Schizophrenia is a serious mental health condition. It affects 1% of the U.S. population and around 24 million people worldwide. Symptoms like hallucinations and delusions are the better-known aspects of schizophrenia, but the less well-known symptoms, like loss of cognitive abilities, can also be debilitating and limit a person's ability to lead an everyday life. An estimated 84% of all people with schizophrenia show symptoms of cognitive impairment associated with schizophrenia, or CIAS. CIAS effects can include memory, attention and concentration, problem-solving, learning, executive function, speed of thought, and information processing. Reduction of cognitive abilities impacts all areas of daily living, including the ability to hold down a job, manage social situations, and follow a regular treatment regimen. They can also lead to social isolation or stigmatization. While antipsychotic medications can help individuals with schizophrenia manage many of their symptoms, such as hallucinations or delusions, there are currently no approved treatments for CIAS. At Atai, we are working hard to fill this gap. We are researching the potential of RL-007, a compound that may offer benefits in reducing the impact of CIAS and helping people living with schizophrenia to lead more fulfilled lives. Good morning, everybody, and welcome to Atai's webinar focused on the cognitive impairment associated with schizophrenia. I'd like to thank everybody for joining, both our speakers, Matt and Rich, as well as the audience members. The goals of today's call or webinar are really twofold. The first is to provide a little more clarity, a little bit more color on the results that we announced last year, late last year, on RL-007 and the initial proof-of-mechanism trial of this compound in schizophrenia and cognitive impairments associated with schizophrenia in particular. We talked a little bit about the EEG results that we found there, as well as some of the symptomatic benefits that were seen. We, again, want to give you a little bit more color there and also touch upon some of the ERP results that were found there. What's equally important, however, is that we want to provide some context for these results and really give the audience a little bit more information on the background of this compound. This is an interesting compound. There's a lot of human experience with this particular agent. There's a lot of data around cognitive improvements. However, there's no publicly available data. I know that's been a source of frustration to several folks within the audience. Again, hope to provide you a little bit more context there. Let's go ahead and advance to the next slide. Perfect. These are our standard forward-looking statements. Let's go ahead and get to the next slide. This is a quick overview of today's agenda. Again, I'll be providing a little bit more by way of introduction, both of Atai as well as, of course, a little bit more on our speakers. Rich is going to jump in and give you a nice overview of CIAS broadly, the background, as well as some of the therapeutic landscape, which, of course, at this moment is quite limited. Matt's going to be going through the background on RL-007, starting with the background, all of the existing data that's been generated, and then go into some of our phase II- A results. Of course, we'll dive into a Q&A and answer any questions that any of you may have on the compound. Next slide, please. All right, I think many of you are familiar with this. I mean, clearly, mental health disorders have really become one of the greatest global health challenges. There's about a billion people, that's with a B, impacted by mental health disorders. Lots of unmet patient need and lots of, I mean, the treatments and innovations have been quite limited. You will see from Rich that this is particularly true for cognitive impairments associated with schizophrenia. We are comfortable in many, for the most part, in treating the positive symptoms of schizophrenia, but you will see that the impact of the cognitive impairments, negative symptoms, etc., are really what drive a lot of the morbidity associated with this condition. We are really focused on compounds that have prior evidence in humans. In some situations, like DMT, etc., those are published data. In this case, of course, those data are not published. As I mentioned earlier, Matt is really going to be focusing on that and giving you the context around why we are interested in this compound in the first place. I'm going to talk a little bit more. I'm going to at least flash out the slide, I should say, about our entire pipeline. We also have a number of enabling technologies. Broadly, these kind of fall into a couple of different buckets. We have digital technologies. We have formulation technologies, and we have now several drug discovery capabilities housed in different companies as well. Really interesting kind of orthogonal technologies. We have mentioned a number of times that we're not interested in the next SSRI, right? We're really interested in things that truly move the needle for mental health treatment. Obviously, we are very excited about RL-007. As I mentioned, we really do believe that the results that we found today are significant de-risking events for this particular therapy. Many of you are familiar with the very unique model, in many ways unique model, of Atai. Obviously, we have a central Atai itself, where most of the capabilities in many different realms are housed. We have a number of subsidiary companies, of course, Recognify being one of those. In general, all of these subsidiary companies leverage the capabilities of Atai, which, of course, are, as I mentioned, quite broad. Obviously, R&D and, again, dragging and dropping, if you will, as necessary, but also broader capabilities from intellectual property to general legal to finance and accounting. We've had some recent successes in terms of validation of the model. I think all of you are going to be familiar with the COMPASS Pathways IPO and the Otsuka collaboration that was announced early last year. At this point, we're about 100 FTEs internally. We have many consultants beyond. Our cash balance, the last indicated cash balance, was $230 million. Okay, let's go to the next slide. As I mentioned, this is just a quick overview of our pipeline. I'm not going to go into any details here. As you can see, RL-007 is one of the furthest