All right. Hi, everybody. Thank you for joining Citi's Virtual Company Panel Day. If you don't know me, my name is Nina Butrudel Garg. I'm one of the biotech analysts here at Citi. For our next panel, we'll be discussing mood disorders and mental health. I'm really pleased to be joined by executives from four companies working in this space, including Atai Life Sciences, Bionomics, Compass Pathways, and Praxis Precision Medicines. Before we do get into Q&A, I just wanted to flag that if you do have any questions, you can feel free to send me an email directly. My email address is listed on the webcast. You can find me on Bloomberg and ping me that way, whatever works for you. I just wanted to turn it over to our panelists. Maybe if we go alphabetically by company name. Maybe Srini, if you want to start, introduce yourself, then give some opening remarks on Atai, and then we can go around, yeah, alphabetically by company name. All right. That sounds good. Thank you so much, Nina, for the invite. Also, thanks for this opportunity. Yeah, briefly, my name is Srini Rao. I'm the Chief Scientific Officer and Co-founder of Atai. Atai Life Sciences is a biopharmaceutical company, essentially, that's focused on developing really differentiated, highly effective therapies for mental health disorders, kind of spanning a number of areas of significant medical need, including treatment-resistant depression, forms of anxiety, opioid use disorder, et cetera. Our platform encompasses both psychedelic and non-psychedelic drugs, but we also have digital therapeutics as well. Really using a very broad-based approach to treating mental health. The end goal here is beyond just getting the madness down. It's really affecting long-term behavioral change. Again, this combination of digital therapeutics and drugs, potentially with enrichment strategies using biomarkers, is our game plan to get there. By the end of this year, we'll have 10 assets in the clinic. It's going to be a very active year. Many more things are going to be going into phase II next year. We have multiple phase Is. We'll get into that a little bit later, I suspect. Have $335 million in the bank at the moment. Obviously covering all of the development through proof of concept, certainly for all of our assets. With that, I'll hand it off to you or the next person. Great. Maybe Errol, if you'd like. Sure. Thank you, Nina. I'll echo Srini's comments. It's really a pleasure to participate on this panel with both colleagues and friends. I'm Executive Chairman of Bionomics, which is based in Adelaide. It was listed on the ASX for a couple of decades. In December 2021, we did our IPO and listed on NASDAQ. We were pleased to get the IPO done at a really tough time. Bionomics is targeting ion channels through allosteric modulation. We are developing drugs for the treatment of both psychiatric and neurological disorders. Our business strategy has a balanced approach between proprietary development and external partnerships. Within this scope of proprietary development, we have a lead asset called BNC210, which is a negative allosteric modulator of the alpha-7 nicotinic receptor. It's in the clinic currently in two clinical trials. One is for the acute treatment of social anxiety disorder. This is a 150-patient trial, which started at the beginning of the year. We hope to complete this by the end of this year. We received fast-track designation from the FDA in November of 2021 for this indication. In addition, we're also in a chronic treatment trial for post-traumatic stress disorder. This is a trial that started in July of 2021. With the chronic treatment nature, we'll read out in the middle of next year. This is a 200-patient trial. Again, both of them are U.S. trials, the PTSD trial is across 25 centers. Now, balanced with the proprietary development, we have a long-standing relationship with Merck in the U.S. for the development of drugs for the treatment of cognitive deficits in Alzheimer's disease, cognitive impairment, schizophrenia, and attention deficit disorder. In collaboration with Merck, we have two compounds in clinical development, which have completed safety studies. There are several biomarker studies that are ongoing. Just to finish up, the money that we have raised in 2021 through private placements, as well as the IPO, will take us to readouts in both the clinical trials that I have talked about, the social anxiety disorder trial, the PTSD trial, will allow us to make some investments to get phase III ready, to establish some operations in the U.S., and effectively takes us to the end of 2023 in terms of the runway that we would have. With that, let me stop and turn it back to you, Nina. Okay. Guy? Yeah. Hi, Nina. Thank you very much for the invitation to be on the panel. Just as a starter, I'll be making forward-looking statements like the others, I guess. I just refer the audience to our risk filings in the SEC. My name is Guy Goodwin. I'm Chief Medical Officer of Compass Pathways. Compass is a company focused on transforming mental health care. It is ambitious. We want to treat disorders that are difficult, disorders where other treatments have failed patients. Our lead candidate, COMP360, is psilocybin with a supportive psychotherapy. We're just about to enter phase III trials later this year to really see whether we have confirmation of the phase II studies for treatment-resistant depression. In the treatment-resistant depression start, the two B trials, we showed a highly statistically significant difference between different doses of psilocybin. We were extremely content also to see reasonable durability in the effects. We felt that we got good evidence of a drug effect, which is obviously critical to approval by the FDA. We were very confident also that in about a quarter of the patients we treated, we were seeing significant durability. Together with that, we were seeing quite important supportive measures from the patients themselves. We were obviously relying on the MADRS rated remotely to judge the outcome formally. We also informally from the patients themselves got excellent estimates in the responders of quality of life and of subjective reductions of distress to levels that are really comparable with the patient population. We felt that that has been an excellent start. We look forward to progressing forward later this year. Together with that, we just announced that we are starting a small phase II study in PTSD. That is another indication that we think is one of considerable unmet needs for the clinical population. We look forward to making those results available as we go forward this year and next. Thanks very much. Okay. Great. Marcio? Thank you so much. Thanks, Nina. Thanks for the invitation. Just joining