn't been any innovation for the past 50 years. What we've been doing is simply repurposing the same biological mechanisms over and over again, all targeting the monoamine, serotonin, norepinephrine, dopamine. And you add to that benzodiazepines and mood stabilizers and you pretty much cover the range of medicines available to treat mental health conditions. So these treatments, they're all symptomatic. They do nothing to address the fundamental maladaptive patterns of thinking that are at the root of most of these conditions. They work as long as they're taken. They have to be taken for a long period of time, and people relapse after stopping these treatments. These are, therefore, what I call the equivalent of band names for serious mental illnesses. With psychedelics, we have the opportunity to fundamentally change the way of the treatment of illnesses. And I'm proud to be part of a dedicated research team in the quest to transform the mental health treatment landscape. Now to CYB003. As mentioned, CYB003 is a deuterated psilocybin analog that we are developing, as a next-generation therapeutics for the treatment of major depressive disorder. As announced last August, we dosed our first patient in the Phase I/IIa trial having leased the clinic with a full IND package in just 18 months since starting preclinical work. What differentiates CYB003 in this optimized profile? Which makes it well suited to delivering and scaling in the existing health care infrastructure. CYB003 in preclinical studies, and based on the interim results we will share with you today has demonstrated a rapid onset of effect, which lasts for a short duration, low variability in plasma levels, which provides for consistent dosing, the rapid lead distribution to the brain, meaning there are no peripheral side effects, and low doses can achieve robust psychedelic effects. Now there's already a substantial body of evidence from small academic studies and data from virtualistic use that support the role of psychedelic like psilocybin and its analogs like CYB003 in the treatment of many mental health conditions like depression and alcohol use disorder. We chose major depressive disorder as our initial indication for CYB003, because the rationale is robust, and there is a need for new treatment in this area, which is a tip. Earlier, Doug referred to the tremendous loss of life and productivity due to depression, every life lost is one too many. And almost 2,000 people are dying due to suicide every day. To which, depression is a single largest contributor. So we have already initiated our study with CYB003 in MDD, and we expect top line data to read out in about 6 months time. In the next few slides, I will describe this ongoing study, and I will also describe the interim data from the completed cohorts. So this was the initial trial design, it was a randomized double-blind design in adults 21 to 65 years old, who were at least moderately depressed. Now that was assessed using the MADRS, which is the Montgomery as per depression rating scale. We also chose to include only those patients who were inadequate responders. Now these are patients who have tried at least one antidepressant and have not responded adequately, but they are not treatment resistant, the standard definition of treatment resistant, which we used was failure to respond to 2 or more antidepressants, given for an adequate duration and at an adequate dose. We signed the assessments on the MADRS to evaluate rapid onset of anti-depressive effects, as well as more traditional endpoints of 3 and 6 weeks. When we designed the study, the idea was to quickly establish safety and preliminary PK at low sub-psychedelic doses, and then rapidly escalate to doses that we believe would have therapeutic efficacy. Now safety of this class of drugs is quite very described in the literature. So what we wanted to do was expose as few people as we could to sub-psychedelic dose. That with cohorts 1 and 2 were small or mini-cohorts with 4 participants. And the important thing to note about this design is that each participant was getting 2 doses 3 weeks apart. Participants were randomized in a 1:3 ratio to receive placebo or active on day one. On day 21, all participants received active doses. So that gave us a total of 7 exposures per cohort to the study drug in each of these mini-cohorts. If you compare this with traditional bigger single ascending dose studies, they typically include 8 to 12 patients per cohort. So we still got a similar number of exposures compared to a traditional single ascending dose type of cohort. In total, we have planned to enroll about 40 patients with MDD in the study. However, we still realize that we needed to make some changes to the study based on data that we will gather. So at the sub-psychedelic doses or at the sub-psychedelic dose of 1 milligram that we administered in cohort 1, it was clear to the participants that they were not experiencing any psychedelic effects. And therefore, would not be getting any therapeutic benefit. As such, their motivation to stay in the study was poor, and we had one dropout after the first dose. So we have to immediately reassess the situation. Now prior to the start of the study, we had done extensive PK/PD modeling work, which had given us information about what sort of psychedelic effects we could expect at which dose levels. So we made a decision. And the decision was to switch to healthy volunteers at the lower dose levels, where we expected psychedelic effects to be in the lower range. And because healthy volunteers had no expectation of a therapeutic benefit, we did not have the risk of losing participants in this study. Therefore, in cohorts 2 and 3, we enrolled healthy volunteers with an aim to collect primarily safety and pharmacokinetic data. This would allow us to select doses for our MDD cohorts called 4, 5 and 6, where we will now be enrolling patients with depression. This also gives us the ability to do preliminary dose ranging at different dose levels in cohorts with the MDD patients. Typically, these dose range studies are conducted after proof-of-concept studies. But by incorporating this element in our first study, we will significantly accelerate our program. From this dose-ranging work, we will be able to select effective doses that we will test in our pivotal Phase III study starting next year. In addition to the above changes, we also incorporated a cohort to test for bioequivalence an effect of food. We are currently developing a formulation for our Phase III studies, and we will take the opportunity to test bioequivalence of a Phase III formulation with the one we are using in the current study. So far, we have completed dosing in the first 3 cohorts, where we tested doses of 1, 3, 8 and 10 milligram. Cohort 4 comments dosing on February 24, and we will be administering dose of 12 milligrams in this cohort. Taken together, these strategic amendments allow us to significantly accelerate our early development milestones and enable us to commence our pivotal study swiftly. So let me take a couple of minutes to describe how each cohort looks like. So firstly, all participants will undergo a screening period that will