Good morning, everyone. I'm Florian Brand, the co-founder and CEO of Atai Life Sciences, and it's a pleasure to welcome you today to our R&D Day. We have an incredible agenda today, and we'll hear from key opinion leaders and some of our own senior R&D team. To kick things off, I'll walk you through our founding story and how we anticipate making a positive impact for mental health patients. We will deep dive into one of our key indications, treatment-resistant depression, or TRD. We'll start with an engaging fireside chat hosted by Dr. Heather Berlin, in which she will discuss the clinical and regulatory aspects of TRD with Dr. Gerard Sanacora and Heddie Martynowicz. Our co-founder and chief scientific officer, Dr. Srinivas Rao, will discuss PCN-101, our ketamine program in TRD.
This program has a phase IIa readout coming up around the end of this year. Srini will focus on contextualizing this specific upcoming data set. He will then briefly discuss COMP360, a psilocybin therapy program, and Compass Pathways' upcoming phase III program in TRD. As you're aware, we hold a significant investment stake in Compass and are very excited about their progress. Afterwards, we'll hear from Dr. Glenn Short, our SVP of Early Development, who will discuss VLS-01, our DMT program, and describe the phase I trial we recently initiated. He'll then hand it over to Dr. Rolando Gutierrez, our chief medical officer, who will touch upon other programs in indications other than TRD. He will begin with a discussion of GRX-917, our deuterated etifoxine program. We are looking forward to presenting to you today with some new positive phase I data on this program.
Rolando will then continue by discussing RL-007, our phase II program in cognitive impairment associated with schizophrenia, or CIAS. Here, we will briefly review existing clinical data and provide new details on the design of our upcoming phase 2 IIb trial, which we anticipate initiating by the end of this year. Finally, Srini will wrap things up by speaking about our deuterated mitragynine program being developed for opioid use disorder. He will revisit the positive phase 1 data that we released a couple of weeks ago. As a reminder, our discussion today may include forward-looking statements about Atai's future results and performance. Our clinical and non-clinical programs are subject to risks and uncertainties that may cause actual results to differ. Atai does not undertake any obligation to update such statements which speak only as of today.
With that, let me begin by addressing why we founded Atai in the first place and how we approach developing differentiated and effective solutions for mental health patients. We formed Atai in 2018 to address the escalating mental health crisis that we experienced firsthand through the suffering of our own friends and family members. Atai's vision to heal mental health disorders so that everyone everywhere can live a more fulfilled life is thus very personal to us. Even pre-pandemic, nearly 1 billion people around the globe lived with mental health conditions, and COVID-19, unfortunately, made this much worse. Most recent numbers from the U.S. indicate that adults experiencing symptoms of depression and anxiety have increased roughly four-fold. According to the World Health Organization, depression is the second leading cause of disability worldwide.
The U.S. economic burden from adults with major depressive disorders alone is estimated to be $300 billion annually. Sadly, even against this backdrop of patient suffering, there has been a significant unmet need and lack of innovation in mental health care. Existing options are often inadequate, including a slow onset of action, a lack of durability, high relapse rates, or long-term side effects. If you look at the statistics, only seven new compounds have been approved by the FDA for depression since 2017, and this is compared to 116 in oncology in the same time period. You see, mental health patients need more options, and that is why Atai exists. To that end, we have assembled a pipeline of eight clinical stage programs targeting several major indications with the goal of achieving clinically meaningful and sustained behavioral change in mental health patients.
Our R&D team will cover a subset of these programs in greater detail today. At the outset, let me make a few general points about our pipeline. We are focused on large commercial opportunities and our target indications are all areas of significant unmet need affecting millions, if not hundreds of millions of patients. Each of our compounds in clinical development have shown prior evidence in humans, and we pursue a diverse range of mechanisms of action. We do this for two reasons. First, because the conditions we treat are complex and heterogeneous. Second, because we believe this diversification improves the risk profile of our pipeline. Additionally, all of our programs are designed with the patient in mind. We generally anticipate them to have a fast onset of action and optimized side effect profile and the potential to support durable behavioral change.
Last, I'll note that all the programs on this slide are in the clinic. They have either already achieved proof of concept in the case of COMP360, or have a clear path to efficacy data in the next two years. We expect these efficacy data sets to be value inflection points for Atai. Let's now take a deeper look at some recent milestones and near-term catalysts. Over the past 12 months, we saw significant progress across all these programs, including at Compass Pathways, strong phase IIb data with COMP360 in TRD, and the announcement of their phase III TRD program expected to kick off this quarter. On RL-007 in CIAS, positive phase IIa biomarker data demonstrating clinically meaningful pro-cognitive effects in schizophrenia patients. On KUR-101, deuterated mitragynine, initial positive results from a phase I trial. On GRX-917, deuterated etifoxine, positive phase I data.
Looking ahead, we expect to achieve additional important milestones. On PCN-101, our R-ketamine program in TRD, top-line results of our phase IIa POC trial around the end of this year. On RL-007, the initiation of a phase IIb trial in CIAS by the end of this year. On VLS-01, our DMT program, phase I data in the first half of 2023. On DMX-1002, our ibogaine program, phase I data in the first half of 2023. As we recently announced, EMP-01, our MDMA derivative program, phase I data in the second half of 2023. It's clearly an exciting time at Atai across our innovative pipeline, and we believe we are well-positioned with a strong balance sheet and a runway into 2025 to continue delivering for patients by making significant progress on our programs.
I would now like to transition to our fireside chat that will be moderated by Dr. Heather Berlin. She will be joined by the key opinion leaders, Dr. Gerard Sanacora and Heddie Martynowicz, to discuss the clinical and regulatory landscape in depression. I am looking forward to an insightful and interesting discussion between these three leading experts. First, we have Dr. Heather Berlin, a neuroscientist and clinical psychologist. She currently serves as Associate Clinical Professor of Psychiatry and Neuroscience at the Icahn School of Medicine at Mount Sinai. Her research is focused on the neural basis of psychiatric and neurological disorders, while her clinical work is centered on lifespan treatment of anxiety, mood, and impulsive compulsive disorders. Next, we have Dr. Gerard Sanacora, who is an Associate Professor and Director of Yale's Depression Research Program. Dr. Sanacora is a well-regarded KOL in the treatment-resistant depression space.