by all my colleagues here and friends as Errol said. Very excited to be talking. We're all developing therapies like different but complementary, I would say, for patients with CNS conditions. At Praxis, we're focusing in three areas, psychiatry being a large one of them. I'm sure we're going to be discussing much of this today. We have three readouts in psychiatry alone before the end of the year. It's kind of a very interesting and intense time for us here in major depressive disorder coming up, two studies, and in PTSD, which I'm sure is going to be part of our conversation. Another area of focus for the company is movement disorders. We just had a positive readout last week. We're very excited with essential tremor and much more to come between now and the end of the year and beyond. The last area that serves as, I would say, a platform for discovery and for proof of concept for us is epilepsies. Each one of them, as you all are very aware, have very large unmet needs, very large markets as well, I would say, fortunately and unfortunately, since there is all this patient suffering that we can help. Very interesting in terms of developments. The interest on the community and the understanding of those networks of those markers of the disease progress has increased very substantially in the last few years. I think that's what ourselves, Praxis, and many of our colleagues here on the panel have been taking advantage of and why we are really revolutionizing the way CNS is now tackled in general. Very excited. Six readouts between now and the end of the year as a company. That's very exciting as well and nerve-wracking a little bit. I'm sure we're going to discuss some of that. Thanks again for the invites. Of course. Awesome. I did want to ask one general question. Whoever wants to kind of answer this, feel free to step in. One of the questions or one of the, I guess, concerns that often comes up in my conversations with investors is just psychiatric conditions and mood disorders specifically are very difficult to run clinical trials in and detect the treatment effect, as obviously you all know, largely due to placebo effects. I guess, how do you guys think about designing clinical studies to really minimize the risk of an outsized placebo effect and maximize your ability to actually detect a treatment effect? Whoever wants to step in. Maybe I'll take a crack at it on a common disorder, which is PTSD, that others can comment on. We're really approaching this issue on a number of fronts, including providing comprehensive training to the investigators, the clinical staff in our ATTUNE trial, educating study participants, I think, during the screening process and on study in our protocol designs. All the trial staff involved in the rating of the participants receive comprehensive training on what a placebo response is and what can contribute to the placebo response and the best practices they can put in place when managing their trial participants. Now, at the participant level, each participant is read a short script at the visit prior to doing their rating questionnaires that reminds them that they may be either on placebo, active drug, and that there is no expectation for them to improve, stay the same, or worsen, and they're asked to provide an honest response. Now, we're also aware that in psychiatric clinical studies, the placebo response can be enhanced by the number of times the participants are required to go through the efficacy questionnaires. In our phase IIb PTSD at ATTUNE study, which includes a 12-week treatment phase, the protocol has been designed such that the participants complete their efficacy measurements at only three time points after starting BNC210 or placebo. For us, it's four weeks, eight weeks, and 12 weeks. Additionally, in the phase IIb study, the participants are randomized equally in number to either GRX-917 or placebo, again, making sure that there is an equal expectation as to whether they are receiving active drug treatment or placebo. Hopefully this will get the discussion going. It is a tough one for all of us, I think, in terms of dealing with the placebo response. Errol, I'm going to jump in, Nina, if that's okay as well. Errol de Souza is a big part of that, right? Placebo reminder scripts, right? It's something that he just mentioned we are using as well in all our trials. I would say maybe I'll take a step back. There is an availability bias on expectation of inflation of placebo. That is actually not supported by the literature, right? If you look into the actual literature in the last 15-20 years, there is no inflation of placebo. There are some trials that actually didn't have very good controls, didn't put things in place, like Errol just mentioned, that created this impression that placebo is not under control. Upon proper controls, the ones that were discussed, and I would say in our case, a few other things, like using a secondary or external validation of the severity and the diagnose, we use CAPS-5, as I'm sure it's available for others being used successfully, and reducing the number of visits, reducing the number of assessments, as Errol just mentioned. On top of that, I would say specifically for depression, which is a little bit different behavior for PTSD in terms of the time-dependent placebo effects. In PTSD, it tends to be more stable over time. In depression, it tends to be a little bit more amplified because depression is not a chronic condition. PTSD tends to be in general. We also separated the primary endpoint from the last visits to really create this, in our case, stacking the cards to some extent in terms of the expectation of the effects versus the durability of the effects. For us, it's day 15. For Praxis 114, it is the primary. Patients are treated all the way to day 28, and they have an assessment at day 29. We are assessing two different things. That is being shown as well together with having just a minimal number of arms, as Errol just mentioned, that those things together are being shown to help. I would say the last thing I would say on this topic is it starts and ends with the right patients in the trial. If you get the wrong patients in this trial, you're going to have the amplification of placebo. We spend a significant amount of time making sure the right patients are getting in, right diagnose, right severity, proper site, so on and so forth. With that, it should not be much of a mystery. I'll jump in here. Sorry. Oh, go ahead, Guy. Yeah. I mean, I was just going to say that this is an issue, obviously, when drugs unblind you. I mean, placebo is fine if you can't detect the active treatment. I mean, the problem for a number of our drugs, particularly the ones we work with, they do unblind the patient