last up to 28 days, and this is for safety and eligibility assessments. And they will also undergo preparatory sessions. After screening, participants will be randomized to receive either active drug or placebo in a 9:3 ratio, respectively. The plan is to pull placebo patients from the 3 MDD cohorts at the end. So we will have a total of 9 placebo patients after 3 cohorts are completed. This will allow us to compare the 9 placebo patients with 9 active places at each dose level. Once randomized at the dosing session, participants will be administered the study drug. And during this dosing session, they will be supported by facilitators trained in our EMBARK protocol. At the end of the dosing session, we will collect efficacy data using the MADRS and data on psychedelic effects. This will help us determine how rapid the onset of effect is. We will also correct efficacy data on the day after dosing, again, to determine rapid onset of effects, and then 3 weeks later before the second dose. This 3 week time point is to assess the effect of a single dose. And here, we will compare single dose of active versus placebo. In the 3 weeks that follow the first dose, safety and weekly efficacy data will be collected and integration session, again, based on our EMBARK protocol will take place. Now traditionally, psilocybin studies, for example, have used a single administration approach, a single-dose approach. We've chosen a regimen of 2 administrations 3 weeks apart, because we believe that will give us the best chance of demonstrating robust as well as durable efficacy. Therefore, in this segment, all participants will receive an active second dose after 3 weeks. And 3 weeks after administering the second dose, we will assess efficacy again. So what this design allows us to do is to assess the benefit of a single dose versus placebo. In those patients who received active on day one, it allows us to assess the incremental benefit of a second dose of CYB003. And those who received placebo as a first dose, it also helps with retention. Thus, by the end of the study treatment period of 6 weeks, we expect to have a wealth of data. We would have assessed rapid onset of effects right after dosing session, the day after the dosing session at 3 weeks after a single dose and 3 weeks after a second dose. Finally, we also have an optional period of assessment, that will help us determine the durability of treatment effect, and this is out to 12 weeks. On the whole, this design provides the necessary safety and efficacy data to enable pivotal studies. Now moving on to the interim results. So first, the PK data. At doses ranging from 1 milligram to 10 milligram observed PK was as we expected. And we saw a fantastic PK profile for CYB003, the drug was rapidly absorbed after overall administration and was clear well from the body. Peak levels in the plasma were reached quickly in about an hour. The exposures we observed there within margins of safety and these are margins determined by our GLP tox studies. Importantly, we saw no variability in PK with consistent of variations, which are traditionally considered extremely favorable in PK studies. Another important observation was, as you can see in the figure on the top right, where we have dose normalized PK data. With escalating doses, the exposures remain predictable. And again, while the data are blinded, we can also see from the series of small figures at the bottom right, which depicts dose normalized data from individual participants receiving different dose levels, that there was minimal intra-individual variability with repeated dosing, which basically implies that same doses will consistently produce the same effects in individuals. Now moving on to the pharmacodynamic data or the psychedelic effects. These are, again, in the context of slow acting SSRI medications which takes weeks give us some fantastic results. When we did observe psychedelic effects at 3 milligram, robust effects that are consistent with therapeutic efficacy were seem starting at 8 milligrams. So all of these statements referred largely to 8 and 10 milligram doses. Onset of psychedelic effects was rapid with noticeable effects we observed and reported at 12 minutes post oral dose, maximum or peak effects were reached in about 90 minutes and this thing lasted for a short deviation of about 2 hours. Now using the visual analog scale for any drug effect at a dose of 10 milligrams, 2/3 of the participants reported the maximum score, which is 100. We can put this psychedelic effects again in the context of therapeutic efficacy based on some other psychedelic ratings. Firstly, the Mystical Experience Questionnaire or the MEQ30, which is a validated measure of psychedelic effects, and has been described in the literature to correlate with clinical efficacy. So more than half of the participants at 8 milligram or more had a complete mystical experience that is defined as an MEQ total score of more than 60%. Analytical experience is considered to be strong mediator of therapeutic efficacy in psychedelic studies. At the 10 milligram dose, the effects were even better with almost 70% of the participants achieving a complete mystical experience. Looking next at the Persistent Effects Questionnaire or the PEQ data. Again, almost 60% of the participants reported their experience being the most or among the top 5 most meaningful experiences of their life. Similarly, almost 60% reported their CYB003 experience as either the most or among the top 5 most psychologically insightful experience of their lives. All of these are described in the literature as an important predictors of therapeutic efficacy. So these data are for doses up to 10 milligrams. And as a reminder, in the MDD cohorts, we have started dosing at 12 milligrams. Moving quickly to safety. CYB003 was very well tolerated at doses up to 10 milligrams. All reported adverse events were as expected. They were mild to moderate in intensity, there were no severe adverse events. There were no serious adverse events. And the most common adverse events were again as expected, headaches, nausea, transiently elevated blood present. There's no discontinuances due to adverse events and all adverse events resolved without any need for any clinical intervention. So to summarize, CYB003 demonstrated a favorable PK profile, it was absorbed rapidly and showed low variability in plasma levels. Psychedelic effects were rapid in onset, beginning at 15 minutes after dosing and the peak lasting for about 2 hours. Using standard psychedelic rating scales we found that effects consistent with therapeutic efficacy were seen in most of the participants at doses of 8 and 10 milligrams. CYB003 was well tolerated up to 10 milligrams, adverse events were as expected. They were mild to moderate in intensity, they resolve without intervention, and there were no serious adverse events. Again, as a reminder, we have commenced dosing in MDD patients in cohort 4, where we are testing a dose of 12 milligram and the Phase IIa portion of the study is underway. So thank you for listening, and I will now hand over to Dr. Fava, who will speak about the treatment landscape and unmet needs in mental health.