Dr. Sanacora's work is focused on the understanding of the pathophysiological mechanisms associated with mood and neuropsychiatric disorders. He is also involved in several clinical trials to test the efficacy of newly developed therapeutics. Last but not least, we have Heddie Martynowicz, President of Neokee Pharma Consulting. Heddie has over 30 years of experience supporting various pharmaceutical companies. In a previous role at Janssen, Heddie was the regulatory leader for the mood disorder therapeutic area and had direct responsibility for SPRAVATO. With that, I'm very excited to hand it off to Dr. Berlin.
Thank you, Florian. I'm very excited to be here at this fireside chat with Gerry and Heddie. Thank you both for being here. As Florian mentioned, this session is going to focus on the clinical and regulatory landscape in depression with a focus on treatment-resistant depression or TRD. To get us started, I'd like to ask Gerard to provide some context on the topic. First, Gerard, what is TRD? How prevalent is it, and what's the current treatment paradigm?
The question of what TRD is actually a little bit more complex than it may initially seem, and I think the definition varies depending on how it's being used in what context. I think most recently, based largely on the results of the STAR*D study, people assume TRD is when a patient with major depressive disorder has not responded to two trials of adequate dose and duration of antidepressants in the current episode. There's some variations on whether this needs to be two different classes of antidepressants or not, but that's the general definition. In terms of the prevalence, you know, there's a few ways of trying to approach that.
If you think that, you know, it's estimated that about 21 million adults in the U.S. are suffering from depression and rates of non-response vary anywhere from about 30% up to over 50%, you can estimate where those levels will be. I think some of the best evidence comes from a recent study using claims data from several large U.S. payers that estimated 12-month prevalence of medication-treated depression to be about 9 million people and about 1/3 of those, about 30% or close to 3 million meeting the criteria for treatment-resistant depression.
Wow. That's a lot of people. They've tried and failed at least two trials. What are the current treatments? What for depression or treatment-resistant depression?
Yeah. It's actually there are really only two pharmacologic treatments approved at this time for treatment-resistant depression. That was going back well over 10 years ago, olanzapine plus fluoxetine or Symbyax was approved, I believe, in around 2009. And then more recently, SPRAVATO or intranasal esketamine in 2019. Those are related to approved treatments. Pharmacologic, there are a few neurostimulation devices that have also been approved in the form of vagal nerve stimulation, in forms of rTMS and ECT.
Right. In developing new treatments for TRD, what are we looking for? What are you looking for when assessing new treatments and compounds to treat it?
I think it's really the standard triad that we look at. We're looking at efficacy, safety, tolerability, and cost. Breaking that down a little bit further, you're looking at both short-term, and I think what's also very important is long-term efficacy, or we might think of more effectiveness, and then tolerability and safety, both for the individual, but also for society. We have to be considering how that plays in. Cost, and the same thing, both for the individual, short-term, long-term costs, and how it can actually fit into the current healthcare system.
What are your thoughts on at-home therapies for TRD? You know, is there an unmet need there?
Out of all the ones we discussed, really the only at home would be Symbyax, in that sense. I think, you know, there are some benefits to, you know, second-generation antipsychotics added to depression in general, but I think they have their limitations. I think at this point, those are usually tried pretty early on in the treatment course, and they are difficult treatments for many people to tolerate. That leaves a great unmet need for treatments that are affordable and accessible to people with treatment-resistant depression. It's a large burden, both economically, but also the time burden on both the patient and their caregivers. Especially most of these treatments, you can't even just come to the treatment and leave yourself. You actually need a caregiver or at least somebody that can transport you back and forth.
A part of the promise of some of these new compounds that are in development is that they're rapid-acting. I'd love to get your thoughts on this and why this is important to patients and also to clinicians.
Yeah. I think, you know, the initial findings of ketamine's rapid onset of antidepressive activity really was transformative. Prior to that, it was just kind of the norm in the field that it took weeks, if not months, to really have an antidepressant-like response. The finding that there was a rapid onset of antidepressant effect following within hours to days with ketamine really sort of changed the landscape. Since that time, there have been other both pharmacologic compounds and now even treatments like rTMS that have been modified that seem like it may have a more rapid onset of effect. I think it offers great hope to the patients, but also to the providers or the clinicians.
I think it, you know, there's the obvious side that the faster onset of effect can bring people back to higher levels or normal levels of function sooner. Maybe a little bit less obvious, but I think probably equally, if not more important, is the fact that it instills hope and optimism in patients and in the clinicians, honestly. One of the major problems with treatment, especially pharmacologic treatment with antidepressants, is attrition. People just not following through with the long-term treatment with these medications.
You know, it's really hard as a clinician. I'm trying to convince somebody who just got done telling me that every minute of their life is misery, and then I'm telling them, "Well, you may have to take something that's gonna take weeks before you feel better, and in fact, you may feel worse before you feel better." It's really hard to motivate people to do that. Having that rapid onset effect has a big benefit in actually improving the compliance, and I actually think from a neurobiological perspective, may have a synergistic effect of this hope and optimism along with some of the neuroplastic changes that the drug provides.
Mm-hmm. I think along the lines of that, you know, compliance, the other thing that I've seen in patients is that when they start to get better, but it's so gradual, like, over the course of many weeks, that they don't associate the improvement with the medication. Then suddenly they say, "Oh, well, you know what? I'm just getting better naturally. I don't need to be on this medication anymore." Then they wanna go off the medication. If there's such a clear, you know, cause and effect, you know, 'cause when you look at that time delay, it's very hard for people to associate the improvement with the actual medication, and then they tend to go off the medication, right?
