Good morning. Welcome to the Cybin R&D Day. At this time, all attendees are in a listen-only mode. A question-and-answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. 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, welcome to Cybin's R&D Day. Thank you for joining us today. I'm Doug Drysdale, the CEO of Cybin, and I'll be your host this morning. We have an exciting and informative program today highlighting progress on two key clinical programs. CYB003, our deuterated psilocybin analog for major depressive disorder, CYB004, our 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 interim readouts from our phase 1/2 CYB003 trial. Very excited about this, it's worth noting that CYB003 is the first-ever deuterated 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 A.M. 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 hold a moderated Q&A session after the prepared remarks. To submit a written question, please fill out the form on the webcast homepage.
A webcast replay will be available later today on Cybin's website in the investor 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. Let's begin. What do we mean when we say we're revolutionizing mental health care? You know, Cybin takes a 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. 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 falls 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 time 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. 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. 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, strategic partnerships, and a robust pipeline. We're looking at a range of treatments, routes of administration to give patients and providers 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've quickly become a multi-program clinical-stage company with the financial stability and access to capital to support our strategy and our clinical milestones. Let's get into the programs themselves. CYB003 is our proprietary deuterated psilocybin analog being evaluated for 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 each day is staggering. Only about a third of those treated for MDD derive benefit from existing treatments. There's clearly an opportunity for improvement here. Turning now to CYB004, our proprietary deuterated DMT molecule, which we recently announced that we plan to evaluate for generalized anxiety disorder or GAD. You know, 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. The prevalence of depression in this population is also high. Let's move on to the key updates for today. 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. 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. Very encouraging, and we certainly gained deeper understanding of dosing dynamics that will further support our pivotal trials. Looking ahead, we expect phase 1/2- A top line data readout, including a look in efficacy in late quarter three of this year. 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. You'll hear more about this from Amir. This data also supports the completion of our phase II-A portion of the study and our preparation for pivotal trials. 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 cohorts showed no safety or tolerability issues with IV DMT. We saw dose-related increases in both DMT exposure and behavioral effects. There's a correlation between dose and effects that was seen. 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 of CYB004, and we expect that to commence in early quarter two. We continue to leverage the benefits of duration. In other words, improved bioavailability, brain penetration and half-life to work on formulation development of CYB004 and to explore less invasive and more convenient dosing methods for CYB004 as compared to IV infusion than bolus.
We expect to complete this formulation work in parallel to this current ongoing study. A phase I top line data readout, including both DMT and CYB004, is expected in quarter three of calendar 2023. Our team continues to rapidly accelerate this program towards developing a highly competitive, short-acting and convenient treatment option for providers and for patients. 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 Massachusetts General Hospital's Depression Clinical and Research Program, which became one of the most highly regarded depression programs in the country. He's now the Executive Director of Massachusetts General Hospital's Psychiatry Clinical Trials Network & Institute, the first CRO specialized in the coordination of multicenter clinical trials in psychiatry. Associate Dean for Clinical and Translational Research and Professor of Psychiatry at Harvard Medical School. A big thank you, Dr. Fava, for joining us today. Lastly, to discuss CYB004, we're joined by our very own Professor Pradeep Nathan, Cybin's Vice President of Clinical Development.
Pradeep is a neuroscientist with research interests in the molecular and neural substrates of psychiatric and neurological disease phenotypes. For these specialties include drug discovery and development, experimental medicine, neuroscience, brain imaging, behavioral neuroscience, neuropharmacology, and clinical trials in neurology and psychiatry. Thank you all for joining us today. 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, our proprietary deuterated psilocybin analog, which is currently in phase 1/2- A development. 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 monoamines serotonin, norepinephrine, dopamine. You add to that benzodiazepines and mood stabilizers, and you pretty much cover the range of medicines available to treat mental health conditions. 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 equivalence of band-aids for serious mental illnesses. With psychedelics, we have the opportunity to fundamentally change the way we treat mental illnesses. 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 therapeutic for the treatment of major depressive disorder.
As announced last August, we dosed our first patients in the phase 1/2-A trial, having reached the clinic with a full IND package in just 18 months since starting preclinical work. What differentiates CYB003 is its optimized profile, which makes it well-suited to delivering and scaling in the existing healthcare 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, rapid redistribution to the brain, meaning there are low peripheral side effects, and low doses can achieve robust psychedelic effects.