potentially. One of the solutions is obviously not to have placebo, but to use different doses because obviously proof of concept comes from comparing a low dose with a high dose, which is the approach we took in our phase II. The only problem with that is, of course, that it may very well be that the FDA would request to see placebo because of safety. They want to see a safety baseline against your active treatment. I think in terms of proving efficacy, avoiding placebo is not a bad idea for proof of concept. How do you address that in phase III, obviously, is a moot point because that is not usually what people do, but we will see. Yeah. I mean, I will say, I guess one comment to that just generally is that I agree that the magnitude of unblinding could be much greater with a psychedelic. Of course, this is something that many different compounds, many different classes of compounds have grappled with over the years. If you think about gamma-hydroxybutyrate, but even think about gabapentin or pregabalin, they are very sedating for most people. Most people can sort of pick that up. Again, just something to think about. This has been a long discussion across many different areas. Going back to the placebo effect, I mean, I guess there's a couple of additional things. We've talked about the number of arms minimizing that. In sort of other general things that drive placebo effect include duration of trial. Part of that is with respect to adherence for a drug that's dosed daily. Of course, a multi-center trial, right? I mean, just generally speaking, the more trial sites you have, the more issues you have, your effect size goes down. I think speaking also for Guy, certainly with the psychedelic compounds, the expectation is that the effect size is quite large, right? We do have a number of such compounds in development. That has kind of a virtuous circle type effect. We obviously can run smaller trials because the signal detection is much greater. Thus, there's fewer centers, etc. Rapidity of onset is really key, right? If you think about an SSRI, it takes multiple weeks. There's sort of fatigue. People start to drop off. I think all the compounds that are being developed by the folks at this particular panel, all of those are relatively rapid acting. Certainly, that's true of the psychedelics. That may also help mitigate things depending on when your primary endpoint is. We've talked about adherence, or I just mentioned adherence. Again, some of these are intermittent therapies, clearly not an issue around adherence, right? You've got absolute control over that. These are additional factors that we can sort of fold in, particularly with some of the psychedelic compounds to mitigate placebo response. Absolutely. Great. I did want to talk a little bit about PTSD now, just because I know each of you is working on at least one PTSD program currently. Maybe if we could just go around quickly and each of you can kind of give us the highlights of your PTSD program, what you're working on, and ultimately what you think would be a win in PTSD with your program. Just kind of a side question for Errol and Srini. Your two companies do have a collaboration as well in PTSD. Maybe if you could also weave that in, that would be great. Yeah. I can do that. Yeah. I mean, I can jump in. We have a structure where we have Atai itself. Then we have a number of subsidiary companies. It's kind of a decentralized model. The company that's actually developing something for PTSD is a company called Empath Bio. We're essentially developing a derivative of MDMA. There's another company, a not-for-profit called MAPS, that has been through multiple trials at this point, phase III trials, in fact, for MDMA in PTSD. There was a publication, I guess, maybe a year ago or a year and a half ago that showed some really nice results with that compound. Essentially, it was three separate visits, some weeks apart, two therapists each time. Basically, the subject's given MDMA. Then it's essentially reflection or talk-type therapy that occurs during the antagonistic effect. That's the basic model there. Our derivative has some aspects of pharmacology that are different, which I think could be beneficial. That, of course, is something that's a hypothesis that we need to confirm. MDMA is super complex. It definitely releases serotonin. It also does all sorts of stuff like impacting the dopamine system, the norepinephrine system. The latter is driving peripheral release of norepinephrine, drives some of the cardiovascular effects. There were some pretty marked blood pressure effects that were noted with MDMA. PTSD folks can have higher BMIs potentially as a coping strategy for the PTSD. It's something that's of some concern. We anticipate our derivative having much less of an effect. The question of how much is central versus how much is peripheral is something that is obviously also TBD. I also speculate that by mitigating this norepinephrine effect, you might actually get better efficacy. Of course, that's very speculative, right? Because the whole idea with MDMA is allowing you to sort of tap into experiences that you don't otherwise want to touch, right? Giving you a better therapeutic alliance with yourself is how I would normally quip about this. Norepinephrine, of course, can make you feel anxious. The question is, is that impacting efficacy? We don't know. We have that potential here to potentially try to improve on that. Let me just follow up because what I'll do is I'll just talk about BNC210 as monotherapy for PTSD and then bridge what Srini built upon as to what we're thinking about in our collaboration together with Empath Bio and with MDMA. BNC210 has shown in animal models both anxiolytic-like effects, antidepressant-like activity, and has demonstrated sort of enhanced fear extinction. All of these are attributes that would show sort of validity in terms of its utility for the treatment of PTSD. Let's focus now on the clinical data of the compound that would bring in, I think, more validity. In clinical studies, we've demonstrated clear-cut reductions in anxiety, reductions in anxiety related to threat avoidance. In a panic situation, the patients, or in this case, it was healthy volunteers, recover from the panic attack much faster. We had actually completed a full PTSD study, albeit with a different formulation before, where we had actually shown at earlier time points, at a four-week time point, clear-cut significant antidepressant effects and good trends towards lowering anxiety, but just missed the CAPS-5 endpoint. You may ask, well, where's the hypothesis when you missed the primary endpoint? That is when you look at it from a dose efficacy standpoint. Thankfully, we are taking blood samples and looked at blood