assets, one of the most advanced assets that we have. Obviously, we'll be talking about the results of our phase II- A proof-of-mechanism trial. Of course, as I've mentioned, and as Matt will also highlight, we will be moving into a double-blind placebo-controlled phase II trial of this compound in the not-too-distant future. All right, with that, let me jump—let's go to the next slide. Let me just give you a little bit of background on our speakers. Rich is someone I've known for quite some time. He's a professor of psychology, psychiatry, and neuroscience at Duke. Salient to the current discussion, he's an expert on measuring symptoms and, in fact, was the founder in 2004, I believe, of NeuroCog. There was a sort of a central mandate there around instruments and around validation of instruments for assessing symptoms, again, broadly, but certainly schizophrenia. In fact, cognitive impairment and schizophrenia is where I met Rich in a previous program. Again, very happy to have him on board, as I mentioned, on this talk and more broadly involved with our program. As I mentioned, Rich is going to give you a little bit more context around the indication itself. Matt is the CEO, President, and Co-founder of Recognify. He was instrumental, along with a couple of other folks on the team, in getting this very exciting, very interesting asset essentially out of Allergan and into the hands of Recognify, thus Atai. Previously, he was an entrepreneur in residence at ForSight Ventures. Prior to that, CSO of Diaxonhit and has a PhD out of Salk here in San Diego. All right, next slide. I believe I'm going to be handing off at this point to Rich, who will be giving you an overview, as I mentioned, of CIAS. Great. Thanks, Srini, I appreciate it. It is a great opportunity to be here to talk to everybody about cognitive impairment and schizophrenia. I am going to talk a little bit about the background, about why cognition is important, why this is an unmet need, and a bit about the current programs in place to try to do something to address this really incredible, devastating aspect of mental illness. Next. This is my disclosure. As Srini mentioned, in addition to being a professor, I have a company outside of Duke that is called VeraSci. We support clinical trials, including some of the ones that I am going to be discussing today. Next. People probably know a bit about schizophrenia. They, like many psychiatrists, often think of schizophrenia in terms of the delusions and hallucinations, the paranoid ideas that Martians are taking over their brains, hearing voices, and these very striking aspects of the illness that really get a lot of attention from the media. Also, for obvious reasons, because they're dangerous, have been the primary target of treatment, the so-called antipsychotics. There have been antipsychotics available now for 70 years, and yet the disability associated with schizophrenia has really not changed much over the course of that 70 years. Schizophrenia is one of the most disabling illnesses of young people in the world, only behind alcohol use disorder and depression. Next. If we look at some of the statistics associated with that disability, two-thirds of people with schizophrenia never have any intimate relationships that lead to marriage. They often, in young age, after psychosis going forward, when everybody else is developing relationships, kind of planting their stake in the productivity that they're going to have, people with schizophrenia are unstable and don't get that kind of traction in developing the kind of things that make us all productive members of society, well, most of us. The other thing, and as a result, by the way, they are very unlikely to work. Less than 15% of people in the United States with schizophrenia have a job, and 20% of them are homeless at any time. If you drive around the cities of America, you often will see people living under the bridge, living in terrible conditions. Most of those folks have schizophrenia. Unbelievable devastation associated with this illness. It turns out that this devastation actually isn't caused by the delusions and the crazy ideas and the hallucinations. It's actually caused by the cognitive impairment. I'm going to talk a little bit about what that cognitive impairment is and how it leads to this dysfunction among people with schizophrenia. Next slide. Yeah. First, the costs associated with schizophrenia. These estimates are a bit old, about eight years old. At that time, and things have only gotten worse, the estimated cost of schizophrenia in the United States alone was $156 billion. Some of that was from direct healthcare costs, but a lot of it was from indirect costs, up to $120 billion or so, due to the fact that people with schizophrenia for the entire course of their lives, right? Onset is often 18- 25 through to death. They don't work. People need to not work to take care of them. And they have other healthcare problems associated with their illness. Of course, if you're living under the bridge, you're probably not getting your annual checkup, not taking the other medications you need to treat heart conditions and cancer and things like that. It is a tremendously devastating illness with real costs to the United States and to economies around the world. Next. This is the severity of cognitive impairment in schizophrenia. I need to apologize to those of you who are not psychologists, but there are going to be a couple of statistics that I need you to understand. Very simple. First is T-score. A T-score is a statistic that psychologists use where the mean in the general population is 50 and the standard deviation is 10. Pretty simple. Average person in the general population on these cognitive tests gets a 50. People who are doing really well get a 70. People who are really doing really poorly get a 30. When you look at these aspects of cognition that are particularly impaired in people with schizophrenia, they perform about one to two standard deviations below the healthy control mean. T-score is ranging between 40 and 30. If you look at the overall sum of all of these aspects of cognitive impairment, the T-score is 25. That is two and a half standard deviations below the healthy control mean. If you put that into metrics that might be a little bit more familiar, it is the lowest 1% of the population. In IQ score terms, it would be lower than 70, which is the cutoff for pervasive developmental disorder