There's already a substantial body of evidence from small academic studies and data from ritualistic use that support the role of psychedelics 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 acute. 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 the single largest contributor. We have already initiated a study with CYB003 and MDD, and we expect top-line data to read out in about six 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. This was the initial trial design. It was a randomized double-blind design in adults 21- 65 years old who were at least moderately depressed. Now that was assessed using the MADRS, which is the Montgomery-Åsberg Depression Rating Scale. We also chose to include only those patients who were inadequate responders. Now, these are patients who have tried at least 1 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 two or more antidepressants given for an adequate duration and at an adequate dose.
We timed the assessments on the MADRS to evaluate rapid onset of antidepressant effects as well as more traditional endpoints of three and six 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 believed would have therapeutic efficacy. Now, safety of this class of drugs is quite well described in the literature. What we wanted to do was expose as few people as we could to sub-psychedelic doses. Therefore, cohorts one and two were small or mini cohorts with four participants each. The important thing to note about this design is that each participant was getting two doses three weeks apart. Participants were randomized in a one is to three ratio to receive placebo or active on day one. On day 21, all participants received active doses.
That gave us a total of seven exposures per cohort to the study drug in each of these mini cohorts. If you compare this with traditional Biggles single ascending dose studies, they typically include 8-12 patients per cohort. 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 this study. However, we soon realized that we needed to make some changes to the study based on data that we were gathering. At the sub-psychedelic doses, or at the sub-psychedelic dose of 1 mg that we administered in cohort one, 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. We had 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. 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. Because healthy volunteers had no expectation of a therapeutic benefit, we did not have the risk of losing participants in the study. Therefore, in cohorts tw and three, 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 four, five, and six, 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 ranging studies are conducted after proof of concept studies. 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 and effect of food.
We are currently developing a formulation for our phase III studies, and we will take the opportunity to test bioequivalence of our phase III formulation with the one we are using in the current study. So far, we have completed dosing in the first three cohorts, where we tested doses of 1 mg, 3 mg, 8 mg, and 10 mg. Cohort four commenced dosing on February 24th, and we will be administering doses of 12 mg 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. Let me take a couple of minutes to describe how each cohort looks like. Firstly, all participants will undergo a screening period that will last up to 28 days, and this is for safety and eligibility assessments. 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 pool placebo patients from the three MDD cohorts at the end. We will have a total of nine placebo patients after three cohorts are completed. This will allow us to compare the nine placebo patients with nine active patients at each dose level. Once randomized at the dosing session, participants will be administered the study drug. 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 collect efficacy data on the day after dosing, again, to determine rapid onset of effects and then three weeks later before the second dose. This three-week time point is to assess the effect of a single dose, and here we will compare a single dose of active versus placebo. In the three weeks that follow the first dose, safety and weekly efficacy data will be collected, and integration sessions, again, based on our EMBARK protocol, will take place. Traditionally, psilocybin studies, for example, have used a single administration approach, a single dose approach. We've chosen a regimen of two administrations three weeks apart because we believe that will give us the best chance of demonstrating robust as well as durable efficacy. In this study, all participants will receive an active second dose after three weeks.
Three weeks after administering the second dose, we will assess efficacy again. What this design allows us to do is to assess the benefit of a single dose versus placebo. In those patients who receive active on day one, it allows us to assess the incremental benefit of a second dose of CYB003. Those who receive placebo as their first dose, it also helps with retention. Thus, by the end of the study treatment period of six 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 three weeks after a single dose, and three 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. First, the PK data. At doses ranging from 1 mg- 10 mg, observed PK was as we expected. We saw a fantastic PK profile for CYB003. The drug was rapidly absorbed after oral administration and was cleared well from the body. Peak levels in the plasma were reached quickly in about an hour. The exposures we observed were within margins of safety, and these are margins determined by our GLP tox studies. Importantly, we saw low variability in PK with coefficient 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 the PK data.