I completely agree with you, Heather. In fact, maybe we'll get a chance to talk to it later. That's a real powerful part of these medicines, but we also have to find a way of managing that really strong conditioning effect. That's something maybe we can talk about for the long-term treatment strategy.
Jay, I know you've also been involved pretty heavily in the ketamine research over the years, including an open-label trial of R-ketamine for TRD. Could you share some of your thoughts on how they work and also just how other psychedelics are being used as part of the clinical landscape now for the treatment of TRD?
The history is very interesting. In fact, some of the earliest studies ever done with ketamine goes back to 1974, where there were studies actually looking at the ability of ketamine to induce abreaction as a psychoanalytic type hypothesis. That really kind of just faded out, and nobody picked up on that. That was a study actually done in Iran, I believe, in 1974. Really, the current thread of research that brought us to the current state was initiated with the idea that it was the glutamatergic neurotransmitter system played a central role in the pathophysiology of depression and other mood disorders.
It was really much better evidence that regions of the cortical brain, the prefrontal cortex, and other frontal regions were the sites of the pathophysiology, or at least the primary sites of the pathology, not necessarily the regions that were being focused on for the monoaminergic system like the raphe and the locus. It was the idea that you may be able to target a glutamatergic pathway, and that was really what led John Krystal, Dennis Charney, Rob Berman, and others to do that initial study. Since then, you know, we realized it's probably much more complicated. It's not simply targeting the glutamatergic neurotransmitter system with an NMDA receptor. There's probably multiple factors that are involved in the benefit.
It looks now that it really is initiating a cascade of effects that ultimately impact neuroplasticity and really allows the brain to become more adaptive. There's probably multiple pathways that influence that. I would say now the evidence suggests that there's you know the direct effects, the direct pharmacologic effects, both the proximal and as we said the more downstream effects that's initiated by this cascade, but also some non-specific effects that we mentioned briefly before, the idea of hope and optimism and how these come into play. I do believe possibly even in a synergistic fashion to promote more rapid and durable benefit.
Do you think that's what makes these compounds so promising? Is it that they're more broad spectrum and they're having more of the psychological effects as well? You know, like, 'cause we talked about they're fast-acting, they're giving the hope and optimism. But is it this idea that, you know, there's much more involved in depression than we initially thought in the serotonin hypothesis? You know, it's not just serotonin receptors. We spent a many, many years in psychiatry just targeting serotonin receptors, and we only got so far. As you said, there's, you know, one-third treatment-resistant patients. You know, are those the things that make these new, newer compounds so promising?
I think those are two of the main factors that contribute to it. One is, I think targeting the glutamatergic system is much more direct. Glutamate is the most ubiquitous, abundant neurotransmitter. It's really hard to manage it 'cause it is everywhere in the brain, and it really is driving excitatory neurotransmission. You have to manage it carefully. It's also very tightly coupled to the processes of neuroplasticity. Unlike some of the monoaminergic systems that are a little bit soft to touch on the system, although we could even see with some of the psychedelics that even those can have a more rapid direct effect through some of the serotonergic system.
I think it's a combination of that direct physiologic response and some of the indirect mechanisms that we spoke about that together create this very large and potent antidepressant effect.
Now, Heddie, I'd love to ask you for some context in terms of the regulatory framework for TRD, based on your experience of bringing SPRAVATO to market, which is one of only two FDA-approved treatments for TRD. What are some of the key considerations for drug developers to keep in mind during the development process? And also, what are the regulatory hurdles associated with developing new treatments for TRD?
Thank you for that question. From a regulatory perspective, the good news is that there is an established regulatory pathway for getting new drugs approved for TRD. There are available regulatory guidelines from the U.S. and Europe, and of course, we can draw on the experience of SPRAVATO, which is the most relevant and most innovative new treatment that was just approved in 2019. As Gerry had mentioned, there's only two pharmacotherapies that are approved for TRD. I think that although they have advantages, it's clear that they have some limitations for both patients as well as for prescribers. That, you know, there's currently, you know, a need for, you know, new treatment options and particularly those with maybe novel mechanisms of action.
You know, from a high-level perspective, new treatments, particularly those that have very unusual side effect profiles such as psychedelics, they will need to demonstrate a positive benefit risk ratio. More importantly, to implement or identify mitigation strategies that will ensure that the patient's safety is inherent.
I'd love it if you can talk a little bit about the FDA's position on psychedelics and how that might be changing?
Well, I can only speak to from my experience with SPRAVATO, where I had an opportunity to interact very closely with FDA. You know, my impression is that the division of psychiatry is very receptive to development of new therapies that are gonna be useful to patients. I mean, you can actually use that Spravato is a sort of a prequel to psychedelics right? You know, what I learned is that many of the staff on the division of psychiatry at FDA are actually practicing psychiatrists. They truly understand the patient needs and the need for better and newer treatments.
You know, my experience is that they're very receptive to new treatments and, you know, starting with Spravato, they granted two breakthrough therapy designations, and they continue to, you know, it seems, you know, I'm not involved with these programs, but I see that several psychedelics have also received breakthrough therapy designations such as, you know, MDMA received one for PTSD in 2017, and psilocybin for, well, two of them, for MDD and for TRD. That tells me that, you know, they're embracing these new novel treatments in the same manner. You know, again, just for people that may not know, but, you know, breakthrough therapy designation is given to...
It's a process that's given to sponsors recognizing that these treatments are for serious and life-threatening conditions and where there's clinical evidence to suggest that they provide a benefit over existing therapies. It gives the opportunity for FDA to provide more feedback and help to accelerate the development of new and better treatments. Then finally, I think that I've participated in several clinical conferences like ISCTM, and I know that there has been discussion at ASCP, where, you know, they're very open and supportive and, you know, sharing with sponsors, you know, their current thinking. I think that they're also learning as we all, you know, go along this journey.
Right now, this is being studied, you know, with a very select population with people with TRD. Do you envision that it will become available to a broader array of people? Say, people with just MDD or, you know, major depressive disorder, not just treatment-resistant disorder, treatment-resistant depression.