levels of the drug. When you do a pharmacometric analysis and look at the relationship between exposure and efficacy, we saw a very significant relationship. It also told us the blood levels that we need to be able to see a clinically meaningful reduction in CAPS-5, which for the most part, I think the KOLs would say would be about a six-point reduction that you would need. We have developed a new formulation, which time does not permit me to go into, but clearly exceeds the levels that were predicted. We are back in the clinic now with the treatment paradigm that I talked about before. BNC210 has great utility, we think, as a monotherapy. Now let me bridge to the collaboration that we have with Empath Bio and why it would make sense for us to think about a combination therapy. It is really a broader discussion around where psychedelics and other treatments are going to go with combination therapy. Based on what Srini described, the MAPS trial, what it showed was some really nice, intriguing data where MDMA by itself was not a treatment for PTSD. Let me make that clear. It's an adjunct to psychotherapy. It requires three intensive eight-hour in-clinic sessions plus additional psychotherapy sessions, okay? That's a heavy burden both on the patient, a patient population that really doesn't want to come for psychotherapy, along with the payer. What we're thinking about is, depending on where the FDA is with MDMA itself and our collaboration with Empath Bio, imagine a treatment paradigm where the patient comes in for the first session with MDMA, goes through that. They get BNC210 in the outpatient setting, which may reduce the need for the second and third session or other psychotherapy sessions, or take it from an eight-hour session down to a one-hour session, which has huge benefit for patients, for prescribers, and for payers. That is the treatment paradigm. This is not that different than what people are looking at with the ketamines and SSRIs. For me, the psychedelic paradigm, which is really opening up, I think, new treatment paradigms, eventually, we are going to have to start thinking about these combination therapies. From a Bionomics standpoint, we want to be ahead of the game in terms of thinking about them rather than playing catch-up once, for example, MDMA gets approved. Hopefully, that addresses both BNC210 and our collaboration with Empath Bio. Just one other follow-up point. I think you hit upon a really key issue around MDMA proper. That, of course, is the scalability. One approach, I think that, well, these are complementary approaches. One approach is to actually indeed have these follow-on therapies like BNC210. The other element that we're really focused on, of course, is digital therapeutics. I mentioned reflection therapy. There are ways of potentially simplifying and/or automating aspects of that. We have, for the outpatient work, both preparatory as well as the follow-on elements, we are using more standard digital therapeutics in the sense the app-based things that actually provide activation commitment therapy, behavioral DBT. We have all of these different modalities that we can deliver electronically on a more frequent basis as opposed to coming in every two weeks or what have you. It's something that's continuous and presumably beneficial for the patient. There's certainly some data outside of the MDMA space, certainly, for these digital apps having efficacy. Let me jump in and talk a little bit about 114 and why I think it's also complementary to everything you're saying here, right? Maybe take a step back again and talk about the paradigm in PTSD, which is that there is pretty much nothing that works for these patients right now. It's a very large part of the population. I think that is a Hollywood version of PTSD, unfortunately. There is a reality of PTSD with so many ways and pathways patients get there, different sub-etiologies, I would call, of the disease. So many people not really wanting to talk about it, relieve the effect, and so on. Kind of some of the characteristics of the disease, as Errol mentioned, is fear avoidance, right, or the reconstruction of the event, or the sleep disorders, anxiety in general, kind of a depressive state, kind of all combined to some extent. When you look into PRAX-114 preclinically and clinically, we're able to drive down the anxiety pretty, I would say, nicely in animal models and in healthy volunteers and patients with depression, not with PTSD apps. The fear parts of at least in the animal models is very pronounced, the reduction on the fear avoidance on those animals. It's supported by some experimental data in patients with PTSD that have lower levels of neuroactive steroids as well, the endogenous neuroactive steroids. The scientific rationale is very strong to use something like PRAX-114 into this population. The key question has always been, can we give this safely, right? You want these patients to feel better, not to feel worse like they feel with some of the medications right now. At the dose we are planning to use, or we are using right now in the clinic, 40 and potentially 60 milligrams after 15 days, we have very low levels of somnolence or sedation, if any, in this population. It allows for the structure of the sleep to be recovered, for the anxiety to be reduced, to fear avoidance, and so on, without really all the side effects. That's one of the main reasons why they discontinue therapies right now is they're not helping, and they're making them feel worse. That's the scientific rationale. We're running an 80-patient trial right now, which should result by the end of the year. Maybe I chime in on the back of that and say we're also interested in this area because of these effects on depression and anxiety. We've obviously documented with a single dose, which lasts for up to 12 weeks in a significant number of patients. If that were to produce an effect in these PTSD groups, it would be extremely useful without the need for formal psychotherapy addition. We're doing a very exploratory study. It's just going to be 20 patients. It's open label. There's not going to be a control group. We're going to find out about feasibility, acceptability, adverse effects, and hopefully, some indication of whether there's a significant and important reduction in symptoms. Clearly, we're looking to see and to see whether this is an area where we should also be putting more resources. We'd be very excited to share the results in due course. It should be interesting. There's a mechanistic component of imaging, which will help to objectify some of the changes if we do see them. That's where we are. Great. I did want to talk a little bit about depression too. I know each of you is working either on kind of depression or