With escalating doses, the exposures remain predictable. Again, while the data are blinded, we can also see from the series of small figures at the bottom right, which depict dose normalized data from individual participants receiving different dose levels, that there was minimal intra-individual variability with repeated dosing. Basically implies that same doses will consistently produce the same effects in individuals. Moving on to the pharmacodynamic data or the psychedelic effects. These are again, in the context of slow-acting SSRI medications which take weeks. These are some fantastic results. While we did observe psychedelic effects at 3 mg, robust effects that are consistent with therapeutic efficacy were seen starting at 8 mg. All of these statements refer largely to 8 mg and 10 mg doses. Onset of psychedelic effects was rapid, with noticeable effects being observed and reported at 12 minutes post oral dose.
Maximum or peak effects were reached in about 90 minutes, and this peak lasted for a short duration of about two hours. Using the Visual Analog Scale for any drug effect at a dose of 10 mg, two-thirds of the participants reported the maximum score, which is 100. We can put these psychedelic effects again in the context of therapeutic efficacy based on some other psychedelic rating scales. 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. More than half of the participants at 8 mg or more had a complete mystical experience. That is defined as an MEQ total score of more than 60%. A mystical experience is considered to be strong mediator of therapeutic efficacy in psychedelic studies.
At the 10 mg dose, the effects were even better, with almost 70% of the participants achieving a complete mystical experience. Looking next at the Persisting Effects Questionnaire or the PEQ data, again, almost 60% of the participants reported their experience being the most or among the top five most meaningful experiences of their lives. Similarly, almost 60% reported their CYB003 experience as either the most or among the top five most psychologically insightful experience of their lives. All of these are described in the literature as important predictors of therapeutic efficacy. These data are for doses up to 10 mg. As a reminder, in the MDD cohorts, we have started dosing at 12 mg. Moving quickly to safety. CYB003 was very well tolerated at doses up to 10 mg. 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. The most common adverse events were, again, as expected, headache, nausea, transiently elevated blood pressure. There were no discontinuations due to adverse events, all adverse events resolved without any need for any clinical intervention. 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 two 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 mg and 10 mg. CYB003 was well-tolerated up to 10 mg. Adverse events were as expected. They were mild to moderate in intensity.
They resolved without intervention, and there were no serious adverse events. Again, as a reminder, we have commenced dosing in MDD patients in cohort four, where we are testing a dose of 12 mg, the phase II-A portion of the study is underway. 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.
Well, 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. Let me start with a review of what we have for major depressive disorder. In addition to the typical psychosocial therapies that are kind of evidence-based, like CBT and IPT. The most commonly used treatments for major depressive disorder have been monoamine-based pharmacological therapies, things like SSRIs, SNRIs, and typical antidepressants.
More recently, we're seeing the emergence of glutamatergic and gabaergic pharmacological therapies like ketamine, esketamine, the combination of bupropion and dextromethorphan, brexanolone and zuranolone, although not yet approved, but in the same kind of gabaergic mode as brexanolone. We also have somatic therapies like ECT, VNS, and TMS, and of course, alternative and natural therapies. Now, you know, if you look at how monoamine-based antidepressants work, they all seem to modulate neurotransmitters like serotonin, norepinephrine, dopamine, but they have clear limitations. I think that if you look and the efficacy is rather modest.
In the largest clinical trial of depression ever conducted, the STAR*D study, we found that only 33% of patients treated in level 1 of STAR*D with citalopram, with an average dose of 40 mg, only a third of the patients remitted. As you can see from the distribution of scores on the QIDS- SR, you have people that despite treatment, continue to have moderate, severe, or even very severe symptoms. In level two of STAR*D, when patients who didn't respond to the initial SSRI were switched to other monoamine-based therapies like bupropion, sertraline, venlafaxine, their remission rates were approximately 25%. Again, cumulatively, slightly above 50% chances of remission with the two trials.
The percentage of remitters who don't respond to level one and level two monotherapies and then go on to mirtazapine or trazodone, on average, their remission rate is 10%. Again, cumulatively, with three trials of 12 weeks each, over about nine months, only about 60% of the patients remit, which is not ideal. In addition, among those who relapse, a significant proportion of those who respond, relapse, particularly those who respond after the second or third trial. Another significant limitation of the current antidepressant therapies is that the speed of onset of efficacy is relatively slow.