Thank you so much, Amir, it's a pleasure to be here today and to have the opportunity to talk about the treatment options that we currently have for patients with depression and anxiety. So let me start with a review of what we have for major depressive disorder in addition to the typical psychosocial therapies, the kind of [indiscernible] like CBT and IPT. The most commonly used treatment for major depressive disorder has been monoamine-based pharmacological therapies. Things like SSRIs, SNRIs, atypical antidepressants. More recently, we've seen the emergence of glutamatergic and gabaergic pharmacological therapies like ketamine/esketamine, the combination of bupropion/dextromethorphan, brexanolone, and zuranolone not yet approved, but in the same kind of gabaergic brexanolone. We also have some magic therapies like ECT, VNS and TMS, and of course, the alternative in natural therapies. Now the -- if you look at how monoamine-based depressions were clearly all seem to modulate neurotransmitters like serotonin, norepinephrine, dopamine. And -- but they are clearly mutations. And I think that if you look, the efficacy is rather modest in the largest clinical trial depression ever conducted study, we found that only 33% of patients treated in Level 1 of STAR D with citalopram with an average dose of 40 milligrams, only 1/3 of the patients were admitted. And as you can see from the distribution of scores on the [indiscernible] SR, you have people there despite treatment continue to have moderate to severe or even very severe symptoms. In Level 2 study, where patients who didn't respond to the initial SSRI were switched to other monoamine-based therapies like bupropion, sertraline and venlafaxine, the remission rates were approximately 25%. So again, cumulatively slightly above 50% chances of remission with the 2 trials. And then with the percentage of remitters who do respond to Level 1 and Level 2 monotherapies, and then go on to mirtazapine or sertraline, on average, the remission rate is 10%. So again, cumulatively, with 3 trials of 12 weeks each over about 9 months, only about 50% of the patients remit, which is not ideal. In addition who -- those -- among those who relapse, a significant proportion of those who respond relapse, particularly those who respond after the second or the third trial. Another significant limitation of the current anti-depression therapies is that the speed of offset of efficacy is relatively slow. You -- again, going back to the STAR D trial, half of the patients who remitted on citalopram and Level 1 of STAR D did show between week 6 and 13. So though some patients remit within 6 weeks, the other half will remit later. Sexual dysfunction is another common side effect of [indiscernible] and you can see that this is a study by an impact of showing that almost 1/3 of the patients have sexual dysfunction. And weight gain is another issue with monoamine based therapies with about 20% of the patients on SSRIs gaining significant weight. And insomnia being another tolerability issue, with insomnia being relatively common in SSRIs and SNRIs. And finally, I think the residual symptoms are common. That is -- these treatments don't quite bring to complete resolution, a major depression disorder. In fact, as you can see from -- study from our group about 30% of the patients have a variety, who have responded under the presence. Between 30% and 50% have significant residual symptoms. And of course, the more residual symptoms you have, the more likely you are of relapse. In the case of anxiety or generalized anxiety like in the case of depression we have psychosocial therapies. We have slightly different pharmacological therapies. Benzodiazepines, gabapentin, pregabalin And these spines gabapentin, pregabalin, SSRIs, SNRIs, atypical antidepressants, alternative and natural therapies. Now given the limitations of monotherapies both in anxiety and depression, it's common for clinicians to use either augmentation or combination strategies with augmentation, being the use of a psychotropic agent without per se the indication of depression to enhance the effect of the antidepressant. And in the case of depressant 4 atypical antipsychotics are FDA approved for inadequate responders to antidepressant therapies, aripiprazole, quetiapine, brexpiprazole, and cariprazine. And no drug is yet an indication for inadequate responders to anxiety therapy, antianxiety therapy GAD. And the combination is a use of 2 other depressants or 2 antianxiety to enhance the therapeutic effect. The -- these are some of the aripiprazole studies that are shown in efficacy in depression, there is an augmentation as you can see robust effects for aripiprazole. Ketamine, this is a study we're seeing in colleagues that have published, we published a few years ago in the American Journal repeated doses showing nice separation between drug and placebo for IV ketamine. Of course, esketamine this is the Phase II trial that we published article psychiatry using the sequential parallel comparison design and showing a robust effect of the doses of esketamine. And as I mentioned earlier, esketamine has been approved [indiscernible] for the treatment of resistant depression. SAGE-217 or zuranolone has been shown efficacy in depression. And this is the New England Journal of Medicine paper, and the NDA has been submitted. So -- but moving away from gabaergic, glutamatergic and monoamine based therapies moving on to the psychedelics landscape, a number of companies have clearly been very active in this space, starting psychedelics or psychedelic analogs to look at their efficacy in depression, anxiety and so forth. I'm going to review some of the studies. The study of psilocybin-assisted psychotherapy versus escitalopram by Carhart-Harris and colleagues in the New England Journal of Medicine last year, showing a clear advantage in the first week for psilocybin versus escitalopram. And with the second dose 3 weeks later, maintaining their benefit over continued dosing of escitalopram. And of course, when you compare the adverse events, the overall larger comparable among the 2 fatigue is greater on the citalopram, anxiety is greater on escitalopram, but migrate slightly more common on psilocybin. The Davis published the same year a study of psilocybin-assisted therapy in MDD compared to delay treatment. And as you can see, there was a significant advantage of the -- of psilocybin both week 5 and 8, although -- whether delayed treatment is a good comparison kind of is questionable, but it really indicates the change observed with the psilocybin depression. A study by Palhano-Fontes and colleagues look at ayahuasca versus placebo and treatment of antidepressant. And ayahuasca was adjusted to contain 0.36 milligrams per kilogram of DMT, and again, significant advantage over placebo. And then this is the study by a guy Goodwin and colleagues from Compass in New England Journal of Medicine this year, showing that 25 milligrams of psilocybin was significantly better than 10 and 1 milligram. And as you can see from the paper, the response rates were significant, but they were also accompanied by greater [indiscernible] emergence on the higher dose, which may be the reflect of people not ever got better and perhaps the lack of benefit may have induced some [indiscernible]. It's at least one explanation that has been suggested with more adverse events, of course, on the higher doses. And as you can see this is the table from the same paper comparing the tolerability across the 3 doses. I think from a neuroscience standpoint, I think that many people argue that psychedelics modulated default mode network or DMN. DMN is involved, as you know in daydreaming and mind wandering, and also in the retrieval of autobiographical memory or sense of self. And so, we see increased DMN activity in remediation and craving, relapse to substance abuse. And it has been reported that we see decreased treatment activity with psilocybin, LSD and ayahuasca. And, of course, this is a paper by Pasquini showing significant decreases of DMN within the posterior cingulate cortex for the ayahuasca group compared to placebo. So what are the advantages of secondary treatment, rapid efficacy is -- certainly is one. But also long-lasting effects because of the effects of neuroplasticity, synaptogenesis and default mode network. Another advantages of psychedelics may be the transdiagnostic utility. They seem to be promising depression, resistant depression, resistant anxiety, PTSD, substance abuse and even pain. Challenges, clearly, expectation issues are very robust. People participating in these trials, how to minimize expectations or at least have an adequate form of placebo, a complicated delivery model, people cannot just take them and just drive home right away. Insurance coverage is something that has not been discussed yet, but I'm sure that the companies are greater to commercialization, have started those conversations. And then the spravato experience has shown that there is resistance to adoption of complicated delivery models. And the other issue is the intermittent delivery of care. People -- these long-lasting benefits require perhaps intermittent administrations. And that has not been the model, psychiatry typically, it won't go too well, we keep you well, people taking things in the long-term, and this will be a very different paradigm. In summary, currently available pharmacological treatments for depression and anxiety, and multiple limitations, modest efficacy, hospital responses delayed, burdensome side effects, psychotherapies modest efficacy and a hard to access. We have a shortage in the U.S. of over 50,000 psychologists, they had to catch up. And more promising pharmacological therapies are clearly targeting glutamate, gaba, and of course, the psychedelics. Thank you very much, and I'm going to now pass the baton to Professor Nathan.