or intellectual disability. These are really profound levels of cognitive impairment in people with schizophrenia. Next. As I mentioned before, these cognitive deficits, more than any other aspect of the illness, account for the difficulties that patients have in terms of getting a job, keeping relationships, functioning in the community, being able to even benefit from the psychosocial rehabilitation programs that are available to them. Next. An important question, certainly from the perspective of what the unmet need is, is, well, which patients with schizophrenia have this cognitive impairment, CIAS, cognitive impairment associated with schizophrenia? Our estimate is that almost all patients have some level of cognitive impairment compared to what they would have been if they had never developed the illness. If we look at these scores here, and again, these are a different metric. This is actually an IQ-type score where the mean is 100. Standard deviation is 15. You can see right in the middle there between the light blue 25% is 100. That's the average of the general population. You can see there's a nice inverted U-shaped curve from the healthy group. Same with the schizophrenia group. It's just shifted about two standard deviations down from the healthy control. You think, what about that 2.2% there that appears to have above-average performance on cognitive tests? Okay. They're performing cross-sectionally. At the current time, they're performing in the range of what's considered normal in the healthy population. However, people have probably heard of somebody who was at an Ivy League school or who was in medical school and had a psychotic break, never recovered, developed schizophrenia, and the rest of their life stayed in that same state, difficult to get a job, difficult to get married. Those folks almost certainly performed cognitively much better prior to the onset of their illness. Do they have cognitive impairment? I think so, right? Somebody who loses that amount of cognitive function is doing much worse than they would have otherwise. They are just as likely to benefit from treatment as somebody who is at the lowest end of the spectrum. When the question is, does this apply to a certain portion of patients with schizophrenia? Our answer is that it applies to almost everybody. You can just count up the number of people with schizophrenia, and those are the people who could benefit from a new drug. Next. Yet there is nothing approved. I believe the current total is 27 antipsychotic medications are approved for the treatment of schizophrenia. 27. All of them basically doing the same thing, blocking dopaminergic neurons in order to reduce hallucinations and delusions. That's it. They do nothing for cognition. They do nothing for the other aspects of the illness, like negative symptoms, not interest, lack of motivation, lack of engagement with the world. Why not? There are about 200 CIAS trials listed on clinicaltrials.gov. However, a lot of those are early-phase single-site studies. A lot of those are academic studies. Some of those are not even with a pharmacologic intervention. Some of them are with psychological interventions. There are no treatments. You wonder why hasn't there been any success. Largely, it's from shots on goal. When you compare the number of clinical trials, the investment from the government, as well as the investment community in drugs to improve CIAS, it's very small compared to other aspects of medical illness like cancer and cardiovascular disease. NIH spends 25 x more on cancer than schizophrenia. Of course, as we know, the industry investment in clinical trials dwarfs what the government does. There are over 1,000 ongoing clinical trials in cancer for every one in CIAS. Sometimes people see that and they think, "Well, that's because it's easier to get a drug approved in cancer than in psychiatry." Not true at all. In fact, if you look at the latest statistics, the progress from phase I to FDA approval is 5.1% for cancer indications, and for psychiatry, it's 6.2%. Why? It's a little unclear to me. I think some of the reasons have to do with stigma, bias. I think everybody knows somebody with cancer, with cardiovascular disease, a relative, even Alzheimer's disease. It is much easier for investment to be placed in that area, easier for senators and congressmen to approve the allocation of resources there, of course, because a lot of them are in the age of risk of cardiovascular disease and Alzheimer's disease, but not so much for schizophrenia. It is a stigmatized disorder. I think that means that, in a way, it is underinvested, right? Because if there is a stigma associated with it and there is just as much likelihood of getting success, why would not there be as much opportunity from the investment community? Next. There had been some recent positive developments, I think, that everybody should be very heartened by. FDA, the current psychiatry division in FDA, has clearly recognized the severity of the unmet need. The whole MATRICS program that started a number of years ago has built up a methodology that is very clear. Mechanisms of action that are successful, such as this one, have been emerging. FDA is aware of that. They have been expediting some of the CIAS drug development programs. The potential economic gain to all of us for a successful treatment in CIAS is enormous and we know it will be welcomed by the government folks who are involved in making decisions about whether a drug can come to market. Next. Here are a few of the programs that are currently in place to kind of set a little bit of the context for the Recognify compound. The biggest program, actually the biggest program in history so far, is the Boehringer Ingelheim GLyT1 inhibitor, a glutamatergic drug. I'll show the results in just a minute. Some successful phase II results, and the phase III program is now underway. Biogen has a positive allosteric modulator, an AMPA compound, which also has glutamatergic effects. They are currently in the midst of a phase II program. That was a compound, by the way, that they licensed from Pfizer a number of years ago when Pfizer got out of CNS altogether. Neurocrine Takeda. Not much about this trial is publicly available. What I can tell you is from the public press releases, they had the original phase II- A clinical trial was focused on negative symptoms. They also measured cognition in two ways, which is important. They