Sure. I would answer that in two ways. One, you're always considering the risk-benefit ratio, and these more novel treatments typically do have, I don't know if I would say more severe, but at least a very different profile of adverse events that really has to be considered against the relative efficacy or effectiveness of the treatments. If you really want an indication, an FDA indication to support the use, I think you would have to do studies in either less treatment-resistant populations or less severely ill populations to get that coverage.
As far as I'm aware, the FDA is not really regulating the practice of medicine, so you'd have the ability to use this off-label in different populations, but that you really are faced with the challenge of the third-party payers, whether or not they would cover these relatively expensive treatments, for off-label use, especially for milder or less severely ill patient populations.
If that makes sense, though. If those first-line treatments, which might be less expensive, but if they're not working, then this, you know, option which might be slightly more expensive but more effective for treatment-resistant population makes sense.
I think if you can prove the you know the cost efficiency and the pharmacoeconomics works out then. If the safety and tolerability are there then I don't see any reason why you can't do that. I think you would have to present that evidence both to the regulatory agency and to the payers before you can get to that point.
Yeah. Now, another trial in Atai's pipeline is their ketamine program for treatment-resistant depression. As Florian just mentioned, it has a phase IIa readout, which is coming at the end of the year, that's gonna test efficacy at 24 hours of a single dose, as well as safety and tolerability. Gerry, you know, what are you looking to, you know, what do you think this readout later this year is gonna find?
Well, I go back to that triad that we mentioned before of looking for, you know, some signal of efficacy, indicators of safety and tolerability. Those really are the two that in some way is gonna affect the cost of this. Because really a big part of the cost of these treatments are whether or not you need supervision of a healthcare provider and whether this has to be done in very selective settings. What I'd like to see, I mean, this is a relatively small study in terms of patients. I think it's about 30 people per arm. You know, you're not really powered to see small differences. You would need to see very large differences, especially between doses, to see anything.
I think really what you're looking for is a signal. I'd like to see some evidence of efficacy showing that it does have an effect. It seems that some of the more acute effects, such as on cognition and perception, may be less than we see with drugs like ketamine or esketamine. That may actually alter the functional unblinding somewhat. When we do treatments with many of the psychedelic drugs or we do treatments with ketamine, there's a high degree of functional unblinding. Meaning that the patient, and for the most part, the clinicians know who's getting the active drug, and who's not. That can have a big impact on that, the delta between the active and placebo treatments.
Safety, you know, the numbers are relatively small for a safety study, but I think there's enough considering we know what we're looking for. We're really looking for major measures of sedation and dissociation or other real cognitive disturbances that we've been looking at for a while now. We can measure them and we kind of know what we're looking at. This type of a sample size, I think, will give us a clue, a pretty good clue on what the safety profile will be if we do run a larger study.
Yeah, that's really interesting. It's the idea that the esketamine seems to have more of those sort of dissociative side effects, which then if it's supposedly a blind study, the people are knowing that they're getting the drug 'cause you're having this effect, and that might, you know, have them show a bit more improvement because of, you know, part of that effect of knowing you're having the drug and having those, you know, dissociative impacts can have a, I guess, sort of a placebo effect in a way, right?
Yes. Even the flip side may be more important is not having that effect. May actually have, you know, the effect of letting you know that you didn't get the medicine and actually set up a negative expectation bias.
You know, on the plus side with the R-ketamine, if people were to use it at home, which is what, you know, we're sort of targeting right now is at-home use, that it demonstrates less dissociative effects than the esketamine it's shown, right?
That is correct.
Heddie, can you discuss some of the factors that are relevant to enable these at-home, the use of at-home, TRD therapies?
Sure. Obviously, Spravato is the benchmark, right? It's important to recognize that it was developed for in-clinic use. If you know, R-ketamine is developed for use at home, it will need to have an acceptable side effect profile better than Spravato. You know, the side effects that Gerry mentioned, you know, need to be mild and self-limiting and not requiring special, you know, treatment or monitoring. Also, I think it will be important to identify mitigation strategies to ensure that patients are able to identify the side effects and how to deal with them and are able to address take any necessary actions, you know, at home.
You know, finally, the most important thing is that, you know, you need to have discussion with FDA on identifying what those, you know, regulatory requirements are. I think it's really gonna be driven by the safety profile and that, you know, you can demonstrate and of course, the clinical program needs to include in-home use. If you demonstrate in-home use, you know, there's a very good probability that you're going to be approved for in-home use.
Finally, I mean, thinking about the future, you know, what do you hope that the biopharma industry, inclusive of the regulatory bodies as well, will accomplish, say, in the next 10 years as it relates to treating depression?
From my perspective, I'm optimistic that with the new evolving technologies, data sciences that we'll be able to collect a lot more passive data, and using artificial intelligence, we'll be able to analyze and make sense and maybe identify more objective measures for efficacy. Because I think that is a... Right now we're currently relying on subjective measures, and it requires large studies, a lot of negative failed studies. Having objective measures in the next 10 years would be really wonderful because it would fuel development of new treatments and maybe make studies smaller. That would be a huge advance.
I think that, you know, having those tools, it would make it more easier and to evaluate novel mechanisms of actions because, as Gerry mentioned, there are some treatments, lots of treatments out there, but there's need for better ones. Having more objective endpoints would really be useful.
Yeah. I completely agree with Heddie on several of the points that she raised. The need to develop methodologies that could allow us to run more effective, smaller studies and to actually move some of these studies into real world situations. That, that's really one of the real struggles we have. For people that aren't aware of this, either your clinical trial recruitment is one of the most difficult, you know, things, and then actually getting true patient populations that are reflecting the patients that are gonna be using this. You know, and actually the ecological validity of these studies are really in question. Ways of improving that, I think is gonna be very important. Honestly, the biggest issue I think is
Especially in behavioral health care is access and accessibility, and really figuring out how we can get these studies done rapidly, but in a way that is going to make these treatments available to as many people as possible safely and responsibly. I think this starts to get to the area of how do they start to assess you know more complex integrated treatment approaches. We did talk a little bit about some digital type assessments, either passive monitoring or actually digital therapeutics that are incorporated. If we do believe our neurobiology that we're talking about, that these treatments are inducing neuroplasticity, which is kind of the big buzzword now. The idea is can we use this neuroplasticity in some productive manner by pairing it with some type of other therapeutic.