Thank you, Dr. Fava for providing an excellent overview of the current treatment landscape in mood and anxiety disorders. So I'm Pradeep Nathan, I'm the program leader for CYB004 program. And I'm really excited to have the opportunity to share with you the progress we're making on CYB004, deuterated dimethyltryptamine or DMT molecule. By way of background, in its natural form, DMT is rapidly metabolized in the body by the enzyme on monoamine oxidase, and it's not orally bioavailable. As a result, DMT is short acting. We believe that our proprietary deuterated DMT has potential to overcome existing limitations of DMT in its natural form. CYB004 is a new chemical entity with the composition of matter patent granted through 2041. Preclinical studies suggest that CYB004 has an optimized PK profile with increased bioavailability and longer exposures that could potentially extend the therapeutic window. This gives us the opportunity to develop other formulations, including subcutaneous, intramuscular for ease of use and scalability. Psychedelic drugs, which are agonists at serotonin receptors, including 5-HT1A and 5-HT2A receptors have demonstrated great promise to treat mental health disorders with rapid and durable efficacy demonstrated in a number of recent clinical trials in mood and anxiety disorders. CYB004 is being developed for GAD with and without depression. And in subsequent slides, I will explain why we have chosen this indication. We have made incredible progress in the clinical development of CYB004 in a very short time with a Phase I study of DMT and CYB004 ongoing. We expect top line data to be presented in quarter 3 of 2023. So we have selected GAD as a primary indication for CYB004, and this is based on 3 key criteria. First and foremost is a scientific rationale. We want to ensure that we have a solid biological rationale for pursuing this indication. And in reviewing this criteria, we've asked, is there a good biological rationale? And is the scientific and clinical evidence strong? Second is the unmet need. We want to target an indication with a significant unmet need and where we can make the greatest impact to patients. And we have asked in doing so, what is the standard of care in GAD? Are the treatments adequate? And is there room for improvement? And finally, the market opportunity. We want to ensure we are targeting an indication where there is a high economic burden and a growing market size. So let me go through our key criteria in a little bit more detail. So first, the scientific rationale. DMT has a rich pharmacology with agonist effects at multiple receptors, but the most potent of DMT's pharmacology is on serotonin 2A and IA receptors. While the 2A receptors are primarily linked to its psychedelic effect, both the 5-HT1A and 5-HT2A receptors have been primarily linked to its anxiolytic and antidepressant effects. Of interest, the 5-HT2 receptor has been thought to have effects on synaptogenesis and synaptic plasticity, which may underlie the durable effects observed with psychedelic drugs including DMT. There's also a good overlap between the pharmacology of DMT and the biology of mood and anxiety disorders. Both 5-HT2 and 1A receptors are highly expressed in brain circuits, relevant for anxiety disorders and depression, including the front limbic circuits. And hence, DMT as a drug is well placed to modulate key brain circuitry that underlie clinical symptoms. And consistent with this pharmacology and biology, there is strong recent clinical evidence that 5-HT1A and 2A agonists have anxiolytic and antidepressants, such as the peer reviewed and published studies recently showing effects of LSD and anxiety disorders, the [indiscernible] in treatment-resistant depression and the effects of DMT in major depressive disorder. So the second criteria is the unmet clinical need. The lifetime prevalence of GAD is approximately 3.7% globally, with rates ranging from 1.6% in low-income countries to 5% in high-income countries. It's one of the leading causes of global disability. GAD has a high rate of comorbidity with other psychiatric disorders and in particular, depression with approximately 70% of GAD patients having a depressive episode in their lifetime. GAD with depression is associated with poor quality of life and prognosis and an increased risk of suicide. Current treatments, including antidepressants and psychotherapy have modest efficacy, remission rates are 20% to 25%, and we know that 1 in 5 patients don't achieve adequate clinical response. There's also a large discontinuation rate for antidepressant, and this is also associated with high relapse rates. Since there is undoubtedly a significant unmet need in GAD, an opportunity for us to develop better treatments to have greater impact to patients' lives. Finally, the market opportunity. The market size of GAD is expected to increase by approximately 500% by 2027 in the U.S., while the global market size is expected to grow to USD 12 billion by 2030. And hence, there is a significant market opportunity where current treatments are not very effective. I will now move on to providing an update on our CYB004 programs. We have previously shared data that deuteration of DMT can increase its exposures. Displayed in these graphs are preclinical data on CYB004, showing that deuteration of DMT increases its exposure and slows some metabolism when given as an infusion, as shown on the left-hand side of the slide and the bolus plus infusion as shown on the right. So these data are exciting because this might open up opportunities to look at different formulations such as subcutaneous or intramuscular. And this could potentially give us the opportunity to increase the therapeutic window of DMT and overcome the limitations of natural DMT, which is short acting. We have made considerable progress in accelerating the clinical development of CYB004. We have made 2 strategic and scientific steps to move the program forward. The first key step was the acquisition of a Phase I DMT study last June. We felt that this was necessary because of the limited published clinical data on the pharmacokinetics and pharmacodynamics of DMT. The study named CYB004-E is being conducted in the Netherlands at the Center for Human Drug Research or CHDR and will generate one of the largest clinical data sets on DMT. The data is important because we will use this data to build a robust understanding of the pharmacokinetic and pharmacodynamic relationships, which will support dose optimization for future studies. Through this strategic acquisition of the Phase I study, we have accelerated our clinical development time lines by almost 9 months. The second key step in our efforts to accelerate the clinical development of CYB004 was to make important protocol amendments in the CYB004-E study. And this is done to support the valuation of different dosing regimens and doses and more importantly, to support the inclusion of a first time in-human study of CYB004 to examine the advantage of deuteration on the human PK and PD parameters. These amendments are important steps that will help us build a robust PK/PD model to support dose optimization for future studies. The data may also support less invasive and more convenient dosing methods, including subcutaneous and intramuscular routes of administration. I would like to now go through the objectives of the study design and present some high-level data from our ongoing CYB004-E study. First, the objectives. The primary objectives for Part A and Part B were to determine the safety, PK and PD of escalating doses of DMT in healthy subjects. For Part C, which is the first time in human study of CYB004 to evaluate the safety, PK and PD parameters of increasing doses of CYB004 in healthy subjects. And the second objectives were to understand the relationship between drug exposure or PK and physiological and behavioral effects or PD, and build a robust PK model for further dose optimization in future studies. Turning now to the design. The overall CYB004-E study had 3 parts. Part A. Part A is a single ascending dose study of DMT. This part of the study was the one that was acquired last June. This is a single ascending dose study in smokers, had a 90-minute infusion of DMT and 4 cohorts were tested. And this part of the study has now been completed, and I will present the high-level data of this part of the study in a subsequent slide. Part B and C are the parts that have incorporated the new changes to the design through the amendments we made to the protocol. Part B will test DMT and the key design changes there are inclusion of healthy nonsmokers, inclusion of a shorter bolus and infusion regimen and options for flexible dose exploration. We are on track with Part B and have commenced dosing. Part C will be, we'll move on from DMT to CYB004 and this will be the first time in human study of CYB004, and similar to Part B, the study will be conducted in healthy nonsmokers and explore a shorter bolus plus infusion regimen with options for flexible dosing. I will now go through the design of each part in a little bit more detail. So Part A, as I said, is up to 4 cohorts of 10 healthy smokers. The study utilized an adaptive single dose, double-blind, randomized, placebo-controlled design. And the DMT was continuously infused for 90 minutes. DMT doses were increased proportionately from cohorts 1 to cohorts 4. Blood samples were collected at regular intervals during and after the infusion for PK analysis and the PD effects were measured using established questionnaires probing psychedelic and behavioral effects. Described in this slide are top line blinded data from Part A of the 4E study. From a safety perspective, we can report that DMT doses were well tolerated with no serious adverse events. The most common adverse events were headache, nausea, fatigue, somnolence. And these adverse events were mild in intensity and consistent with what has been reported in the literature. Finally, there's no clinically relevant changes in clinical laboratory or ECG parameters. With regard to the PK, we observed a dose proportional increase in PK in the target concentration range. And consistent with the PK, we also observed a dose-related increase in behavioral measures of subjective psychedelic experience. The full detailed data will be presented in quarter 3 of 2023 on completion of the CYB004-E study. The PK and PD data from Part A was important in supporting the design of Part B and in particular, the dose optimization. Moving on to the design of Part B and C. Part B is a study with DMT with an optimized dosing regimen. It is a 2-way crossover design with 10 healthy nonsmokers. The study is a single-blind ascending fixed dose order crossover design. 2 different DMT bolus and infusion regimens will be tested to target different steady-state DMT concentrations. Part C is the first time in human study of CYB004. It is made up of 2 cohorts. The first is a 3-way crossover with 12 subjects, which each subject tested following a low dose and mid-dose of CYB004 or placebo in a randomized double-blind, placebo-controlled design. The second is a 2-way crossover study with 12 subjects, where each subject will be tested following a high dose of CYB004 or placebo in a randomized double-blind, placebo-controlled design. For both Part B and C, blood samples will be collected regularly for measurement of PK and PD effects will be measured using established measures of psychedelic and behavioral effects. I would like to end my presentation with some key highlights from the CYB004 program. First, our preclinical data has demonstrated that deuteration of DMT leads to higher exposure and slower metabolism. We have made significant progress in our clinical program and the data from Part A of the 004-E study suggests DMT infused over a 90-minute period is well tolerated within the dose range tested. We also observed dose-related increases in exposure and behavioral effects. Dosing in Part B, which is the DMT bolus plus infusion, has commenced and the study is on track with our time lines. Data from Part B and Part C will be used to build a robust PK/PD model to support optimization of doses and exposures for future studies. We believe CYB004 has the potential to offer a less invasive and more convenient dosing options for patients, and these are currently being explored in studies. Top line data for from the CYB004-E study is planned for quarter 3, 2023. So this concludes my presentation. Thank you for your attention. I will now hand over to Doug Drysdale for his concluding remarks.