measured cognition as a performance outcome, cognitive tests that we do. They also asked questions to the relatives about, "Is this patient getting better on the drug?" They got positive signals on both of those endpoints, even though they were both secondary endpoints. Now they're going to go back and start a study, a phase II- B trial that focuses on cognition as the primary endpoint. They've changed the endpoint. Whether that signal is real is going to be determined later. Those are the major programs where cognition is the primary endpoint. The other aspect of this in terms of cognition is cognition as a secondary endpoint. I mentioned that all 27 of those antipsychotics depend upon dopamine blockade as a way of reducing psychotic symptoms. There are some new programs that people are probably aware of where dopamine blockade is not the mechanism of action, but other mechanisms of action for these antipsychotics. It may be that those also have benefits to cognition as a secondary endpoint. That whole field is opening up a bit, but not much is known about the effects of those drugs on cognition. It's going to be a few years before we find out. The important thing about these mechanisms, though, to kind of set the stage a bit for what Matt is going to talk about, is that many of these programs focus on very specific selective mechanisms of action. What's interesting about Recognify is it has a much more complex mechanism of action that modulates a variety of different receptor systems. One of the reasons that that's promising is that other drugs for schizophrenia have also had a complex receptor system activation. The best example is clozapine. Clozapine, while it has this untoward side effect, potentially a fatal side effect, it has greater efficacy than any other antipsychotic drug. That is largely seen as being associated with the multi-receptor profile that clozapine has. Next. Final slide for me. This is just data from the Boehringer Ingelheim program. I wanted to make one point about this. The blue dotted line, that is the dose that was the best compared to the black in placebo. It was about a two-point change on the MATRICS battery, the FDA endpoint. Patients with schizophrenia perform about 25 points lower than healthy control mean. That is a very small bump in improvement in cognitive performance. This drug is not curing the cognitive impairment of schizophrenia. If this result continues on into the phase III program, I believe it will be approved if they also have their co-primary measure improved as well. I believe that it will be approved whenever the program's done in about three years. It is unlikely, if this result is replicated and it's approved, that this is curing cognitive impairment of schizophrenia. This is 10% of the improvement. There will be a need for other drugs to do something as good or better in the future. Thanks again, Srini, for the opportunity to talk to everybody about cognitive impairment and schizophrenia. During the question and answer period, I'm happy to address any questions people may have. Thanks. Hey, Rich. Thank you so much for that amazing overview and really, again, kind of contextualizing what we're doing in the broader space of cognitive impairment associated with schizophrenia and the other therapies. At this point, I want to hand it over to Matt to kind of give you a little bit more about the drug itself and the results that we found. Matt? Thank you, Rich, and thank you, Srini, for the introduction and the great context of the huge medical need that we're trying to address here. Next slide, please. I'd like to just start by calling out our combined clinical team of both Recognify members and Atai members that have really come together in a strong way and in a complementary way to really push this program forward. Particularly, I'd like to call out Gary Walker, who's a co-founder with me at Recognify, who's really been doing the heavy lifting during this initial clinical study in CIAS. Next slide, please. Obviously, Rich and Srini touched on this, and what I'll be telling you about today is a unique neuromodulator that has demonstrated clinically significant changes in learning and memory and cognition in general. What I want to try to do here, and as Srini alluded to, not a lot of data has been published, actually very little, close to none, around this compound and really give you some context of what some of the underlying data is and partly what really attracted Atai to this product and really its clinical benefit that's been demonstrated already and how we're extending those observations into CIAS to demonstrate CNS activity with EEG, ERP readouts, but also looking at and gaining clinical response on cognitive measures. Next slide, please. We view this product as a D-risk pharma-developed product. We were able to get it into Recognify with an impressive preclinical and clinical data package. It comes with multiple replications of statistically significant pro-cognitive signals in learning and memory. This is really important because learning and memory defects are an essential component of CIAS patients and how their lives are impacted by the disease that they're suffering from. Also, this product is really well tolerated. This is also important when you're taking a product into a fragile population that is already struggling with their morbidities from the disease. Next slide, please. Just to give you some context of why we're calling this a D-risk product, part of it consists from the. Has a very consistent PK/PD exposure response relationship. Why this is important is it gives us confidence in the active dose range that we're investigating and how we can translate that both from the preclinical space to the clinical space and ultimately to CIAS patients. It has a complete CMC package, so it's ready to move forward and further into clinical development. As I mentioned, it has excellent safety and tolerability and multiple clinical cognitive signals. Next slide, please. Obviously, the product has been tested preclinically quite broadly, and this is mainly because of its core mechanisms of action of enhancing neuroplasticity. This neuroplastic effect that the compound has translates into pro-cognitive effects, anxiolytic effects, and other functional recovery effects that have been demonstrated both in vitro and in vivo in the preclinical space. Also, importantly, the product is non-sedating, and there's no