You again, going back to the STAR*D trial, half of the patients who remitted on citalopram in level one of STAR*D did so between week six and 13. Though some patients remit within six weeks, the other half will remit later. Sexual dysfunction is another common side effect of SSRIs and SNRIs. You can see this is a study by Anita Clayton showing that almost a third of the patients have sexual dysfunction. Weight gain is another issue with monoamine-based therapies with about 20% of the patients on SSRIs gaining significant weight. Insomnia being another tolerability issue, with insomnia being relatively common among SSRIs and SNRIs.
Finally, I think that the residual symptoms are common. That is, these treatments don't quite bring to complete resolution the major depressive disorder. In fact, as you can see from study from our group, about 30% of the patients have a variety who have responded to antidepressants. Between 30% and 50% have significant residual symptoms. Of course, the more residual symptoms you have, the more likely you are of relapsing. 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, SSRIs, SNRIs, atypical antidepressants, and then alternative and natural therapies.
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 indication of depression to enhance the effect of the antidepressant. In the case of depression, four atypical antipsychotics are FDA-approved for inadequate responders to antidepressant therapies, aripiprazole, quetiapine, brexpiprazole, and cariprazine. No drug has yet an indication for inadequate responders to antianxiety therapy in GAD. The combination is the use of two antidepressants or two antianxiety agents to enhance the therapeutic effect. These are some of the aripiprazole studies that have shown its efficacy in depression as an augmentation. As you can see, robust effect for aripiprazole. Ketamine, this is a study that Singh and colleagues published.
We published a few years ago in The American Journal of Psychiatry. Repeated doses show a nice separation between drug and placebo for IV ketamine. Of course, esketamine, this is the phase II trial that we published Biological Psychiatry, using the sequential parallel comparison design and showing a robust effect of the doses of esketamine. As I mentioned earlier, esketamine has been approved as Spravato for the treatment of resistant depression. SAGE-217 or zuranolone has been shown efficacy in depression. This is The New England Journal of Medicine paper. The NDA has been submitted. Moving away from the biology, glutamatergic and monoamine-based therapies, moving on to the psychedelics landscape.
A number of companies have clearly been very active in this space. You know, studying psychedelics or psychedelic analogs to look at their efficacy in depression, anxiety, and so forth. I'm gonna 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. With the second dose, three weeks later, you know, maintaining their benefit over continued dosing of escitalopram. Of course, when you compare the adverse events, you know, they're, you know, overall, nausea comparable among the two. Fatigue is greater on escitalopram.
Anxiety is greater on escitalopram. Migraine is slightly more common on psilocybin. The Davis published the same year a study of psilocybin-assisted therapy in MDD compared to delayed treatment. As you can see, there was a significant advantage of psilocybin at both week five and eight. Although, you know, whether delayed treatment is a good comparison, you know, kind of is questionable, but it still indicates the change observed with the psilocybin depression. A study by Palhano- Fontes, and colleagues look at ayahuasca versus placebo in treatment-resistant depression. The ayahuasca was adjusted to contain 0.3, 0.36 mg/kg of an N,N-DMT. Again, significant advantage over placebo.
This is the study by Guy Goodwin and colleagues, you know, from Compass in The New England Journal of Medicine this year, showing that 25 mg of psilocybin was significantly better than 10 mg and 1 mg. As you can see from their paper, you know, the response rates were significant, but they were also accompanied by greater suicidality on emergence on the higher dose, which may be the reflect of people not, you know, not everybody got better. Perhaps, you know, the lack of benefit may have induced some greater despair or suicidality.
That's at least one explanation that has been suggested with more adverse events, of course, on the higher doses. As you can see, this is the table from the same paper comparing the tolerability across the three doses. I think from a neuroscience standpoint, I think that many people argue that psychedelics modulate the 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. So, we see increased DMN activity in rumination, in craving, relapse to substance abuse, and it has been reported that we see decreased DMN activity with psilocybin, LSD, and ayahuasca.
Of course, this is the paper by Pasquini showing significant decreases of DMN within the posterior cingulate cortex for the ayahuasca group compared to placebo. What are the advantages of psychedelic treatment? Rapid efficacy certainly is one. Also, long-lasting effects because of the effects on neuroplasticity, synaptogenesis, and the default mode network. Another advantage of psychedelics may be the transdiagnostic utility. They seem to be promising in depression, resistant depression, resistant anxiety, PTSD, substance abuse, and even pain. Challenges, you know, clearly expectation issues are very robust for people participating in these trials. How to minimize expectations or at least have an adequate form of placebo. A complicated delivery model, you know, people cannot just take them and just drive home right away.