Great. Thank you, Pradeep. And also thank you to Dr. Fava and to Amir. I think we can all agree that Cybin has some truly groundbreaking work in process. I'm so proud of this team that continues to execute just both surgically and flawlessly. We've given you a lot of information to take in today, but it's our hope that you can come away from today's session with an understanding that for CYB003, the interim data confirmed what we expected in humans and what was observed in our preclinical studies, including achieving 3 important goals for CYB003, rapid and short-acting effects, low variability in plasma and low dose levels that achieved already robust psychedelic effects that were safe and well tolerated. These data continue to support dosing in MDD patients at psychotic doses and in fact, dosing patients about 12 milligrams with CYB003 has already begun. And let's remember just how rapid the effects of psychedelics appear to being on patient symptoms when compared to SSRIs, which are the current standard of care, as you heard from Dr. Fava. For CYB004, Phase I Part A showed no safety or tolerability issues with IV DMT and we will take those learnings into a more complex parts B and C of that study, as you heard from Pradeep, Part B has already begun. So the current study design has been expanded to include first-in-human dosing of CYB004, to accelerate our understanding of the dose dynamics, and this exciting piece is expected to commence in April. And finally, efforts are underway to investigate other less invasive and potentially more convenient dosing methods for this treatment, for CYB004. All of this work supports our central goal of generating solid safety and efficacy data, over time, we'll gain regulatory approval and help the patients who so desperately need new solutions. And Cybin is proud to be a leader in this important transformation of mental healthcare. As you've heard this morning, 2023 promises to be a really exciting year of great progress for our CYB003 and our CYB004 programs. Already during this first quarter, we've completed the CYB003 Phase I part of the study, assessing PK and psychedelic effects and have initiated dosing in MDD patients of psychedelic doses. For CYB004, we received approval earlier this month for the first in human dosing and have initiated Part B dosing in the CYB004-E study, quickly moving that study along. Moving to quarter 2 in 2023, the CYB004, we plan to complete GMP manufacturing of that product and importantly, initiate CYB004 first-in-human dosing. And for CYB003, we plan to initiate bioequivalence cohort for CYB003 [indiscernible] in preparation for our pivotal studies. In quarter 3, we expect to complete CYB003 dosing in MDD patients, and we have 2 important data milestones in the third quarter. Our top line data readout from the CYB004-E trial, including both DMT and CYB004 cohorts, and we expect to have CYB003 Phase I/IIa top line data, including a look at efficacy around the end of that quarter, also support an NDA submission for CYB003 pivotal studies in quarter 4. And I think based on what we've seen today for CYB003, we're very excited about that efficacy readout is coming just a few months from now. The Cybin team is extraordinarily committed to walk through this work as I think is evidenced by the speed at which we're making meaningful progress advancing these programs. So I hope that these in-depth presentations today have provided greater clarity around our in-human programs and confidence in the science support in these programs. In closing, I'll reiterate that we see an enormous growth opportunity, both for us as a company and for the psychedelics industry as we progress along this regulatory pathway. And the data we presented today on CYB003 and CYB004 give us continued confidence in their potential as breakthrough mental health treatments. So we look forward to sharing more future updates on these programs as the most progress, and thank you very much for your attention today. And with that, operator, we'll open the call up for questions. Thank you.