anxiety. Maybe specifically to Marcio, I know you are having your MDD readout for PRAX-114 in June, so coming up soon. I was just wondering if you could talk a little bit about what really you're looking for from an efficacy and safety and tolerability perspective. I know you mentioned what you've seen so far on somnolence. I guess we'll start there. If you could talk a little bit about what you want to see on efficacy, whether you think you can see kind of a marginal benefit versus some of the other gabapentins that have been in development for MDD, and then what you think from an adverse event perspective would be kind of differentiating from other programs as well. Absolutely. We're very excited, right, in the next few weeks. June is just the corner here. We're going to see the results for ARIA. It's our study. We enrolled 216 patients with moderate to severe depression. I want to start there because the first thing before we even ask about effect is, are those patients truly moderate to severe depression, right? We talked a little bit about that. We went for great length to make sure the proper patients were on those trials. It's a little bit of a sad, I would say, realization that we had running a trial here in the U.S. on how many people that were not really having a stable moderate to severe depression had to screen out or fail on the trial, a very significant number, in order to get really the population was ideal for clinical trials. I think that influenced other experiments, especially during COVID, on not having the right patient then. Starting from that base, right, that you have those patients with MADRS higher than 23 at baseline, probably going to land anywhere between 25-26 in average, just like guessing at this point. What we want to see here, what we expect to see, right, is a very significant change from the baseline where they are with very significant depression to day 15, which goes through day four and day eight that we have to visit their virtual visits and the presumptional visits for those patients. That is around 0.4 in the effect size. What that means, right, in terms of modeling, is three points or more separation from day 15 on the MADRS. That is basically what means is it's much faster than anything that is out there. It's a much larger effect size when we standardize, like I mentioned, 0.4 or so. That is not all the story does not allow these patients need, right? If you then discontinue the drug and they go back or they become erratic, that we're not really serving these patients, right? We have to look into the patient first. Treating them until day 28 and measuring at day 29, the secondary endpoints here, we expect to see basically a straight line from day 15 to day 29 for the treatments. Whatever happens with placebo, they are maybe giving one point or so. It's still a separation there because our hypothesis for 114 is that we need to continue treating until the episode is resolved or until the patient is really in remission for depression. Maybe just to recap the expectation, right, very significant, clear at day 15, numerical separation at least expected, hopefully, statistical as well, day 29, although it's not required, with very low side effect in terms of especially the ones more related to this mechanism like sedation, for example. We expect to see less than 10% or so in that regard, which would be adequate for chronic treatments. Okay. Great. I guess just to follow up on that, just what do you think, I guess, what about the molecule and about the study specifically do you think could drive maybe a larger effect size than what we've seen with other gabapentins in MDD recently? Yeah. The hypothesis for gabapentins, specifically the ones that are highly extra-synaptic preferring like 114, is this ability to drive the overall anxiety, core depression, insomnia, to levels that are in either remission or much better without the drawbacks that are known for the mechanism, right? Full sedation, tolerance, and so on and so forth. From a more chemical standpoint and biochemical standpoint, 114 is the most extra-synaptic preferring gabapentin, like 10-fold to the extra-synaptic versus synaptic. From a distribution standpoint and from more PK-related properties or drug properties, we are pretty certain that the drug is in the system. Maybe that is something that was not quite understood before, right? You need given concentrations in the brain to be there present always for the effects to be driven the way we just described. To our knowledge, 114 is the only drug in late-stage development that has this ability to be taken with or without foods, to be given the exposures that are necessary or given this before bedtime. It is fairly complicated to control something else other than the drug itself. If you need a significant amount of fat, for example, others might require, it is not desirable. As we heard before, it is not only PTSD patients that have problems with appetite disturbance. Depression patients have issues there as well. You are forcing something on them. It is a combination between the drug itself, the way it is delivered, the concentrations we get into the brain, and then the design of the trial. As I mentioned before, from the get-go, we separated the primary endpoint from the last visits to really show the rapid effects, but to maximize the probability of success and to show the durability within the trial. That is what we are going to be showing, and fingers crossed, in the next few weeks. Okay. Great. Srini, I did want to ask you a little bit about GRX-917, so the deuterated etifoxine program, just because there is, some might say it's a similar mechanism to kind of a GABA PAM. I guess maybe this is a question both for you and for Marcio. I know you're focusing more on anxiety. There's some investor questions just around whether targeting GABA and kind of the neurosteroid pathway may be a better target for anxiety or MDD patients with elevated anxiety. I guess maybe thoughts from both of you or anybody else who would like to comment as well on that. Maybe I can start with GRX-917 and some of the rationale there, and then obviously, Marco, jump in. As you mentioned, GRX-917 is a deuterated form of etifoxine. Etifoxine is a compound that's been around for quite some time. This was developed and marketed, brought to market in 1979 in France. It's been available there and in several other territories, but really not been in any of the major territories like Germany in Europe, or the U.K., and certainly not in the United States. People really didn't know what it did pharmacologically for the longest time. When it came on the market, everybody thought it was a benzo. It was pretty obvious that it wasn't. I don't know if you've ever had a