Insurance coverage, you know, is something that has not been discussed yet, but I'm sure that the companies that are greater to commercialization have started those conversations. You know, the Spravato experience has shown that, you know, there is resistance to adoption of complicated delivery models. The other issue is the intermittent delivery of care. You know, people, these long-lasting benefits require perhaps intermittent administrations, and that's not a that has not been the model. You know, in psychiatry, typically, it won't got you well, we keep you well, people taking things in the long term, and this would be a very different paradigm. In summary, currently available pharmacological treatments for depression, anxiety, have multiple limitations, modest efficacy, onset of response is delayed, burdensome side effects.
Psychotherapies have modest efficacy and are hard to access. We have a shortage in the U.S. of over 50,000 psychologists. Very hard to catch up. Most promising pharmacological therapies are clearly targeting glutamate, GABA, and of course, the psychedelics. Thank you very much. I'm gonna 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. 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, our deuterated dimethyltryptamine or DMT molecule. By way of background, in its natural form, DMT is rapidly metabolized in the body by the enzyme monoamine oxidase, and it's not orally bioavailable. As a result, DMT is short-acting. We believe that our proprietary deuterated DMT has the potential to overcome existing limitations of DMT in its natural form. CYB004 is a new chemical entity with a composition of matter patterns granted through 2041. Pre-clinical 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 and 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. 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 three of 2023. We have selected GAD as a primary indication for CYB004, and this is based on three key criteria. First and foremost is the scientific rationale.
We want to ensure that we have a solid biological rationale for pursuing this indication. 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. We have asked, in doing so, what is the standard of care in GAD? Are the treatments adequate, and is there room for improvement? 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. Let me go through our key criteria in a little bit more detail. 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 1A 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 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 frontolimbic circuits. Hence, DMT as a drug is well-placed to modulate key brain circuitry that underlie clinical symptoms.
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 the effects of LSD in anxiety disorders, the effects of psilocybin in treatment-resistant depression, and the effects of DMT in major depressive disorder. 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%-25%, and we know that one in five 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. Hence, there's 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 for GAD is expected to increase by approximately 500% by 2027 in the U.S., while the global market size is expected to grow to $12 billion by 2030. 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 exposure and slows the metabolism when given as an infusion, as shown on the left of the graph, sorry, the left-hand side of the slide, and the bolus plus infusion, as shown on the right. These data are exciting because this might open up opportunities to look at different formulations such as subcutaneous or intramuscular. 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 two 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 Centre 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 timelines by almost nine 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.
This was done to support the evaluation 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. The secondary objectives were to understand the relationship between drug exposure or PK, and physiological and behavioral effects or PD. Build a robust PK model for further dose optimization in future studies. Turning now to the design. The overall CYB004-E study had three parts. Sorry. 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. It had a 90-minute infusion of DMT and four cohorts were tested. 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 have other 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 non-smokers, 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 will move on from DMT to CYB004, and this will be the first time in human study of CYB004. Similar to Part B, this study will be conducted in healthy non-smokers 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. Part A, as I said, has up to four cohorts of 10 healthy smokers.
The study utilized an adaptive single-dose, double-blind, randomized placebo-controlled design, and that DMT was continuously infused for 90 minutes. DMT doses were increased proportionally from cohorts one to cohorts four. 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. 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. 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 three 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 two-way crossover design with 10 healthy non-smokers. The study is a single-blind, ascending fixed dose order crossover design. Two 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 two cohorts. The first is a three-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 two-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. The data from part A of the CYB004-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 timelines. 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 CYB004 from the CYB004-E study is planned for quarter three 2023. 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. 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. You know, 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 pre-clinical studies. Achieving three 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 psychedelic doses and in fact dosing in patients at 12 mg with CYB003 has already begun. Let's remember just how rapid the effects of psychedelics appear to be 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. We'll take those learnings into a more complex parts B and C of that study. As you heard from Pradeep, part B has already begun. The current study design has been expanded to include first in human dosing of CYB004 to accelerate our understanding of the dose dynamics.
This exciting piece is expected to commence in April. 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 that over time will gain regulatory approval and help the patients who so desperately need new solutions. Cybin is proud to be a leader in this important transformation of mental health care. 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 at psychedelic doses.
