Praxis Precision Medicines, Inc.

Good day and thank you for standing by. Welcome to the Praxis Precision Medicines 4Q and FY 2021 Corporate Update Q&A call. At this time, all participants are in a listen-only mode. After the speaker's brief presentation, there will be a question and answer session. To ask a question during a session, you will need to press star 1 on your telephone. If you require any further assistance, please press star 0. I would now like to hand the conference over to Spriggy today Alex Kane, Vice President of Investor Relations and Corporate Communications, for a very brief presentation. Please go ahead.

Thank you. Good morning, everybody, and thank you for joining us today for our fourth quarter and fiscal year 2021 Corporate Update Q&A call. With me on the call is our President and CEO, Marcio Souza, our Chief Medical Officer, Bernard Ravino, and our Chief Financial Officer, Tim Kelly. Following the press release and video update issued earlier this morning, we will focus today's call on your questions to provide additional perspective on the updates provided earlier. We ask that you keep to one question initially, and then please feel free to rejoin the queue for follow-up questions as needed. Before we proceed, I would like to remind you that during today's call, we may make certain statements that are beliefs forward-looking and subject to various risks and uncertainties. For additional detail on forward-looking statements and the risks associated with our business, I encourage you to consult our FCC filings and in particular, our 10K file today. With that, I will now pass the call over to the operator to open up the line for Q&A. Operator?

Thank you. And as a reminder, to ask a question, you need to press star 1 on your telephone. And our first question will come from the line of Yasmin Rahim from Piper Sandler. You may begin.

Yes. Good morning, team. Thank you so much for taking my questions. And we really like the new format of pre-recording the remarks. The first question that I had for you that we get quite a bit from clients is, now as the studies ARIA has completed, or is in the last stretch of enrollment completion, and you're looking at the patient population, can you give us an idea of how homogeneous is the patient population that you've gotten into ARIA? I know, Bernard, you made some remarks earlier, but if you could just allude a little bit more, what you see, what's the standard? deviation, just an HMD 17 baseline scores among these populations. Any color that you could see on the baseline that could be helpful.

Hey, Elzin, thank you so much for the call, for calling in, and I appreciate the feedback as well on the format. So I'll hand over to Bernard, but maybe my quick remark there is it's spot on on what we were expecting. with a lot of blood, sweat, and tears to get there because there was a lot of controls to put in place, as Bernard reminded all of us earlier today. We're very happy where we are, but Bernard, why don't you expand on that?

Yeah, a little bit of color. So our eligibility was HAMD 17 of 23 or higher. Typically, people come in a couple of points just above that cutoff, And I think that the key for us was to mention we had a higher than expected screen fail rate, which we think was actually really important because it means that the eligibility criteria and the review processes, including SAFER that we set up, were really working. If we hadn't had those, we would have had a lot of people who either didn't have MDD or didn't have adequate severity. And in terms of standard deviation, so what you really look for is like the change from baseline is the key for the standard deviation for powering. And that's right around where we expected it to be, about seven points. So overall, it looks like the processes and the assumptions that we had when we initially set up the study and powered the study seem to be holding true.

Thank you, team. And then if I may ask one other question. When we look in historical studies, MDD studies, have you looked at what percentage of treated population actually really runs quite high on or quite low in response? So I guess what I'm trying to see is as you're looking at these two curves, placebo and treatment, you're seeing probably a difference between them. But how confident can we be that maybe some of those lower HMD scores, whether that they would be not, that they were actually on treatment, not on placebo. So just some commentary around that would be really helpful. And thank you for taking my question.

Yeah. So, yes, if you look back, let's call the last 30 or so years, controlled trials ran in moderate to severe major depressive disorder patients, right? And we're going to have three or four deaths have known valid data on the two weeks mark. They are all pretty tight, actually, on the two weeks, on one week, two weeks, three weeks, and so on. So the separations that we see that we expect to see here by driving mechanistically better quality of sleep, less anxiety, less core depression, pretty early on, like a matter of days, and then maintained throughout, should be pretty clear. Without really that expansion of the MD-17 scores, as you just said. So it is tight. Like, we are only looking to blind the data at this point in time. So it's like anything I say here or Bernard say is going to be pure speculation, to be perfectly honest, right? We set up the trial to do some things to separate at day 15 with an effect size of around 0.4, which would be three points on the MG17 at that, on the primary endpoints. We have a target for a number of patients that are required. We're in very good shape for that, completers at day 15 at this point in time, so we feel really good about it. So, historically, as we compare, as we simulate, as we re-simulate historically, we feel really good about it. And that is not a large proportion of patients deviating from the central tendency here, if you were to look. Again, some rare exceptions on trials that we don't consider to be valid, but the majority of them. Right, Bernard? Anything there?

No, no, I think you covered it. In terms of, like, retention rates, adherence, adverse event rates, those all look as we predicted. So as Marcio said, it's all based on blinded data review aggregate data, so we can't tell you how the groups will separate until we unblind. But it just means that the assumptions overall in the planning stages appear to be panning out.