I thank you both so much for your insights and for being here. Thank you so much.
Thank you.
Thank you.
Let me start by thanking our KOLs for the informative and thought-provoking panel discussion. I'd like to now transition to discuss in more detail PCN-101, our R-ketamine program. We're developing PCN-101 as a rapid acting agent for use in patients with TRD. We anticipate this therapy to be administered in an at home, unsupervised setting, a major point of differentiation from current therapies. As Florian mentioned, the results of our phase IIa proof of concept study, will be available around the end of the year. This trial is designed to assess the safety, tolerability, and efficacy of a single administration of intravenous PCN-101 in patients with TRD. We ultimately anticipate a redosing schedule that's comparable to that of S-ketamine and ketamine, which is something we look forward to testing in the next trial.
To enable such dosing by the patient, we have a subQ formulation that will be entering phase one clinical testing soon. Let me begin by providing some background on R-ketamine and the data generated to date. By way of background, ketamine is a dissociative anesthetic that was developed decades ago and remains in wide use today. Publications from the early 2000 suggested that this compound also possessed antidepressant activities. Importantly, it was the first drug to demonstrate rapid onset antidepressant activity in a clinical trial. From a chemistry perspective, this compound is a racemic mixture, meaning it consists of two separate enantiomers. R-ketamine is one of these enantiomers, with the other one being S-ketamine. These two forms are related to each other in the same way your hands are to one another. In other words, they're structurally mirror images of each other that are non-superimposable.
Ketamine's dissociative and anesthetic activities are thought to be driven by its ability to block glutamatergic NMDA receptors. The initial assumption was that this pharmacology drove its antidepressant activities as well. Ketamine's NMDA antagonist activity is predominantly mediated by the S enantiomer of ketamine, with the R enantiomer being much less potent in this regard. As we'll detail in the next few slides, despite this relative lack of pharmacological potency, R-ketamine is found to have greater antidepressant potency in animal models. Moreover, the effective doses of R-ketamine are devoid of preclinical drug preference behavior, a proxy, in this case, of clinical dissociation. Briefly, this slide shows the efficacy of both S and R-ketamine at ascending doses on the forced swim test, a standard model of antidepressant efficacy.
The panel on the left shows the efficacy measured at 1 hour, and you can see that only the highest dose of S-ketamine, 30mg/kg or MPK, showed a statistically significant change from placebo. This contrasts with R-ketamine, where even a tenfold lower dose, 3 MPK, showed a significant antidepressant effect. As can be seen in the panel on the right, at 24 hours post-dose, the antidepressant effects of R-ketamine at the 10 and 30 MPK dose levels persists. The benefit of S-ketamine is completely lost at this time point. Importantly, R-ketamine lacks abuse liability at therapeutic doses as measured by conditioned place preference or CPP, a standard rodent model of drug preference. This is demonstrated on the left-hand panel, where doses of up to 20 MPK encompassing the range of doses associated with efficacy were comparable to saline on CPP.
These data contrasts with those of S-ketamine, as shown on the right. Recall that from the last slide that 10 MPK was the lowest effective dose. As you can see here, this dose was associated with positive CPP. Insofar as preclinical CPP may be viewed as a proxy for clinical dissociation for this drug class, these data give us a reason to believe that therapeutically R-ketamine may have a greater therapeutic index than S-ketamine. In other words, for R-ketamine, there may be a separation between the dose levels associated with efficacy versus those that result in concerning side effects. This concept is preliminarily supported by published data from a third-party study in which seven patients with TRD were administered a single IV dose of R-ketamine.
The dose of R-ketamine used in this trial was 0.5 MPK which corresponds to a total dose of roughly 35 milligrams on average. The graph on the left shows the effect of acute administration of R-ketamine on depressive symptomatology, as assessed by the Montgomery-Åsberg Depression Rating Scale, or MADRS. In summary, you can see a rapid reduction in depressive symptoms that starts within an hour and is maintained over the course of several days. The magnitude and duration of this efficacy is generally comparable with what one sees with both S and racemic versions of ketamine. The difference, however, is the fact that these changes are not accompanied by dissociation. This lack of dissociation is evidenced by the graph on the right, which shows that R-ketamine administration causes minimal changes on the Clinician-Administered Dissociative States Scale, or CADSS, a standard measure of dissociation.
A CADSS score of 4 or below is considered normal, and you'll see the median CADSS scores did not reach this threshold at any time point. Conversely, one can expect a CADSS score of 15 or above when administered with an efficacious dose of S or racemic ketamine. To better understand the safety and tolerability of IV R-ketamine and to facilitate dose selection, we completed a phase I study September of last year. The agent was well-tolerated over the dose range explored, and no serious or unexpected adverse events were observed. Here on the screen, we show the CADSS data for the 30 mg and 60 mg doses that we chose to move forward with it into our phase II trial. These doses also correspond well to the range where efficacy was observed in the third-party open label trial previously shown.
Overall, the 30 mg- and 60-mg doses may be respectively considered sub- and borderline-dissociative in this healthy population. With that, I'd like to provide everyone with a brief reminder of the design of the phase 2a trial, as well as the trial objectives. This trial consists of three arms and is double-blind and placebo-controlled in design. As I mentioned, we chose 30 mg and 60 mg IV as the doses to test in this trial, and subjects receive a single administration of one of these doses or placebo. The sample size is 93 subjects evenly allocated across the three arms. The primary endpoint of the trial is the placebo-subtracted change from baseline in the MADRS at 24 hours post-dose. In addition, key tolerability assessments include the CADSS, as noted previously, a measure of dissociation, and the MOAA/S, a standard and widely used measure of sedation.