For CYB004, we've received approval early this month for the first in human dosing and have initiated part B dosing in the CYB004E study, quickly moving that study along. Moving to quarter two, 2023. For CYB004, we plan to complete GMP manufacturing of that product and importantly initiate CYB004 first in human dosing. For CYB003, we plan to initiate a bioequivalence cohort for CYB003 capsules in preparation for our pivotal studies. In quarter three, we expect to complete CYB003 dosing in MDD patients, and we have two important data milestones in the third quarter. A top line data readout from the CYB004E trial, including both DMT and CYB004 cohorts, and we expect to have CYB003 phase 1/ 2-A top line data, including a look at efficacy around the end of that quarter, all to support an FDA submission for CYB003 pivotal studies in quarter four.
I think based on what we've seen, today, for CYB003, we're very excited about that efficacy readout that's coming, just a few months from now. The Cybin team is extraordinarily committed to this work, as I think is evidenced by the speed at which we're making meaningful progress advancing, these programs. I hope that these in-depth presentations today have provided greater clarity around our in-human programs and confidence in the science supporting 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. The data we presented today on CYB003 and CYB004 give us continued confidence in their potential as breakthrough mental health treatments. We look forward to sharing more future updates on these programs as the months progress.
thank you very much for your attention today. and with that, operator, we'll open the call up for questions. Thank you.
Great. Thank you, Doug. At this time, we'll be conducting a question and answer session with our speakers. Please hold for a brief moment while we pull for questions. Our first question comes from Patrick Trucchio from H.C. Wainwright. Please go ahead, Patrick.
Thanks. Good morning and congrats on all the data. I think just first a clarification question. In terms of the phase 1/ 2-A trial, will cohorts four, five, and six also include a second active dose? In terms of the top line data expected in the third quarter, at that time, will we have data from cohorts four, five, and si? What are the expectations in terms of improving on MADRS for those cohorts?
I think the first two questions are simple, yes and yes. Yes, two doses in each cohort. Yes, we expect all three cohorts to read out in quarter three. Maybe, Amir, you wanna talk about expectations around MADRS improvements. I think that'd be helpful.
Yeah. I mean, that's an interesting one because clinical trials are tricky. You don't always see what you expect, and sometimes you're seeing 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- 0.3 in the studies that we've conducted and seen so far. We expect something better. We expect effects to be robust. We expect them to be durable. We have a time point in the trial out to 12 weeks, which will demonstrate hopefully that these effects are durable with just two doses of CYB003.
Got it. That's helpful. 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. The data thus far are very promising in terms of kind of, what we consider, you know, kind of, phenotypic signatures of the effect of the drug. You know, though these were in healthy volunteers, we see these effects that are being correlated with clinical improvement in patients with depression. They're promising. The next stage is the most exciting one, is the one that where we're taking a treatment that has shown kind of a, shown, you know, kind of from the PK perspective, all these, and the, you know, in terms of side effects, similar profile, to traditional psychedelics.
We're gonna see the degree of improvement that we're going to 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 gonna use the, our safer methodology that is the independent verification of the patients who meet the criteria, have the disease, have the severity, have the treatment history prior to exposure to the treatment. That's a way of mitigating kind of nonspecific effects. The, you know, response to the question.
If, you know, if these treatments make it to the clinic, you know, get eventually down the road, I think they will require education because they will require a change in the way we practice. You know, I'm a practicing clinician. I'm used to prescribing treatments that people take every day. Although, you know, years ago, we had the Prozac weekly, you know, 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, you know, very frequent treatments, you know. That would be a new paradigm that will, you know, require education and getting clinicians comfortable.
Yeah. Just one last one. Just on slide 61, you outlined, you know, several challenges. I'm wondering, what do you think drug developers could do during the clinical development or in the commercialization of these psychedelic agents to overcome those challenges?
I think, you know, one is demonstrate that these treatments do not require extraordinary measures of monitoring. Trying to show that maybe, you know, in two or three hours, the patients could be out of the clinic. That would be a great improvement versus overnight stay. You know, an overnight stay becomes more complicated. The challenge of Spravato is that you have repeated, you know, multiple times, you have to come in for three 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. Trying to demonstrate the safety and, you know, the lack of need of overnight stay would be very, very important. Simplification of the process.