benzo for a procedure or something. You end up feeling essentially drunk, right? I mean, there's cognitive impairments, there's heavy sedation, there's ataxia, there's a lot of different things that occur acutely. Of course, chronically, there's dependence and abuse liability that can be a problem. This compound had none of that. Most of this data was available pretty early on. People then thought maybe it's activating some other part of the GABA receptor, which is a fair assumption. It was not particularly potent at doing this. That didn't quite make sense either. Over the course of the last decade or so, it's been realized that this compound is an agonist, a TSPO, which is a mitochondrial protein that's actually responsible for producing endogenous neurosteroids. Correct me if I'm wrong, but 114 is a neurosteroid, essentially. This is essentially increasing the production of things like allopregnanolone. That is the mechanism by which we think it is doing something very, it is obviously very similar in some ways to what 114 is doing or zuranolone is doing. That is obviously the reason for our excitement around this. In terms of indication, totally agree regarding depression. Of course, brexanolone is approved for postpartum depression. We have heard about where 114 is headed at the moment. I think the part that is swaying us, at least at this point, more towards anxiety is all of the data that is available for this compound, for etifoxine, for the parent, right? This was really approved, if you will, for anxiety and anxiety disorder, specifically adjustment disorder with anxiety. It has been broadly used in that context for a very long time. It behooves us to kind of start there. I think there's many opportunities for label expansion beyond that, including anxious depression. Yeah. I think that's a good segue, right? Neuroactive steroids, I think it's pretty undisputable that they act on when you can get a safe way to activate that pathway in anxiety. I think what is a little bit more confusing maybe lately is anxiety and depression and the overlap. Patients with moderate to severe depression, the vast majority of them have high levels of anxiety periods. That is like, I think sometimes maybe it's oxymoronic to try to separate those things, right? Those patients are coping with a myriad of symptoms, and anxiety is part of that. It's very hard to find patients with high MD or madness that don't have anxiety. I think that's a little bit where you're going as well, right? Yeah, I agree. It's a constellation that you're trying to treat. It would make as much sense to go with 114 in anxiety as Atai is going as in MDD or in other conditions like that were related and discussed today, like avoidance in general or adjustment disorders in general. We have included and throughout the development of 114 patients with high levels of anxiety, not because we're trying to find them, but because that's who those patients are. You've seen very significant reduction in levels of anxiety, but not only. I think that that's the important part about this mechanism. If all you're doing is reduce the anxiety, I think there are capable drugs right now that do that very fast. What you're trying to do here is to maintain the levels of anxiety under control, the insomnia under control, and the core depression, things that are not related to anxiety, for example. We're really looking for, and you're going to be reporting in a few weeks, both sides of the equation here, right? You need to be able to drive the core depression down so these patients would feel better. They would relate better with society and with themselves, and hopefully, we'll be able to help them. Okay. Great. Guy, I wanted to bring you kind of back into the conversation. I know you recently had your end of phase II meeting with the FDA for COMP360 and treatment-resistant depression. I know you'll share updates from that after you have the minutes from the meeting. I guess in thinking about the phase III study and the read-through kind of from phase IIb, I mean, how are you thinking about defining the patient population, some of these other aspects that we talked about earlier in terms of study design, the number of dosing sessions, the appropriate comparator arm, all of those sorts of things just based on your continued analysis of phase IIb and conversations with the. Yeah. I I mean, I think the patient population is obviously the critical one. I’d echo all the issues about choice of subjects that were made earlier. This is the key failure, is to recruit into studies people who are essentially going to give you a placebo response no matter what happens. In our case, perhaps over-enthusiastic responses depending on what they’ve read in the New York Times. That’s the sort of challenge, is to get patients in who represent or are representative of the treatment pathways that ultimately we want these treatments to fit into. We’re going to be taking as much care of that as we did in phase II. We think there are a number of ways in which technically we screen people that we may change. We just think we could do it better. We're going to be very careful about site selection because ultimately that's also very critical to the quality of the trial you deliver and not having too many. These points are all generic, I think, and we'll be following them. As you know, Nina, we're not going to comment much on the phase III design until mid-summer or so when we finally reach agreement on what it should look like. At that point, you will know everything. Look forward to that. Sounds good. Totally understood. Errol, I did want to ask you a question as well around your social anxiety disorder study. I know that's a pretty unique study design using a public speaking challenge. I think that's a design that people are probably less familiar with. Maybe if you could tell us a little bit about how that actually works, the regulatory precedent there, and what you're hoping to see from that study. Great. Thanks. Maybe I can just start off by setting up social anxiety disorder since the other panelists really are not looking at this particular indication. The attractiveness, so social anxiety disorder, the only approved treatment, the SSRIs, and as we know, they act in a protracted manner, require several weeks of treatment. In spite of that, only work in about 30-40% of the patients. There is no acute on-demand treatment that's approved by the FDA. What the docs use totally off-label are either the benzodiazepines, which we've discussed, or the beta blockers. The beta blockers will help with the cardiovascular manifestations of it. The benzos are great from the standpoint of reducing the anxiety but have the liabilities of addiction, motor impairment, sedation to deal