This study is being conducted across multiple sites in Europe and the United States, and as we recently announced, the last subject was just randomized into the trial. A question that has been asked a few times is what we're hoping to see in the trial results. In summary, the goal of the single-dose study is to establish R-ketamine's therapeutic index against both dissociation and severe sedation. We are contemplating the patients with TRD will take about two subcutaneous doses of R-ketamine per week. A dosing frequency that's comparable to what's used with S-ketamine and ketamine. In terms of efficacy, our target is a greater than or equal to 4-point change on the placebo and baseline-corrected MADRS in pivotal trials that may be four or six weeks in duration. Importantly, we're looking for rapid onset of efficacy with much of the benefit evident within the first few doses.
Critically, however, we're looking for a markedly improved tolerability profile compared to Spravato, one that supports a label allowing for unsupervised at-home use. We believe this to be a major point of differentiation in the TRD space. The present single-dose IV study is our first opportunity to test the hypothesis that R-ketamine's therapeutic index, the ratio of efficacy to tolerability, is markedly greater than that of Spravato. As it regards tolerability, it is important to keep in mind that this trial is assessing two doses that were predicted to be non-sedating and minimally dissociative in patients based upon the results of our phase one trial in healthy volunteers. Sedation and dissociation were important factors behind the requirement for two hours of supervised monitoring stipulated in Spravato's REMS. We're looking for R-ketamine to be comparable to placebo on both sedation and dissociation.
We operationally define this as a risk ratio of less than 2, measured on the MOAA/S and CADSS respectively. A risk ratio in this range would be markedly lower than what was seen with Spravato. On efficacy in the present single-dose study, we're looking for a 5 or more point change in MADRS versus placebo at 24 hours post-dose. This is in the range seen in phase II rials with IV ketamine in Singh et al. 2016, and IN esketamine in Canuso et al. 2018. However, we believe this is reasonable given the lack of functional unblinding that is likely to be present in the current study. The efficacy and tolerability results that we see here will inform the doses used in future studies. Specifically, doses may be shifted higher or lower to further optimize a balance of efficacy and tolerability.
This is particularly relevant given the change from IV to the subQ route of administration that will occur in subsequent trials. Finally, it's important to note that repeat dosing of R-ketamine may result in additional efficacy. Such additive efficacy was seen in the pivotal trial involving Auvelity, a recently approved treatment for MDD with a glutamatergic mechanism. Additive efficacy is less obvious in trials involving Spravato. However, it was seen in the previously mentioned placebo-controlled study of IV ketamine by Singh et al., published in 2016. This result hints at the possibility that R-ketamine may be important for driving additional efficacy with redosing. This, of course, is something that we will evaluate in future studies.
In summary, if we deliver such a change on the MADRS in the context of good tolerability, we believe that we will have de-risked the potential for PCN-101 to be a differentiated therapy for TRD. Next, I'd like to spend a few minutes discussing the latest developments at Compass Pathways, a company in which we hold a large equity stake. By way of background, Compass's lead asset is COMP360, their proprietary formulation of synthetic psilocybin. Compass reported the results of their phase IIb trial last year, and on 12 October 2021 , they unveiled the design of their phase III program for the TRD indication. The design of this program was based upon an end of phase II meeting earlier this year and subsequent discussions with the FDA. In a moment, I'll review that design and discuss the key takeaways as it relates to our programs.
First, however, let me recap the key data for COMP360. In November 2021, Compass reported the results of their phase IIb trial of COMP360 in TRD. In this randomized controlled double-blind trial, a single dose of COMP360 was given to 233 patients with treatment-resistant depression. The trial was powered to compare two active doses of COMP360, 25 mg and 10 mg, against an inactive comparator dose of 1 mg. Th e pre-specified primary endpoint was the placebo- and baseline-adjusted change on the MADRS at three weeks. The 25 mg gr oup showed a negative 6.6 difference versus the 1 mg group on the MADRS at week tree, a result that was robustly statistically significant.
Moreover, at least twice the number of patients in the 25 mg group showed response and remission at week three and week 12 compared with the 1 mg group. Using a standard definition of sustained response, the effect of 25 mg of COMP360 was more than double that of 1 mg at 24.1% and 10.1% respectively. As I mentioned, Compass has had extensive engagement with the FDA, and 12 October 2021 released the outline of the phase III program, which I'll now discuss. The phase III program is composed of two pivotal trials and one long-term follow-up study. The first study, entitled COMP005, compares a single dose of 25 mg of COMP360 to placebo in 378 TRD patients with a 2 to 1 randomization ratio. The primary endpoint is change in MADRS at week six.
This trial is designed to extend the results of the single dose phase IIb study that I just described and is expected to read out by the end of 2024. The second study, entitled COMP006, will be a fixed repeat dose trial comparing three doses, 25 milligrams, 10 milligrams, and one milligram. In this study, patients will be administered two doses of drug or placebo three weeks apart with the primary endpoint of week six . The randomization of this study will be 2 to 1 to 1. This study is designed to investigate whether a second dose of COMP360 can improve the response seen compared to a single administration of the drug. Compass anticipates top-line data to read out by mid-2025.
With that, I'd like to now say a few words on what this phase III program design means for our programs here at Atai. A few elements of the agreed phase III program design stand out as being informative. First, I'd note that COMP005 includes a placebo as opposed to an active comparator. This confirms that the agency is comfortable with both placebo and dose-controlled pivotal trials and the potential implications for functional unblinding in the former. Second, the agency seems to accept that psychological and digital elements of digital support are an integral part of the therapeutic approach for psychedelics. Most importantly, they did not require any factorial trials to tease out drug effects versus the effect of these supporting tools.
Finally, the design of COMP006 involves two doses, suggesting that the agency is broadly comfortable with repeat dosing in the context of psychedelic drug therapy. In summary, the feedback provided to Compass Pathways from the agency is constructive and builds on support the FDA has already shown with various psychedelic compounds, including COMP360, through breakthrough designations. The COMP360 phase III design helps to pave the way for other candidates in Atai's pipeline, most directly our DMT program in TRD. With that, I'd like to hand it off to my colleague and good friend, Glenn, to discuss our DMT program I just mentioned.