You know, like right now, for example, for many studies, you may require two monitors, you know. Will you always require two monitors? Will 1 be sufficient and so forth? All these things, I think, will be important.
Great. Thank you very much, and congrats to the Cybin team.
Great. Thanks, Patrick.
Thank you for the questions, Patrick. Our next question comes from Frank Brisebois from Oppenheimer. Please go ahead, Frank.
Hi. Thanks for taking the question. Just a quick one here. I'd love to hear from, Dr. Fava here, maybe the difference in efficacy expectations when you compare an MDD population versus a TRD population? You know, on that point, maybe touch in also in the real world, would you know, contemplate using this more on the severe or the moderate patient? Thank you.
François, I completely agree with you. You know, it's kind of the expectations are going to be lower of improvement in a TRD population compared to an MDD. We know the placebo response rates are greater in MDD compared to TRD 'cause having failed to respond to an antidepressant per se is a prediction of failure to respond to placebo. That's another way of kind of de-risking the development is by taking populations who may have a lower-level of expectation or lower likelihood of placebo response. You know, the other question or the other comment that you made, Can you just remind me the second issue?
Yeah. 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.
Right.
Small.
Yeah, no. So the question is, cost, right? A new treatment that may be more costly on administration, but there may be less cost of the, you know, there's no chronic treatment. Might make this appealing to people who may, you know... Let me ask you a question, François. If you, if you came to me and said, "You know, I've been suffering from depression for the past six months. Never tried anything," you know, I'm gonna say to you, "Okay, we have a terrific treatment, an SSRI.
You're gonna have about a, you know, a third chance of remission, but you'll have a 30% chance of sexual side effects, 20% chance of weight gain, 20% chance of insomnia, a 20% chance of cognitive impairment, memory and. Would you take it? You'd say, "Yeah, give it to me." Would you say, "Doctor, could you have something that maybe doesn't have these side effects or." You know. I'm just saying that, yes, resistant depression is a logical place where insurance companies are gonna attempt to push and say, "Do it for severe, do it later." For customers, for patients, you know, do you really want to go through, as an SD, three antidepressant trials for 12 weeks for nine months, remain depressed, to then determine that you need a psychedelic treatment? I don't know.
I mean, yeah, these are debates that companies that develop psychedelics will need to have with insurance companies. I don't wanna. I'm just saying, I wouldn't limit the use of psychedelics to only severe or resistant because there would be benefits earlier on.
Understood. All right. Thank you very much. That's it for me.
Thank you, Frank.
Thanks for the questions, Frank. Our next question comes from Charles Duncan from Cantor Fitzgerald. Please go ahead, Charles.
Yes. Can you hear me?
Yes.
Hi, John. Charles, good morning.
Hey, good morning, Doug and team. Thanks for hosting this very informative call. 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've started to allude to this, 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 six-week moderate change or is it some moderate change that is durable? How do you see this emerging treatment paradigm relative to the standard of care? Thanks.
Charles, great question. As a clinician, what I like to see is a reduction in the moderate score in a range where the patient says, "I'm good, you know. This is, you know, you know..." The remission as a goal, I think is of remission from major depressive disorder is always our goal as clinicians. When a patient gets better and the moderate gets in the very lowest, you know, single digits, we're in the remission range, which is great. The durability of their score, you know, we know in depressed patients, even those on continued treatment, they may have some fluctuations, but if they have a bad day at work or at home. We don't necessarily assume that it will always be in the single digits on the moderate.
As long as it stays in that range, that would be really terrific. I think that, you know, the durability of the treatment effect is gonna be very important. If you switch to a model of kind of intermittent or very sporadic, you know, very rare administrational treatment, you have 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 rechallenge them. It's important to have that figured out in the clinic. Now we're gonna see if zuranolone gets approved. Zuranolone has a two-week treatment and then, you know, follow up afterwards, that already in some ways is preparing physicians to the paradigm of psychedelics.
Yeah, that's what I thought as well. I guess 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 wanna see in terms of not only effect size, say, in the acute setting, say, a six-week primary endpoint, but then also durability given what you know about, say, this class of drugs generally, maybe it's just picking out psilocybin, versus say even zuranolone, which is not a free drug either in terms of side effects. What do you think the durability is going to be needed to compel the agency?