dose-limiting CNS tolerability effects. Next slide, please. The product not only has a unique mechanism, but it was actually discovered in a somewhat unique way, and that was through an in vivo phenotypic screen. The product has mainly been, the mechanism of the product has mainly been characterized through electrophysiological changes. What's been demonstrated is that the product does enhance basal glutamatergic tone and enhanced LTP. This is demonstrated. Some example data is on the upper right-hand panel where you see an increase in basal activity in the presence of RL-007, then upon stimulation, a significant enhancement of long-term potentiation. You'll see that if you look closely, the blue dots actually represent an intermediate dose, which elicits the largest effect. This is indicative of the bell-shaped dose response of the product across both in vitro and in vivo models. Another interesting aspect of the compound is that it appears to be able to enhance long-term potentiation in the hippocampus. This is in combination with acetylcholinesterase inhibitors in a synergistic way. A demonstration of this is in the lower right-hand panel. This is actually in free-running rats looking at hippocampal LTP response. You can see in the presence of acetylcholinesterase alone, you get a modest enhancement in LTP, a larger enhancement with RL-007, and then what appears to be a synergistic enhancement in combination. Obviously, this demonstrates its unique activation or activity in the cholinergic system and able to overcome and potentially enhance signaling in the hippocampus, which is obviously the central brain organ or region responsible for learning and memory. Another important aspect that's been described is that both the electrophysiological and in vivo behavioral functions of the compound can be blocked by GABAB receptor antagonists and nicotinic acetylcholinesterase receptor antagonists. Importantly, the product does not directly bind to these receptors. Next slide. In the preclinical space, the product has a very broad pro-cognitive effect. I don't have time today to go through all of the data, but just to summarize, this effect has been seen across species in young animals, in aged animals, in chemically challenged animals, cholinergic challenge induced by scopolamine. The PK/PD exposure response relationship is highly consistent across these models and across species. I'm going to show you in a few slides how these effects translate to humans. Next slide, please. Obviously, Rich touched on this and really did a great job of explaining why cognition is such an important target for helping patients suffering from CIAS and schizophrenia in general. Really, the focus of Recognify and obviously Atai is really to look for products that can address not only cause meaningful clinical changes, but also improve quality of life. We really feel that CIAS has a huge medical need that we can address with these cognitive benefits and directly impact quality of life. Next slide, please. We are very fortunate to have a product that already has replicated pro-cognitive signals. Again, this just to summarize, the top study was a PK study in healthy normal individuals. This would be your young individuals. The second study was a scopolamine challenge study. This is the chemically challenged cholinergic model that was also run preclinically. There was also a diabetic pain study that was previously run. These individuals had an average age of about 60. This is a more elderly population. In each of these studies, there was a clear pro-cognitive effect that was expressed in a biphasic way that correlates with the preclinical dose response that was seen in a variety of model systems. Another aspect of these original studies is that these pro-cognitive effects were seen at the lowest dose. One of the aspects of the current CIAS study that we wanted to explore was moving even lower in the dose range to fully characterize the pro-cognitive dose response in CIAS patients. Next slide, please. This is just data demonstrating the pro-cognitive effect in healthy normal individuals. This also demonstrates that the product has very acute responses and can elicit an acute pro-cognitive effect. In this study, patients were dosed with a single dose or seven days of TID dosing. A verbal learning task was applied. What you can see is that even after a single dose, highlighted here in red, even after a single dose, you see a strong pro-cognitive response on verbal learning. That persists over the seven-day treatment period. Another thing you'll notice is that when you push the dose extremely high, you actually start to see suppression of cognitive response. This is something that was seen preclinically, and it's something that has been replicated in these studies in the clinic. Next slide, please. This slide's a little busy, and I'll try to walk you through it. On the top half of the slide is the scopolamine challenge or cholinergic challenge model system that was run on healthy young individuals. Similar to what was seen in the preclinical model, the compound is able to inhibit or enhance cognitive performance in the presence of a cholinergic challenge. In the upper two panels on the left is a verbal learning task and a delayed word recall, so learning and memory. Statistically significant effects were seen in both of these tests, but again, only at the lowest dose, in this case, a 30 mg TID. In this study, it was over a single day of dosing. Again, a very acute response. Similar to what I just showed you in the PK study, when you push the dose too high, you actually start to see suppression of recovery in this population. In this case, it was an extremely high dose of 750 mg TID. One thing to pay attention to also in this study is that to test for central activity, EEG changes were monitored because it's known that scopolamine has its primary effects on alpha and beta bands where you get suppression of alpha and increased beta. What was tested was to see if there were dose-related changes in the presence of the compound, but also how the compound affected the changes that were induced by the scopolamine challenge. The scopolamine alone is in this panel on the upper left, where you can see decreased alpha and increased beta in the middle section. You can see on the right what the scans look like in the presence of the compound and its ability to inhibit these scopolamine-induced changes. This will be reflected