[Operator Instructions] So our first question comes from Patrick Trucchio from H.C. Wainwright.

Congrats on all the data. I think just first, a clarification question. Just in terms of the Phase I/IIa trial, will cohorts 4, 5 and 6 also include a second active dose? And in terms of the top line data expected in the third quarter, at that time, will we have data from cohorts 4, 5 and 6? And what are the expectation in terms of improving [indiscernible] for those cohorts?

I think the first 2 questions are simple, yes and yes. So yes, 2 doses in each cohort. And yes, we expect all 3 cohorts to read out in quarter 3. And maybe, Amir, you want to talk about expectations around [indiscernible] improvements, that would be helpful.

Yes. I mean, that's an interesting one because clinical trials are tricky. You don't always see what you expect and sometimes you see what you don't expect. We didn't expect such robust efficacy from psychedelics that we've seen in these studies. What we estimate from the MDD cohorts is efficacy, which is better than the current standard of treatment, which is generally SSRIs. SSRIs typically show an effect size of 0.2 to 0.3 in the studies that we've conducted and seen so far. We expect something better. We expect effect to be robust. We expect them to be durable, and we have a time point in the trial out to 12 weeks, which will demonstrate, hopefully, that these effects are durable with just 2 doses of CYB003.

Got it. That's helpful. And then maybe just a few for Dr. Fava, if I may. Just first, I'm wondering if you can give us your thoughts on the data that's been generated by CYB003 so far and reported today and how you would envision CYB003 fitting in the treatment paradigm for MDD should it continue on to an eventual FDA approval?