with. Now, BNC210 has shown efficacy in two separate clinical trials. One, as I mentioned, in reducing panic symptoms and in a very nice study in generalized anxiety disorder patients that was carried out at King's College in London. There we went actually head-to-head with lorazepam, the standard of care, and showed we were at least as good as lorazepam, if not better. Why do we go after social anxiety disorder? It was actually driven by the regulatory endpoint and where a company like Vistagen that has a short-acting intranasal ferrin got the FDA to agree to a phase III endpoint, which is essentially an experimental endpoint. You will get this when I describe a particular study where you bring in patients, challenge them with public speaking in their case, and that is the endpoint for registration. I mean, what could be more attractive than that? With that as a backdrop, now let me describe to you our study. In our case, just like Vistagen, study participants commend their screen for social anxiety disorder with marked to severe symptoms. That is a score of 70 using the Liebowitz Social Anxiety Scale. They return to the clinical site for the public speaking challenge that is performed one hour after receiving just a single dose of 210. In our study, we have three arms, placebo, a dose of 225 milligrams that in previous studies we have shown produces efficacy at least as good as the benzo, or 675. We are really exploring the dose range. The participants are then asked to select a speech topic from a specified list, and they have two minutes to prepare their speech. This is called the anticipation phase. Frankly, this is the most anxiety-provoking phase. They are then required to speak for five minutes in front of a small audience. This is the performance phase of the task. Now, during the anticipation phase, the performance phase, and at the end of the speech, the participants complete self-assessments, including the subjective units of the stress scale. Now, this is a new scale. It's actually the primary endpoint that the FDA has agreed to, but we'll also look at this Spielberg state anxiety inventory and self-statements during public speaking scale. It's an experimental endpoint, which at the end of the day is our phase II, but it will also be the phase III endpoint. That's it. It's a very straightforward study. One other thing I may add to that. This is a scale that there isn't a lot of historical precedent other than what Vistagen has shown in the phase II trial. There they've shown a reduction of about 13 points in the subscale. That's about what we are looking at in terms of when you think about powering this study. It wasn't the easiest thing because you don't have a database here to really power. That's approximately what we're looking at in terms of sort of the expectation of a significant effect. Great. Srini, I did want to come back to you just to ask about the data that we're expecting towards the end of this year in treatment-resistant depression with your arketamine program, PCN-101. I guess maybe you could talk to us a little bit about what would be kind of a win there from a safety and efficacy perspective and what you're looking for specifically in terms of the therapeutic window just considering that you are developing that with the intended use in an at-home setting versus clinic. Yeah, absolutely. Yeah, I think it's just to get to levels that everybody, so we're developing arketamine for treatment-resistant depression. Of course, as ketamine, the other enantiomer is approved for treatment-resistant depression as Spravato. One of the challenges with Spravato is that the efficacious dose is also the dose that is associated with dissociation, right? It has dissociation as part of the side effect package. That may be one of the reasons that at-home use may be very challenging for that compound. Both preclinical data and very limited third-party clinical data suggest that arketamine may give you efficacy at a dose that's substantially less than that dose that's associated with that dissociation. That's really the premise here. That's the hypothesis for why this drug could be developed for at-home use. We completed a phase I trial, I guess it was last year, and looked at a range of doses. Perhaps not surprisingly, at very high doses, we know that this is an antibody antagonist, low potency. At high doses, it looks rather similar to as ketamine or racemic ketamine. However, we picked some doses that were well below that. One that was devoid of any kind of activity was somewhat consistent with what the previous open-label study had done by a third party again. Also, we picked another one that was just sub-dissociative. That is what we have taken forward into our phase IIa trial. In some ways, it looks rather similar to what Compass did with their phase II. phase IIb is a little bit smaller, obviously, but essentially it's placebo versus two doses of arketamine dosed intravenously in this context and looking at a MADRS at 24 hours. And so it's 31 times three, essentially. That's the general, it's a single administration. We, of course, anticipate multiple doses with this or repeated dosing, not unlike any other ketaminoid. That's kind of the background here. In terms of what we are looking for and what would constitute a win, obviously, we're looking for statistical significance, but a MADRS change, minimum clinically important difference on MADRS is two. We obviously want to see something greater than that. In one of the positive trials with esketamine, that number was four. With phase IIb, obviously, it was over six. That obviously was quite effective. Substantially greater than two would be a win at 24 hours, but also persistence is sort of comparable to what you see with esketamine. If it works at 24 hours, but then starts to tail off more rapidly, that could be something we'd have to take under consideration. Some preclinical data suggests longer or more durable efficacy. We're looking at a week and as well as 14 days out. We'll have that data. The key, of course, is this efficacy in combination with minimal or no dissociation. As I mentioned, there's two doses, one that really has no impact on dissociation, the other one that has minimal impact on dissociation. At least in healthy volunteers, it's essentially within the normal range. This is on the CADS score. We don't need to get into the details of that, but certainly within the normal range. That's what we're looking for here. I think that would make for a very compelling argument to the FDA about for at-home use. Okay. Great. In the last five minutes here, I did want to ask kind of a wrap-up general question if each of you wants to kind of chime in with some thoughts. Each of you, as we discussed, you're all