AtaiBeckley Inc. (ATAI) Earnings Call Transcript & Summary

So right now, this is being studied 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 major depressive disorder, not just treatment-resistant disorder -- treatment-resistant suppression?

So I -- it's Gerard, I would answer that in 2 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 treatment. 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 lesser severe 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 population.

So if that makes sense now there's first-line treatment, which might be less expensive. But if they're not working, then this option, which might be slightly more expensive but more effective for treatment-resistant population makes sense.

I think you can improve the cost efficiency and the pharmacoeconomics works out, then -- and if the safety and tolerability are there, then I don't see any reason why you can't do that, but I think you would have to present that evidence, both to the regulatory agency and to the payers before we can get to that point.

Yes. And now another trial in atai's pipeline is there or ketamine program for treatment-resistant depression. And as Florian just mentioned, it has a Phase IIa readout which is coming at the end of the year. That's going to test efficacy at 24 hours of a single dose as well as safety and tolerability. So Jerry, what are you looking to -- what do you think this readout later this year is going to find?

Well, I'd go back to that triad that we mentioned before of looking for some signal of efficacy, indicators of safety and tolerability. And those really are the 2 that, in some way, is going to 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 health care provider and whether this has to be done in very selective settings. What I'd like to say, I mean, this is a relatively small study in terms of patients, I think it's about 30 people per on. You're not really powered to see huge -- you're not really powered to see small differences. You would need to see very large differences, especially between doses, to see anything. But 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 cognition and perception, maybe less than we see with drugs like ketamine or S-ketamine. So that may actually alter the functional unblinding somewhat. When we do treatments with many other psychedelic drugs or we do treatments with ketamine, there's a high degree of functional unblinding, meaning that the patient and for the most bought the clinicians know who's getting the active drug and who's not. And that can have a big impact on that -- the delta between the active and placebo treatments. And safety, 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. So we can measure them, and we kind of know what we're looking at. So 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.

It's really interesting. So it's the idea that the S-ketamine 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 in -- they're getting the drug because you're having this effect and that might have them show a bit more improvement because of part of that effect of knowing you're on having the drug and having those dissociative impacts can have, I guess, sort of a placebo effect in a way, right?

Yes. And even the flip side may be more important is not having that effect. They actually have the effect of letting you know that you didn't get the medicine and actually set up a negative expectation by us.

But one of -- on the plus side, with the R-ketamine, if people were to use it at home, which is what we're sort of targeting right now is at home use, that there seems to be -- it demonstrates less associative effects than S-ketamine, it's shown, right?

That is correct.

So then, Heddie, can you discuss some of the factors that were -- are relevant to enable these at home -- the use of at-home TRD therapies?

So obviously, SPRAVATO is the benchmark, right? And it's important to recognize that it was developed for in-clinic use. So if R-ketamine is developed for use at home, it will need to have an acceptable side effect profile better than SPRAVATO. The side effects that Jerry mentioned need to be mild and self-limiting and not requiring special treatment or monitoring. And also, I think it will be important to identify mitigation strategies to ensure that patients are able to identify these side effects and how to deal with them and because -- and are able to address any -- take any necessary actions at home. And finally, the most important thing is that you need to have a discussion with FDA on identifying what those regulatory requirements are. But I think it's really going to be driven by the safety profile and that you can demonstrate. And of course, the clinical program needs to include in-home use. And if you demonstrate in-home use, there's a very good probability that you're going to be approved for in-home use.

And so finally, I mean what -- thinking about the future, -- 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?

So from my perspective, I'm optimistic that with the new evolving technologies, data sciences, that we'll be collecting -- able to collect a lot more passive data and using artificial intelligence will 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. So 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. So that would be a huge advance. And also, I think that having those tools, it would make it more easier to evaluate novel mechanisms of actions. Because as Jerry mentioned, there are some treatments -- lots of treatments out there, but there's need for better ones and having more objective endpoints would really be really useful.