Well, that's a great question, Patrick. So the data thus far are very promising in terms of kind of what we consider kind of [indiscernible] signatures of the effects of the drug. So though these were in healthy volunteers, we see these effects have been correlated with clinical improvement in patients with depression. So their progress in the next stage is the most exciting one is the one where we're taking a treatment that has shown kind of from a PK perspective, all this and in terms of side effects, similar profiles to traditional psychedelics, we're going to see the degree of improvement that we would expect in depressed patients. One of the things that we're going to do to minimize the placebo response because, as you know, expectations are a big modulator of placebo response, and they can really torpedo clinical trials. We're going to use our safer methodology that is the independent verification of the patients meet the criteria, have the disease, have the severity, have the treatment history prior to exposure to the treatment. So that's a way of mitigating kind of no specific effects. And then response to the question, if these treatments make it to the clinic, get eventually down the road, I think that will require education because they will require a change in the way we practice, I'm a practicing clinician, I'm used to prescribing treatments that people take every day. And although years ago, we had the product weekly once a week, and we have now ketamine which is intermittent, but it's intermittent but relatively frequent, with psychedelics, we may be dealing with very frequent treatments. So that will be a new paradigm that will require education and getting finishes comfortable.

Yes. And just one last one. Just on Slide 61, you outlined several challenges. So I'm wondering what do you think drug developers to do during the clinical development or in the commercialization of the psychedelic agents to overcome those challenges?

Well, I think one is demonstrate that these treatments do not require extraordinary measures of monitoring. So trying to show that maybe in 2 or 3 hours, the patients could be out of the clinic. That would be a great improvement versus overnight stay. An overnight stay becomes more complicated. The challenge for us is that you have repeated multiple types, you have to come in for 3 hours of observations, that is complicated. If you do it once or twice, it's not a big deal. So I don't see it as a big deal. But try to demonstrate the safety and the lack of need of overnight stay will be very, very important. Simplification of the process. Like right now, for example, for many studies, you may require 2 monitors, will they always require 2 monitors, whether one be sufficient and so forth. All these things, I think, will be important.

Our next question comes from Frank Brisebois from Oppenheimer.

Just a quick one here. I'd love to hear from Dr. Fava here, maybe the difference in maybe efficacy expectations when you compare an MDD population versus a TRD population. And on that point, maybe touch in also in the real world, would you contemplate using this more on the severe or the moderate patient?

So Francois, I completely agree with you as kind of the expectations are going to be lower on improvement in the TRD population compared to MDD. So we know that placebo response rates are greater in MDD compared to TRD because having failed to respond to an antidepressant per se is a prediction of failure to respond to placebo. So that's another way of kind of derisking, the development is by taking populations who may have a lower level of expectation or a lower likelihood of placebo response. The other question or the other comment that you made, if I understand, can you just remind me the second issue...

Yes. It's in a similar thought process where I'm just wondering in the real world, if you expect physicians to be comfortable with only maybe the severe population…

So then the question is cost, right? No treatment may be more costly on administration, but there may be less cost of the, there's no chronic treatment, might make this appealing to people who may, let me ask you a question, Francois. If you came to me and said, you know, I have been suffering from depression for the past 6 months, never tried anything. I'm not saying to you, okay, we have a terrific treatment SSRI. You look I have about a third chance of remission, but you'll have a 30% chance to potential side effects, 20% chance of weight gain, 20% chance of insomnia, and 20% chance of cognitive impairment, memory, would you take it? You say, yes, give it to me. Or would you say, doctor, could you give something that maybe doesn't have the side effects or, so I'm just saying that, yes, resistant depression is the logical phase where insurance companies are going to have to push the seats, and do it for severe, do it later. But for customers, for patients, do you really want to go through a instant 3 antidepressant trials for 12 weeks for 9 months remain depressed to then determine and you need a psychedelic treatment. So I don't know. I mean, yes, these are things, these are the base that companies that develop psychedelics will need to have with insurance companies, but I'm just saying I wouldn't limit the use of psychedelics to only severe or resistant because there will be benefits early on.

Our next question comes from Charles Duncan from Cantor Fitzgerald.

Yes. Can you hear me? And team, thanks for hosting this very informative call. And thank you to Dr. Fava for sharing your time and perspectives with us. I did have a question for Dr. Fava and then one for the team. First of all, Dr. Fava, I think that you started to allude to this. But I guess I'm wondering if you think about intermittent treatment paradigms versus a daily chronic therapy, what is most important to you? Is it a 6-week MADRS change? Or is it some MADRS change that is durable? And how do you see this emerging treatment paradigm relative to the standard of care?

So Charles, great question. And as a clinician, what I'd like to see is a reduction in the MADRS score in a range where the patient says I'm good. I think, remission from major depressive disorder is always our goal as clinician. So when the patient gets better and the MADRS get in the very low single digits. We're in the remission range, which is great. The durability of that score, we know in depressed patients, even though they will continue treatment, they may have some fluctuations if they have a bad day at work or at home. So we don't necessarily assume that it will always be in the single digits on the MADRS. But as long as it stays in that range, that would be really terrific. Now I think that the durability of the treatment effect is going to be very important. So if you switch to the model of kind of intermittent or very sporadic, very rare administration of treatment in order to educate clinicians, you have to have a way of knowing if at some point, the patient has a return of symptoms, when it happens and how quickly you can re-challenge them. So it's important to have that figured out in the clinic. Now we're going to see if zuranolone gets approved, zuranolone has a 2-week treatment and then follow-up afterwards, that already in some ways is preparing finishes to the paradigm of psychedelics.

Yes, that's what I thought as well. And I guess the question, a follow-on question for you, and I understand you can't really speak for the FDA, but what do you think the FDA is going to want to see in terms of not only effect size, say, in the acute setting, say, a 6-week primary endpoint, but then also durability, given what you know about, say, this class of drugs generally, maybe just picking out [indiscernible] versus, say, even zuranolone, which is not a free drug either in terms of side effects. So what do you think the durability is going to be needed to compel the agency?