developing therapies for mood disorders and other mental health conditions that I think do represent a paradigm shift versus the way that a lot of these conditions are currently treated. Many of them are considered, even depression today, right, is often treated as a chronic disease, even though, as Marcio pointed out earlier, it really isn't for a lot of people. I guess, how do you think about that concept from a commercial perspective and how you really kind of change the treatment paradigm with some of these therapies? Yeah, whoever wants to start, and then we'll wrap up after that. I'll jump in first. Or first, maybe say May is Mental Health Awareness Month, right? I think what those patients need us to do is to develop effective, safe therapies for them and for their families and for the society. On that regards, however we get there, we're going to figure out a way to get the economical model to work, keep that in focus. What that means for us here with 114, specifically with other molecules we are considering in 40, that is one of our preclinical programs, is getting them better, keeping them better so they don't relapse, so they don't come back. There are different ways that are likely going to be more combinations in the future than we have right now. We talked about digital treatments today. We talked about psychedelics. I believe that the gabapentins, especially the safe ones, the durable ones, are going to be a very clear part of their armamentarium in the future. We are considering a very straightforward, maybe the most straightforward way to market this drug if you were to get to the market as we expect to, that is as a continuous treatment, right? We can call that chronic, we can call that episodic, but at the end of the day, you take it, there is not a lot of utilization of the healthcare system, which is important. If you keep starting and stopping a drug and switching drugs, that's not only creating anxiety on the patients, it creates anxiety on the healthcare providers as well and utilize the system, but it's something that is relatively simple to introduce. On that regard, the paradigm shift for Praxis is better, faster drugs that are safe. It's not necessarily the way these patients are taking or interacting with the drug right now. We think that that's probably enough to do our part to help. That's how we're looking into it. We think that for an oral gabapentin, that's the one that addressed most of the markets. Just building on that, we're splitting the difference a little bit, right? We've got psychedelic compounds as well as non-psychedelic compounds that we've talked about. We have the etifoxine derivative, but we also have our ketamine, both of which could be, we're anticipating would be, at-home use, obviously. I think an important element for us is just the broadly recognized bit that therapy of some kind is really important to affect long-term efficacy, right? We're really interested in helping these folks, getting them into remission, and keeping them there. As someone had mentioned, particularly the psychedelics, they're medication-assisted therapy, and the therapy piece is really key. Of course, the issue is you don't have enough therapists, right? That's an important element. That's where we think that digital therapeutics could play a really critical role. That's where we think we can really make a big difference. I've mentioned it on previous calls, but I grew up in a small town in Southeast Kentucky. That is always what I think about in this context because no therapists there, lots of OUD, lots of treatment-resistant depression. What can we do about it? It isn't necessarily going to be easy for someone to go and repeatedly have to go to a clinic to get medications and therapy, but we think we can potentially mitigate that with some of our digital approaches. Yeah, just to follow up on Srini, I think there's such a huge medical need for what we're looking at, and the theme is really faster and fewer side effects. I think what we've heard from all the participants today and at Bionomics, with BNC210, that is the theme, faster acting with BNC210 and reducing anxiety, less side effects versus the standard of care in terms of getting there. The feedback, I'll tell you, we've gotten on the commercial side in terms of a market analysis that we've just completed with payers, community psychiatrists, as well as KOLs, is they're desperate for a profile such as presented where we've got, I think, a unique opportunity to really do right by the patients and shareholders. What could be better in the fields that we're in in terms of making a difference? I think you're right, Nina, to emphasize that this is sort of paradigm shifting and this whole approach that we're all of us to some extent involved in. I think for us, we've just had visits with 50 providers in the U.S. A market access team went around and visited all of them in person. We get this strong sense that there is a growth of these intermediate treatment facilities based on esketamine increasingly reimbursed, based also on neurostimulation, and we feel that we fit right into that. It is certainly true that I think there is a great place for keeping patients well with digital therapeutics. We completely agree about that. I think that the emphasis on therapy in association with the drug is a little misleading for many people. It is sort of based on the MAPS model that we're dealing with assisted psychotherapy. In fact, the drug does the work in the case of psilocybin. The therapist, if you want to call them a therapist, really is there to prepare the patient. 90% of our patients have not had a psychedelic before. This was a fair test of the capacity and the safety to do this in our phase II trial. That preparation needs to be focused, and there is scope for improving it and getting quality control over it using digital technology again. We think that's the key part, the preparation and the support on the day. It may well be that in the long run, it helps to have kind of simple behavioral activation, CBT-type apps, which will help to keep people well. As with all these fast-acting treatments, we're going to have to keep track of the patients in order to detect relapse and to replace or supplement or whatever we have to do to keep people well. That's going to be a challenge all on its own. It is a great time to be in this particular field, I think. Absolutely. Fantastic. Apologies for running a couple of minutes over. I want to thank each of you for taking the time to join us today. Anybody who is listening on the line, there is a break for about 30 minutes, and then we'll have our next session at 12:30 P.M. Eastern. Thank you again, everybody. It's great. Thank you. Thank you, everyone. You're welcome.