Yes. I completely agree with Heddie several of the points that you 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's really one of the real struggles we have for people that aren't aware of this, either a clinical trial recruitment is 1 of the most difficult things and then actually getting true patient populations that are reflecting the patients that are going to be using this. And actually, the ecological validity of these studies are really in question. So ways of improving that, I think, is going to be very important. But 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. And I think this starts to get to the era of how do they start to assess more complex integrated treatment approaches. So 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.

Yes, I thank you both so much for your insights and for being here. Thank you so much.

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 subcu formulation that will be entering Phase I 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 dissociate of 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 2 separate enantiomers. R-ketamine is one of these enantiomer with the other 1 being S-Ketamine. These 2 forms are related to each other in the same way your hands are to 1 another. In other words, they're structurally mirror images each other are nonsuperimposable. 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 on 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 association. Briefly, this slide shows the efficacy of both S and R-ketamine at ascending doses on the 4 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, 30 milligrams per kilogram or MPK, showed a statistically significant change from placebo. This contrast 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 persist. The benefit of S-ketamine is completely lost at this time point. Importantly, R-ketamine lacks abuse liability at therapeutic doses as measured by condition 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 contrast with those of S-ketamine, as shown on the right, recall that from the last slide, the 10 MPK was the lowest effective dose. As you can see here, this dose was associated with positive CPP. And so far 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 7 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-Asberg 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 associate State Scale, or CADSS, a standard measured Association. 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 in September of last year. The agent was well tolerated over the dose range explored and those serious or unexpected adverse events were observed. Here on the screen, we show the CADSS data for the 30- and 60-milligram doses that we chose to move forward with 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- and 60-milligram doses may be respectively considered sub and borderlines associated in this healthy population. With that, I'd like to provide everyone with a brief reminder of the design of the Phase IIa trial as well as the trial objectives. This trial consists of 3 arms that is double-blind and placebo-controlled in design. As I mentioned, we chose 30 milligrams and 60 milligrams IV as the dose to test in this trial, and subjects received a single administration of 1 of these doses or placebo. The sample size is 93 subjects evenly allocated across the 3 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 on measured dissociation and the mOAAS, 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 therapeutic index against both dissociation and severe sedation. We are contemplating the patients with TRD will take about 2 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 greater than or equal to 4-point change on the placebo and baseline corrected MADRS in pivotal trials that may be 4 or 6 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, 1 that supports the 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 to tolerability, it is important to keep in mind that this trial is assessing 2 doses that were predicted to be nonsedating and minimally dissociative in patients based upon the results of our Phase I trial in healthy volunteers. Sedation and dissociation were important factors behind the requirement for 2 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 mOAAS and CADSS, respectively. Our risk ratio in this range would be markedly lower than what we've 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 trials with IV ketamine in Singh, et al. 2016 and in S-ketamine 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 the balance of efficacy and tolerability. This is particularly relevant given the change from IV to the subcu 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 hinted 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 derisked 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' lead asset is COMP360, their proprietary formulation of synthetic psilocybin. COMPASS reported the results of their Phase IIb trial last year. And on October 12, 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 2 active doses of COMP360, 25 milligrams and 10 milligrams against an inactive comparator dose of 1 milligram. The prespecified primary endpoint was the placebo and baseline adjusted change on the MADRS at 3 weeks. The 25-milligram group showed a negative 6.6-point difference versus the 1-milligram group on the MADRS at week 3, a result that was robustly statistically significant. Moreover, at least twice the number of patients in the 25-milligram group showed response and remission at week 3 and week 12 compared with the 1-milligram group. Using a standard definition of sustained response, the effect of 25 milligrams of COMP360 was more than double that of 1 milligram at 24.1% and 10.1%, respectively. As I mentioned, COMPASS has had extensive engagement with the FDA and October 12 released the outline of the Phase III program, which I'll now discuss. The Phase III program is composed of 2 pivotal trials and on long-term follow-up study. The first study entitled COMP005 compares a single dose of 25 milligrams of COMP360 to placebo in 378 TRD patients with a 2:1 randomization ratio. The primary endpoint is change in MADRS at week 6. 