I really don't know what the FDA will want, I think that these are uncharted territories and I think, fundamentally, clinicians, we want to say things that the FDA would want, which is to know how long the benefit lasting. So some indication of that will be [indiscernible] helpful.

It's very helpful. Quickly moving to the team for Amir and/or Amir or Doug, kind of a 2-part question. First of all, for the ongoing Phase I/IIa cohorts 4, 5 and 6. I think the answer to a previous question that you'd have all 3 in the third quarter. And I guess I'm wondering if you can provide clarity on that? And then secondarily, what doses are you thinking? You started with 12 milligrams. I would have kind of thought that you'd start with 10 in human volunteers, you did so. But then what are cohort 5 and 6 doses that you're planning?

Amir, do you want to take that?

Yes. So all 3 cohorts will read out in Q3. That's our expectation. We've already started enrolling in cohort 4 at 12 milligram as you mentioned there. enrollment, we've got patients lined up. So there's good interest in the trial. And we expect to enroll 12 per cohort until the third quarter. Now this is a cohort-by-cohort administration, after we complete each cohort, we look at the data, we look at, of course, blinded data, we will look at safety, we will look at psychedelic effects. And it becomes, therefore, an iterated process as to what will be the next dose. Would we want to stay at 12 milligrams? Remember, we've got 2 doses within the cohort. There is also the opportunity to test whether if somebody, let's say, we start them at 12 milligram, they don't respond to the first dose of 12 milligram. Can we push the dose slightly higher? And will they respond to a higher dose? Because all patients are different. We've been talking about personalized medicine for a very long time. Everybody is different. Everybody has got a different receptor reserve in terms of serotonin receptor. Patients may respond slightly differently to healthy volunteers. And that was one of the thinking when we chose 12 milligrams. So in healthy volunteers up to 10 milligrams, we are fine. But it is our belief that when we go into patients, patients will require slightly higher doses. One unique feature about the study is we are not taking patients off their ongoing antidepressant treatment. They will continue their SSRIs. We don't know if SSRIs will affect the response. But definitely, we do know that the SSRIs have an effect on the serotonin receptor reserve. And therefore, there may be a need for a slightly higher dose in patients who are currently taking an SSRI. That's why we went to 12 milligrams. In future cohorts, there is also an option to come down if we think that 12 milligram has overwhelming efficacy, but maybe it's not the best tolerability, we can come down and use a different or multiple different approaches there. So all options are open. It's going to be an iterative process, and we expect it to read in the third quarter.

Very good, interesting trial design, Amir. Last question for Doug quickly. In next year '24, would you anticipate to be able to move in into a pivotal study? And I think that Amir mentioned earlier that you're working on a Phase III formulation, will that be ready for that particular pivotal study, if so?

Yes. In fact, Charles, the changes that we've made here with the dose escalation, the dose study and the bioequivalence and the food effect, these changes to this study put us in a much better position, a stronger position to file to begin our pivotal study next year. So that filing should happen in the fourth quarter. The ongoing manufacturing is just making sure that we have GMP products for that study as well, which will happen in parallel with the current work that we're doing... So yes. So... for that question, Charles. I think we have time for one more, Tara.

Our final question comes from Elemer Piros from EF Hutton.

Yes. Maybe for Dr. Fava, Dr. Fava, what do you think some of the initial hesitation from psychiatrists would be if and when and once psychedelic therapies are available to treat depression.

So Elemer, it's a great question. I cannot predict the future in terms of how this will be received. That said, I think we can anticipate some challenges. One is the stigma of psychedelics. we have stigma of mental illness to begin with. You then add to the stigma of mental illness the stigma of psychedelics of kind of the perception of what psychedelic treatments are. I mean I think we've been able to overcome that with ketamine. Ketamine was known as a drug of abuse and yet these days, I don't know anybody, any clinician, at least around here who's not comfortable referring a patient to ketamine clinic. So the stigma of ketamine has been overcome. I think that we'll need to do the same thing, education, reassurance and safety, and we're not sending people home. We're not planning to send people home with psychedelics. So I think that these are obstacles that can be overcome. But I think that the more we can be proactive, address issues that are raised by clinicians early on, educational programs, these days nobody is doing educational programs anymore. I mean, well, let me rephrase it. There are very few educational programs for physicians that people can attend. We certainly do them at Mass General. We have [indiscernible] course every year with over 1,000 people attending. Just saying that massive educational efforts will be required in my mind to very significant educational efforts to educate people about psychedelics, how to use them properly, how to monitor, what to expect in all these things, you have to realize most academic centers, drug reps are not allowed. They can't even set foot, so how do you educate people about the treatments?

Right. Dr. Fava, maybe just one last question. During the last couple of years or so, as you've started seeing this the data emerge, was there a moment in your mind that, oh my gosh, there is something here. We definitely need to pursue psychedelics?

Yes. I mean absolutely, there's no question that the data have been extraordinarily promising. In fact, my presentation I captured some of the things that got really my attention. That said, the question is how this data will translate into Phase III? How do we minimize placebo response? All those things, all those small details become very important in Phase III programs. But as I mentioned, with Mass General, and CT&I, we're collaborating with Cybin to help them develop the best possible program for Phase III.

Thanks for the questions, Elemer. This concludes our question-and-answer session for today. I'll now turn it back to Doug for quick closing remarks.

Thank you, Tara. Thank you again to all of our speakers for today, in particular, Dr. Fava, thanks for joining us. Always a pleasure. I want to thank you all for joining us today and for following the progress of these important programs. Remember, you can download a copy of today's slide deck from our website. Thank you for joining us.