in this data will be echoed a bit in the CIAS study data when I get to that. Finally, on the bottom side, this is the diabetic pain study, again looking at verbal learning and delayed word recall. In this study, there were two dose regimens. One was a low dose, and one was a high dose. The low dose ranged from 40 mg-80 mg, one week of dosing at 40 mg, followed by three weeks of dosing at 80 mg, and then a higher dose at 150 mg, escalating to 300 mg. Again, you see at the lowest dose given in the study, highlighted in red, a statistically significant improvement in verbal learning and delayed word recall, again, episodic memory improvement. Next slide, please. When taken together, you can start to see a pattern emerge from the data that's already been generated about pro-cognitive effects in the clinic. You can see that there are acute pro-cognitive effects. These effects were seen in the scopolamine challenge study and the human PK study at 30 mg and 40 mg TID and a more prolonged treatment duration of a month, showing again statistically significant improvement in learning and memory at 40 mg-80 mg TID. Importantly, we did see there was an assessment made of cognitive and physical function. This is a questionnaire that's given to the patients to assess whether they feel they're benefiting from treatment. Again, in the diabetic pain study, this questionnaire came back as statistically significant in a positive way, but again, only at the 40 mg and 80 mg dose where there was a pro-cognitive effect. This is where we may initially see some correlation between the pro-cognitive changes and actually a functional quality of life outcome. Next slide, please. What were our primary objectives moving the product into CIAS? Really, it was as simple as extending prior clinical data to CIAS patients. Initially, obviously, looking at safety and tolerability, looking at CNS activity by EEG changes, defining the pro-cognitive dose range in the CIAS population and exploring lower doses, and also by making an initial assessment of what pro-cognitive signals might we be able to detect in CIAS patients. Next slide, please. This is a schematic of the study designed for a phase II-A. It was a single-centered, single-arm, single-blind, multi-dose study. It had a one-day placebo run-in of four doses followed by two days of TID dosing of RL-007. This dosing regimen was structured so that we could meet approximate CSF steady state following five doses and then do the testing after the sixth dose on day two of dosing. Again, these were independent cohorts dosed at 10 mg, 20 mg, 40 mg, and 80 mg. This was a typical schizophrenia patient population, age 18- 50, on unstable protocol-allowed antipsychotics. The study was run with David Walling at his site at the Collaborative Neuroscience Research Center. Next slide, please. As I mentioned, our primary objective with the EEG ERP readings were really to look at consistent dose-dependent changes across the different brain waves. I show this as an example. This is eyes open condition looking at the different dosing cohorts from 10 to 80. What you can see here is there's a clear difference between the 10 mg dose and the higher doses given in the study. In the 10 mg dose, you see a decrease in the beta bands, whereas in the higher doses, you see a consistent increase across brain regions of alpha and, more importantly, of alpha slow-wave index. The alpha slow-wave index is an indicator of functions of vigilance and wakefulness, so somebody that might be more alert. Next slide, please. For the ERP, what we saw in this preliminary set of data is that there were acute differences between the lower and high doses also in the ERPs. These differences suggest potentially that there's support to sensory memory at the lower to moderate doses with the compound. We did not see with this acute treatment a consistent response across all time points. This may just be due to the very acute treatment regimen and short duration of treatment. The most consistent signal that we did see was on MMN and particularly at the 20 mg dose. I show an example of that data down below. Mismatch negativity is a passive auditory oddball event, and you're really looking for a passive response to a change in a tone. The amplitude really reflects the size of the response and the latency measurement, the rate of response. Mismatch negativity is something that's suppressed in patients suffering from schizophrenia. It is one of the markers that you do want to see move in a positive way in this patient population. As far as P300, we didn't see any effects on P300 at the lower doses and very sporadic effects on P300 at the higher doses. We do know from the data I just showed you that at the 40 mg and 80 mg dose where there were sporadic decreases in P300, after a month of dosing, we do see positive and statistically significant effects on learning and memory. At this point, we just do not have enough data to really make a strong assessment of what these early P300 signals might mean. Next slide, please. Now moving to the cognitive measures. For obvious reasons, we selected a subset of the components of the MATRICS battery. The MATRICS battery is the gold standard right now for assessing cognitive benefit in CIAS patients. The first component that we selected was verbal learning. We have seen multiple positive outcomes on verbal learning in previous studies. This is basically learning a word list that is given in multiple trials. It is testing, again, verbal learning and memory. Second, we selected the BACS Symbol Coding test. An example of what that looks like is on the right, where you're matching up symbols with numbers as quickly as possible. This tests processing speed, attention, and really complex aspects of functional working memory. This is an important test in CIAS patients. Finally, we tested category fluency, which tests processing speed, verbal ability, and executive control, basically naming as many words in a minute from a specific category, in this case, animals, as you can. Next slide, please. This is the summary data of what we saw expressed as T-scores. Rich explained what T-scores are. These T-scores are normalized for age, gender, and education level. I want to draw your attention first to the symbol coding task. This is one of the more sensitive—I will quote from Rich here on the side—one of the more sensitive measures in schizophrenic patients. It also has the highest