You know, I really don't know what the FDA will want.
Yeah.
I think that, you know, these are uncharted territories.
Yeah.
You know, I think fundamentally clinicians will want the same thing that the FDA would want, which is to know how long is the benefit lasting. Some indication of that will be extraordinarily helpful.
It's very helpful. Quickly moving to the team, for Amir and or Amir, Doug, kind of a two-part question. First of all, for the ongoing phase 1/ 2-A, cohorts four, five, and six. I think you answered to a previous question that you'd have all three in the third quarter, and I guess I'm wondering if you can provide clarity on that. Secondarily, what doses are you thinking? You started with 12 mg. I would have kinda thought that you'd start with 10 mg. In human volunteers, you did so, but then what are cohort five and six doses that you're planning?
Yeah. Amir, do you wanna take that?
All three cohorts will read out in Q3. That's our expectation. We've already started enrolling in cohort four at 12 mg, as you mentioned there. Enrollment, we've got patients lined up, there's good interest in the trial. We expect to enroll one per cohort up until the third quarter. 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. It becomes therefore an iterative process as to what will be the next dose. Would we want to stay at 12 mg? Remember, we've got two doses within the cohort.
Yeah.
There is also the opportunity to test whether if somebody, let's say we start them at 12 mg, they don't respond to the first dose of 12 mg, can we push the dose slightly higher, and will they respond to a higher dose? Because all patients are different.
Yeah.
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. That was one of the thinking when we chose 12 mg. In healthy volunteers, up to 10 mg, we were fine. It is our belief that when we go into patients will request 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.
Yeah.
We don't know if SSRIs will affect the response, but definitely we do know that the SSRIs have an effect on the receptor, 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 mg. In future cohorts, there is also an option to come down. If we think that 12 mg has overwhelming efficacy, but maybe it's not the best tolerability, we can come down and use a different or multiple different approaches there. 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, 2024, would you anticipate to be able to move into a pivotal study? 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 and the dose studying 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 studies next year. 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 current work that we're doing. Yes. Thank you for that question, Charles. I think we have time for one more, Tara.
Yes. Our final question comes from Elemer Piros from EF Hutton. Please go ahead, Elemer.
Yes. Thank you very much. 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?
Elemer, it's a great question. Again, I cannot, you know, predict the future in terms of, you know, how this will be received. That said, I think we can anticipate some challenges. One is the stigma of psychedelics. You know, we have a stigma of mental illness to begin with. You then add to the stigma of mental illness the stigma of psychedelics. You know, kind of the perception of what psychedelic treatments are. I mean, I think we've been able to overcome that with ketamine. You know, ketamine was known as a drug of abuse, and yet, you know, these days, I don't know anybody, any clinician, at least, you know, around here, who's not comfortable referring a patient to a ketamine clinic.
Yeah.
The stigma of ketamine is being overcome. I think that you know, we'll need to do the same thing, education, reassurance, and the safety and, we're not sending people home. We're not planning to send people home with psychedelics, you know. I think that, you know, these are obstacles that can be overcome. I think that the more, you know, the more we can be proactive.
Mm-hmm.
Address issues that are raised by clinicians early on. Educational programs. You know, these days, as you know, nobody's doing educational programs anymore. I mean, you know, it's a, you know, or let me rephrase it. There are very few educational programs for physicians that people can attend. You know, we certainly do them at Mass General. We have a psycho forum course every year with over 1,000 people attending. I'm just saying that massive educational efforts will be required, in my mind, to, you know, 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, you know, in most academic, you know, academic centers, drug reps are not allowed.
They can't even set foot, you know, how do you educate people about new treatments?
Right. Yeah. 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?
I mean, absolutely. There's no question that the data have been extraordinarily promising. You know, in fact, my presentation, I captured some of the things that got really my attention. That said, you know, the question is, you know, how this data will translate into phase III. What's gonna, you know, how do we minimize a placebo response? How do we, you know, all those things, all those small details become very important in phase III programs. You know, as I mentioned, you know, we at Mass General, the CTNI, we're collaborating with Cybin to help them develop the best possible program for phase III.
Thank you so much, sir. Thank you, gentlemen.
Great. Thank you, Elemer.
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, 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.