Thanks, Srini. Hello, my name is Glenn Short, and I'm SVP of Early Development at Atai. I will now spend the next several minutes giving you a quick walkthrough of Viridia's VLS-01 program involving the development of DMT for treatment-resistant depression and our recently initiated phase I clinical trial. VLS-01, otherwise known as dimethyltryptamine, is the active psychedelic moiety in ayahuasca, a potable botanical mixture containing several different types of plants that are used ritualistically in parts of Central and South America. VLS-01 elicits these psychedelic subjective effects primarily through agonism of the 5-HT2A serotonergic receptor, and whose action may have utility as a rapidly acting antidepressant. In fact, in third-party animal behavioral studies, DMT was observed to produce both antidepressant and anxiolytic effects in rodents, supporting the additional investigation of DMT for depression.
As we will see in a moment, DMT, in the context of ayahuasca, demonstrates antidepressant effects in humans. Through a collaboration between Atai and IntelGenx, we are aiming to develop a novel formulation of VLS-01 as a buccal oral thin film that is placed on the inner cheek to allow transmucosal drug absorption. Once dosed, we anticipate that patients will experience short duration psychedelic effects lasting between 30 minutes-45 minutes. We are pleased to advance the buccal thin film formulation of VLS-01 into first-in-human dosing in our phase one clinical trial earlier this month. Because of its intended short duration psychedelic effects, the buccal thin film formulation may provide patients and clinicians with a short two-hour in-clinic solution. This would dramatically reduce the time patients spend in the clinic and lessen the logistical burden of drug administration on clinicians in comparison to other developing psychedelic therapies.
In the context of ayahuasca, DMT demonstrated evidence of efficacy in patients suffering from treatment-resistant depression. In a double-blind, randomized, placebo-controlled trial in 29 TRD patients, ayahuasca administration resulted in a statistically significant reduction in depressive symptoms as compared to placebo over seven days of observation. In this third-party study shown on this slide, individuals dosed with ayahuasca showed average MADRS scores at or around 10 after two hours, two days of dosing, with sustained efficacy lasting up to seven days. This evidence is particularly compelling to us as it highlights the potential of VLS01 as a rapidly acting antidepressant and the meaningful impact it may have for those struggling with TRD. Earlier this month, we announced that we had dosed the first subject in our phase I single ascending dose trial of VLS01, with top-line results anticipated in the first half of 2023.
This trial is an open label, safety, tolerability, and pharmacokinetic study designed to evaluate the bioavailability of buccal or thin film versus IV formulations, the safety and tolerability of VLS-01 administered by these routes, and the pharmacodynamics of VLS-01 using quantitative EEG as well as other measures. Additionally, this trial marks the first time that Atai's iDEAL-1 digital therapeutic app is being used to provide contextual mindset and setting prior to VLS-01 dosing. As clinical development of VLS-01 ensues, future versions of the iDEAL-1 app may include aspects of behavioral activation therapy, group therapy, and patient monitoring post-dosing. We anticipate being able to use these behavioral assessments in conjunction with the pharmacokinetic and safety readouts to inform the design and doses tested in future phase 2 clinical trials of VLS-01. Now, I would like to hand it off to my colleague and CMO of Atai, Rolando.
Thank you, Glenn. Hi, my name is Rolando Gutierrez-Esteinou, and I'm the Chief Medical Officer at Atai. Today, I'll be discussing the recently announced positive phase 1 data with GRX-917, the form of deuterated etifoxine in development for generalized anxiety disorder. GRX-917 is designed to deliver clinical effects similar to etifoxine with improved pharmacokinetic properties such as longer half-life and no self-induction of metabolism. I'll review the results in a moment, but first, let me give you a brief overview of the program. As you may know, etifoxine was approved in France in 1979 for the treatment of anxiety disorders and is available in several other European countries.
With more than 14 million prescriptions to date, clinical experience has established the safety record of etifoxine with low incidence of sedation or dizziness and scarce reports of abuse, misuse, or dependence, and rare cases of dermatologic conditions and liver enzyme increases. In third-party double-blind studies, etifoxine has shown non-inferior efficacy compared to lorazepam and clonazepam in anxiety symptoms with a lower incidence of sedation and comparable speed of onset and duration of effect to these comparators. Now I'd like to talk about the recently reported phase I study with GRX-917 in healthy volunteers. Single doses between 25 mg and 500 mg and 7-day dosing of 100 mg-300mg BID were tested in this double-blind, placebo-controlled trial in a total of 100 healthy participants. Safety and tolerability were evaluated along with the pharmacokinetics of GRX-917.
Additionally, quantitative EEG was recorded during the single administrations and after the first dose of the multiple dose component. Adverse events were generally mild in severity, including sedation and dizziness, and with no relation to dose. No severe or serious adverse events were reported, and the pharmacokinetics of the drug were roughly linear. The pharmacodynamic biomarker, quantitative EEG, showed a statistically significant dose-dependent increase in beta power, which is a marker of neurosteroid and benzodiazepine activity on the GABA system. The bar graph shows a comparison between group doses at or below 150 milligrams, called the low dose, and doses at or above 200 milligrams, the high dose, on beta power change from baseline.
The onset of this increase in beta power occurred early and was statistically significantly different between low and high dose groups starting at three hours, coinciding with the maximum concentration, and was evident at the eight-hour time point. The low dose group showed minor or no increases in beta power and resembled placebo. I'll show placebo results in the next slide. The graphic presented here shows the brain distribution of the increases in beta power at three hours when maximum drug plasma concentrations were obtained. On the left, you see no or minimal change with placebo or low doses represented by the blue and green colors. While on the right, you see an increase in beta power represented by orange and red colors centered around several electrodes. The large black dots show which electrodes showed statistically significant change from baseline.