correlation with other outcomes of the MATRICS battery. What we see here is a very acute response in biphasic bell-shaped dose response, similar to what we have seen with other tests and other outcomes. We also see here that we have kind of bracketed the upper and lower limits of the dose response, where at 10 mg, we do not really see any response at all in this acute treatment. We see 20 mg, 40 mg, and 80 mg giving a response. In addition, we did see what appears to be a signal emerging in HVLT at the 20 mg and in the 40 mg a signal in category fluency. Again, something that's clearly different from the higher doses is that on HVLT, we see what could be potentially some suppression of cognitive response in verbal learning. One other point just to quickly point out is that I've shown you Cohen's d scores and not T-scores on the other slides. If you convert these to Cohen's d, these would be medium to high effect sizes across the doses that gave a response. Next slide, please. What did we learn from the cognitive signals? We have a new test that hadn't previously been run that gave a large response in an acute fashion. It's a test that's important for CIAS patients and correlates well with movement on the matrix battery. The observed changes, and we've run this data by multiple KOLs, including Rich, and there's consensus that these changes are larger than what you would expect from simple practice. The effect sizes are in the range that you would expect after six months of cognitive training. These effect sizes also would be expected to correlate with improved work-to-school performance. Again, a measure that has shown correlation with improved quality of life outcomes. Obviously, we replicated the immediate word recall and verbal learning effects in the 20 mg, similar effect size to what we saw in the diabetic pain study. We will need to test whether longer durations of treatment will extend and strengthen these initial findings. Next slide, please. Overall, from the phase II-A, I think we were quite successful in extending the previous observations into the CIAS population. Obviously, the product was safe and well tolerated. We showed central CNS activity by relevant EEG changes. These changes may suggest a more wakeful, attentive state and a relaxed state. We did see the beginning of some ERP changes that may be cognition-related and dose-dependent. Again, replicating what appears to be a bell-shaped dose response and having a response on these initial cognitive assessments that—this is really the most important aspect of what we're trying to do in positioning the product in CIAS—is really look for measures that are going to be a relevant indicator of patient outcomes. Keith Nuechterlein, another one of our advisors, states it this way that, yes, these symbol coding responses are at a level that would correlate with better work-to-school performance, which is an important point. Next slide, please. Where are we going with this in the future? Obviously, we just completed and replicated clinical effects in a small CIAS study. Obviously, the next study will be a double-blind placebo-controlled study to demonstrate statistically significant improvement in cognition. Right now, we're working diligently with our key advisors to assess key elements for the next study, which, of course, are dose, effect size, and treatment duration. The data I've shown you has highlighted what we believe is the optimum dose range for the cognitive effects, which fall between 20 mg and 80 mg TID. The pro-cognitive effect size that we've seen across all studies ranges from 0.2 to above 1. In the CIAS study, it was 0.4-0.8. The duration that's been tested previously ranges all the way from a single dose out to four weeks. Basically, we're using this data right now to formulate a study that will give us the highest probability of success to demonstrate a statistically significant improvement in cognition in CIAS patients. Next slide, please. Obviously, we're optimistic, and we're encouraged by these initial results in this phase II-A CIAS study. We do believe that with the other functional outcomes that RL-007 can support, that this product could be a central pillar for Atai in the neuropsych space, particularly when you think about the pro-cognitive effects in combination with the anxiolytic effects that have been demonstrated preclinically. There is potential in other high-value opportunities in CNS in general. With that, I'd like to thank you for listening and open it up to Q&A. Yeah. Thank you, Matt, for all the detail. There was a lot of information. I hope the audience was able to digest that. Obviously, very, very excited about the results that were outlined, both on the quantitative EEG as well as the behavioral signals that we saw. In particular, I think it's worth mentioning that Keith, that was mentioned as one of our KOLs that's reviewed this data, actually indicated that the sort of changes that we're seeing on symbol coding were actually comparable to approximately six months of cognitive behavioral therapy. So really exciting results. Obviously, looking forward to replicating and extending these results in a more traditional phase II trial focused on cognitive endpoints. All right. With that, I do want to open this up. I know we're running a little over time, so apologies for that. Great. Thank you, Srini. At this time, we'll be conducting our question-and-answer session. If you would like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. Our first question comes from Charles Duncan from Cantor Fitzgerald. Charles, you may go ahead and unmute your line. Yeah. I think I'm set to go. Thanks to Tim for hosting this call, and happy New Year to everyone. I had a question for Dr. Keefe, and that is relative to thinking about the patient heterogeneity with cognitive impairment associated with schizophrenia. I guess I'm wondering if you could compare and contrast that relative to, say, the negative symptoms associated with schizophrenia that you see in different patients, whether or not CIAS is degenerative. And then what is the minimum, call it length of time of exposure that you would like to see the company evaluate in the next double-blind placebo-controlled study to give you confidence that this drug may have activity that could translate into efficacy? Yeah. Thanks, Charles. Great questions, by the way. The degeneration question, first of all, is a controversy in the field. It's