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 3 doses, 25 milligrams, 10 milligrams and 1 milligram. In this study, patients will be administered 2 doses of drug or placebo 3 weeks apart with the primary endpoint of week 6. The randomization of this study will be 2: 1:1. This study is designed to investigate whether 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 control pivotal trials and the potential implications for functional unblinding in the former. Second, the agency seems to accept that psychological and 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 2 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 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. And 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. 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 walk-through 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 the psychedelic subjective effects primarily through agonism of the 5-HT2A serotonergic receptor, and whose action may have utility as a rapidly at antidepressant. In fact, in third-party animal behavioral studies, DMT was observed to produce both antidepressant anxiolytic effects in rodents, supporting the additional investigation of DMT for depression. And 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 buckle oral thin film that is placed on the inner to allow transmucosal drug absorption. Once dosed, we anticipate that patients will experience short-duration psychedelic effects, lasting between 30 to 45 minutes. We are pleased to advance the buccal thin-film formulation of VLS-01 into first-in-human dosing in our Phase I 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 2-hour in-clinic solution. This would dramatically reduce the time patients spend in the clinic and less in 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 patient suffering from treatment-resistant depression. In a double-blind, randomized, placebo-controlled trial and 29 TRD patients, ayahuasca administration resulted in a statistically significant reduction in depressive symptoms as compared to placebo over 7 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 2 hours to days of dosing was sustained efficacy lasting up to 7 days. This is evidence is particularly compelling to us as it highlights the potential of VLS-01 as a rapidly acting antidepressant and the meaningful impact it may have for those struggling with TRD. Earlier this month, we announced that we have dosed the first subject in our Phase I single ascending dose trial of VLS-01, 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 buckle or thin film versus IV formulations, the safety and tolerability of VLS-01 administered by these routes and the pharmacodynamic of VLS-01 using quantitative EEG as well as other measures. Additionally, this trial marks the first time that atai's IDO-1 digital therapeutic app is being used to provide contextual mindset and setting prior to VLS-01 dose. As clinical development of VLS-01 ensues, future version of the IDO-1 app may include aspects of behavioral activation therapy group therapy and patient monitoring post-dose. 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 II 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 I 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 but 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 and 500 milligrams and 7-day dosing of 100 to 300 milligrams 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. And 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 the 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 3 hours, coinciding with the maximum concentration, and was evident at the 8-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 percentage here shows the brain distribution of the increases in beta power at 3 hours when maximum drug plasma concentrations were obtained. On the left, you see no or minimal change with a 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 is 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 this 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 for cognitive 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 pro-cognitive 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 IIa study were presented in December of 2021 and at a KOL event in January of 2023. I will briefly summarize the features of the 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 pro-cognitive effects in the Symbol Coding Test, the Hopkins Verbal Learning Test and EEG compatible with pro-cognitive 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 Test 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 and 40 milligrams randomized 1:1:1. Term of duration is 6 weeks with a week 8 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 end point. We hope to demonstrate clinically meaningful efficacy on cognition and to replicate the favorable tolerability found in all previous clinical trials with RL-007. And 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. Mitragynine 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 2 sequential parts and involved a total of 58 healthy volunteers between the ages of 18 and 55. Part 1 was a single ascending dose design consisting of 5 cohorts. Four of these involved 8 subjects each receiving a single dose of either placebo or KUR-101 in a 6 plus 2 design. The third cohort consisted of 10 subjects in an 8 plus 2 configuration, and these subjects received the same dose of test article twice, once each under fed and fasting conditions. The primary end points 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 a dose 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 that 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?

Thank you, Srini, and thanks to the entire R&D team who contributed to today's discussion. It's a real privilege to work along 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 arketamine in TRD. We believe that these results can potentially be a significant de-risking event as we target in at-home therapy for TRD. And even beyond arketamine, 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.