This pattern is similar to that of benzodiazepines or neurosteroids, especially those found along the midline of the brain. The combination of this dose-dependent pharmacodynamic effect, along with lower incidence and severity of adverse events such as sedation or dizziness, shows a favorable profile compared with existing treatments. We're implementing a new trial in which we will test doses that were active in the quantitative EEG in an established challenge anxiety-provoking test using carbon dioxide breathing, in which known anxiolytic drugs such as benzodiazepines show efficacy. We look forward to telling you more about the results of that trial in the future. Next, I'll discuss our work with RL-007 in cognitive impairment associated with schizophrenia or CIAS, for which there's no approved treatment and remains an area of major unmet needs that affects 80% of patients with schizophrenia.
CIAS is a major cause of unemployment and difficulties with independent living. I would like to tell you about RL-007 and to briefly review results to date, and then I'd like to present the upcoming phase IIb trial that we'll be initiating by the year's end. RL-007 has a complex pharmacology with indirect activity on glutamatergic, cholinergic, and GABAergic systems, and has shown positive effects on various preclinical models of learning and memory in a dose-dependent manner. These effects have been shown in an inverted U-shaped dose response curve, which means that there is a range of doses that produces the effects, procognitive and others, while doses above and below that range do not. Which makes testing the effects of the drug at a particular range of doses important. RL-007 has a robust clinical history, having been studied in over 500 healthy volunteers and patients.
The drug's procognitive effects have been observed in a number of trials, particularly in a scopolamine challenge test, which is a standard model of drug-induced cognitive impairment. In a trial in healthy volunteers, RL-007 reversed scopolamine-induced memory impairment. That study additionally showed changes in quantitative EEG that we aimed to mimic in a phase IIa study in patients with schizophrenia. The results of the phase 2 IIa study were presented in December 2021 and at a KOL event in January 2023. I will briefly summarize the features of this study and its results. We tested doses of 10, 20, 40, and 80 milligrams, evaluating cognition effects with subscales of the measurement and treatment research to improve cognition in schizophrenia or MATRICS battery. As well as quantitative EEG and evoked potentials.
We found procognitive effects in the Symbol Coding Task, the Hopkins Verbal Learning Test, and QEEG compatible with procognitive effects in the middle doses tested, 20 and 40 milligrams. You can see in the bar graph the improvement in performance in the center with the Symbol Coding Task and on the right with the Hopkins Verbal Learning Test. I'd like to turn now to outline the phase IIb study with patients with schizophrenia on stable doses of atypical antipsychotics. The study is set to initiate before the end of the year. The design of this study is double-blind, placebo-controlled parallel group with RL-007 doses of 20 milligrams and 40 milligrams randomized one-to-one to one. Treatment duration is six weeks with a week eight safety check.
The aim of the trial is to study the safety and tolerability of the drug, as well as its efficacy in the MATRICS battery to show effects on cognition, as well as showing the effects in a measure of functioning, the virtual reality capacity assessment tool or VRFCAT, as an exploratory endpoint. We hope to demonstrate clinically meaningful efficacy on cognition and to replicate the favorable tolerability found in all previous clinical trials with RL-007. Now I'd like to hand it off to Srini to discuss KUR-101 and its application in opioid use disorder.
Thank you, Rolando, and it's great to see everyone again. The last compound I'd like to talk to you about is KUR-101, otherwise known as deuterated mitragynine, which we're developing for opioid use disorder or OUD. Mitragynine is thought to be the active moiety in kratom, a substance with an extensive use history in East Asia that has more recently shown increased use here in the U.S. for OUD and the treatment of pain. Naltrexone acts as a mu-opioid receptor agonist with anecdotal reports suggesting reduced potential for respiratory depression and potentially addiction compared to traditional strong opioids. We recently announced positive phase I data for this compound, which I'll be reviewing with you here today. First, let me start by giving you a brief overview of the phase I trial design.
This phase I trial consisted of two sequential parts and involved a total of 58 healthy volunteers between the ages of 18 and 55. Part I was a single ascending dose design consisting of five cohorts. Four of these involved eight subjects each, receiving a single dose of either placebo or KUR-101 in a 6+2 design. The third cohort consisted of 10 subjects in an 8+2 configuration, and these subjects received the same dose of test article twice, once each under fed and fasting conditions. The primary endpoints of part 1 of this trial were safety and tolerability. A pharmacodynamic marker in the form of experimental pain was also included. The second part of the trial involved a double-blind, placebo and active controlled crossover.
The objectives are assessing the safety, tolerability, and analgesic efficacy of KUR-101 at the 90-milligram dose relative to those of oxycodone at 20 milligrams. Now that I've described the design of this trial, I'll dive a little deeper into the recently announced results for part 1 of the study. Most importantly, initial results from this phase I trial showed that single ascending oral dosing of KUR-101 produces dose-dependent analgesia with effects on respiration comparable to that seen with placebo. Additionally, these initial results indicate the KUR-101 is safe and generally well-tolerated. Additionally, no significant food effect was noted. Overall, we're extremely pleased with these results as they're exactly what we hoped to see when KUR-101 initially entered the clinic. Note that analysis of part 2 of the trial continues, and we expect top-line results from that portion of the trial to be available by year's end.
With that, I'd like to hand it back to Florian to provide closing remarks. Florian?
Thanks, Srini, and thanks to the entire R&D team who contributed to today's discussion. It's a real privilege to work alongside such a talented team of scientists and medical professionals. We have covered a lot of ground in today's sessions, and that speaks to the breadth of innovation that is happening at Atai. We have made meaningful progress across our pipeline in recent months, delivering results that have met the high standards we set for our own programs. Looking ahead, we are eager to share top-line results of our phase IIa trial with R-ketamine in TRD. We believe that these results can potentially be a significant de-risking event as we target an at-home therapy for TRD. Even beyond R-ketamine, I hope you'll take away a deeper understanding of the numerous exciting programs and expected developments that we anticipate making a massive impact in treating mental health conditions.
This wraps up our R&D day. Thank you all again for listening in, and have a great day today.