been hard to do studies that are long enough to demonstrate whether schizophrenia is neurodegenerative over time. It's certainly not over a brief period of time, like Alzheimer's. You can look at Alzheimer's patients, and the slow downward progression is very clear. Schizophrenia is hard. There's actually just a very recent paper—I don't think it's been published yet—suggesting that there are these sort of three phases of illness. One is the early one, where there's cognitive worsening. Things are kind of stable for 20 years or so, and then at the end of life, things may be, there may be some degenerative process over there. The thing about Alzheimer's, too, of course, is we know the biological mechanisms of that degeneration. There's no such thing in schizophrenia patients. When you go in and you do autopsies and you look at the brains of people with schizophrenia when they're older and have died, there's none of the plaques and tangles, none of the indications of neurodegeneration that you see in people with Alzheimer's disease. Controversial. I think it's not a crucial issue either way. I think that overall, the cognitive impairment is there from the beginning, even before illness, but at the onset of illness and throughout adulthood, it's substantial enough that it doesn't need to get worse to be really a big problem. With regard to your question about duration, I think that for a phase II-A study, 12 weeks is a good duration. In a phase III program, FDA and other regulatory agencies, particularly Europe, will ask for a six-month duration. I think that's a lot to ask of a phase II program. I recommend usually 12 weeks. You're muted, Charles. Great. Thank you for the questions, Charles. Next question comes from Anvita Gupta from Cowen. Anvita, you may go ahead and unmute your line. Great. Hi, guys. This is Anvita from Cowen, for Ritu today. Have you guys approached the FDA with the phase II-A CIAS data? If not, when do you hope for or plan for a meeting? Additionally, if you could provide some color on what are the endpoints that the FDA might be looking for in the phase II randomized control trial? How does your exploratory endpoint of symbol coding might tie into all of that? Matt, I'm happy to jump in, but why don't you take it? Yeah. Yeah. We haven't met with the FDA yet on these initial findings. Obviously, this was a short acute treatment and really an exploratory study to extend previous observations. We're still working through with our advisors first what type of study we want to run next and what the clinical outcomes and measures will be. Obviously, in schizophrenia, as far as regulatory endpoints that are approved, the MATRICS is really the gold standard. Whether we do the full MATRICS battery or a subcomponent of those, obviously, the symbol coding component is going to be very important in whatever next study we do because of the strong acute effects we saw there and its correlation with overall change in the MATRICS. Those are all things that we're currently working through with our advisors. I don't know, Srini, if you wanted to add anything to that. No. Thank you. That was a good overview. Great. Thank you. Thank you for the questions, Anvita. Our next question comes from Neena Birtritto -Garg from Citi. Neena, you may go ahead and unmute your line. Yes. Thanks for taking the question. My question is just around thoughts on narrowing down a dose range, just given that patients with schizophrenia, I think, are notoriously kind of non-compliant with therapy. I'm just curious about how you're thinking about that in the context of the TID dosing and potential for use in an outpatient setting versus another study with inpatient things. Yeah. The PK does support, and particularly when you look at CSF PK, it does support moving to BID dosing. That modeling has been done. That is something, obviously, we've been discussing with the Atai window bridge that also the chemical composition of the API is amenable to slow-release formulation. There is the possibility that we could eventually move to QD. That is a great question because it is an area we're actively discussing on how to address that. Got it. Thank you. Thanks, Neena. As a moderator, I think we are out of time, but let's just maybe do one more question, then I can wrap up. Okay. Great. Our last question comes from Andrew Tsai from Jefferies. Andrew, you may go ahead and unmute your line. Okay. Thanks. Thanks, everyone. I guess this is a question for a doctor. I mean, I guess what part of the phase II data set gives you the most optimism that this could work in a phaseI-B study? I guess secondary to that is just how would you describe this overall data set relative to the other CIAS data sets that you've seen? Maybe just talk about it qualitatively. Thanks. Yeah. Absolutely. Both great questions. 0.8 standard deviation improvement, or Cohen's d of 0.8, is extraordinary, really. I don't remember ever seeing that. Granted, it's 29 patients, and it's seven or eight patients within that particular group. Replication is obviously essential. The magnitude is there to be groundbreaking. That is the thing that gives me the most hope. As Matt said, if you look at the literature and talk to any informed clinical psychologist that does cognition, they'll tell you there's nothing that is more important than symbol coding. It's related to functioning. It's sensitive to both positive and negative things. Great review 10 years ago by Dwight Dickinson at the National Institute of Mental Health with Jim Gold from the University of Maryland, really going into great detail about why that was the most important endpoint in schizophrenia cognition because of its relation to actual functioning. What was the other question? I guess how would this data set compare so far to the other data sets you've seen for developers? Yeah. I guess I mentioned that. I don't know that I've ever seen anything with a 0.8 standard deviation. Yeah. Of course, we need to compare that to placebo. I would expect about a 0.2 standard deviation change in the placebo group. So that's a 0.6 benefit over placebo. Don't think I've seen that. Thanks for the color. Thank you. All right. Again, as I pointed out, we're at time here. I want to start by thanking both Matt and Rich for all their insights and answering all the questions. Of course, I'd like to thank the audience as well for their attention and their great questions. All right. Thank you so much.