Thank you, Bernard. And thank you, Mai-Chu.

Thank you. Our next question will come from Laura Chico from Woodbush. You may begin.

Hey, good morning, guys. Thanks for taking the questions. I guess I just have two, and I'll stick with Aria as well. I guess first, could you just remind us what steps you're taking to ensure patient compliance with therapy during that four-week window? And then the second question, and I apologize, thanks for releasing the prepared remarks as well ahead of time. That was wonderful. You discussed some of the changes, or I'm sorry, some of the changes you saw in the Phase IIa study with respect to HAM-A, and I'm wondering if you could just elaborate a little further on your expectations in ARIA for impacts or potential impacts on anxiety. What's your sense in terms of the proportion of patients in the study that might have concomitant anxiety? Thanks.

You know, we expect, when you get a population like this that truly has moderate to severe depression, you know, roughly half or so will have high levels of anxiety. There are a couple of different ways to look at it. You can measure it on MA. And we had seen what was about a 50% improvement or so on MA on average. So I think, you know, that's probably similar expectation. The other way to look at it, though, is, within the DSM, the DSM-5, there's kind of a subcategory for people who suffer from anxious distress as part of their depression. So we've been looking at that all the way along in our Phase IIa study. That was a pretty high proportion of patients, but we expect it to be around 50% or so who fit that subcategory. We'll look at that. It's not part of the primary analysis, but we'll look at that as well. And we do expect mechanistically, you know, for all the reasons, hitting extrasynaptic, antidepressant, as well as synaptic. And they're not cleanly divided like that, but we do expect that 114 will have antidepressant and anxiolytic effects. And that, you know, the HAMD in and of itself nicely reflects that. in terms of anxiety items and sleep items. So there are a number of different ways to get to that construct, but fundamentally, like, anxiety levels in moderate to severe depression are just an intrinsic part of it.

And on the compliance part of that that you asked, right, so we use, like, a number of things. First, it starts with getting the right patients. One of the key, we talked a lot about the number one reason why patients and cats after the trial, like there was failure to confirm or the severity for MG17, but shortly thereafter was the assessment by the investigator that patients wouldn't comply with this schedule, which is quite important. It talks about how our investigators, the ones that are really in the field helping us make this trial a reality, were taking that so seriously. So it starts there. Then throughout the study, there is a number of parameters and systems we put in place. Now, this is a relatively long study when you think about a GABA-APEP, right? So we're talking about 28 days of dosing, another week of observation after that. So we wanted to make sure the patients are engaged, but not so engaged that would drive unintended consequences here. So we work with AI-Cure, not with their standard version. I think what we learned In the process, if the standard version did not have what we call practice reaction time, we want to know immediately if something happened so we can intervene. So they were very good. They customized the version with us, our team, like that is someone that is looking to this all the time. And that became like a key tool for us to use. We have very good compliance in general and very good adherence to the trial so far. So we're happy with that parameter. That's one of the reasons why we said we're confident with the patient population. But it's not one thing. It's a constellation of different parameters here to drive good compliance to drug and to procedures because it has to be both of them.

Thank you, guys.

And our next question will come from the line of Ritu Baral from Caledon. You may begin.

Good morning, guys. Thanks for taking the question. I just wanted to have you guys help set expectations around what you might report at, I think it was day 29 or day 30. Marcio, I think you mentioned that you expect maintenance of effect. Does that mean you're expecting maintenance of statistical significance and just sort of generally what you expect at day 29, what you might report beyond day 29. And then you gave us very helpfully what your expectations for somnolence was. Could you speak to how you expect sedation to come in and if that might be a differential driver too? Thanks, and then I'll hop back in the queue.

Sounds good. So thanks. There's a number of things here, right, that we have to consider. Maybe we start with the safety part. So when we chose the 40 milligrams to go on a daily dose nightly, our hypothesis, which is firms on a number of things that we did internally, is dry beta power, which is the best surrogate we have here for the drug being in the brain, And it still, like, not creates that state of sedation or somnolence that is incapacitating, that is next day or is really the patient cannot stay functioning. So that was a key thing for us. We're, again, very happy with what we are seeing so far. It seems to be panning out, and you're going to see in a couple months, I guess, the results. In terms of the effects, when you put all those controls in place, when you believe the drug works as we do, you should expect that the trial is going to behave as it should behave. That means placebo will decline like between zero and whatever time point at the end it is in a controlled way, not on a like erratic or just controlled way. And that means that the expectation is it was going to be a little bit larger placebo reduction between day 15 and day 29. But a bit larger, not like something that's, again, a lot larger there. Because we expect drug to be much larger decline, while the expectation from the FDA on the conversations we had and from ourselves is not that it would necessarily maintain statistical significance at day 29, it's quite possible we will. And because, like everything we're seeing, as Bernard said, our standard deviation so far is actually right on the mark. The kind of patients that came in All right, on the mark. So, again, we're going to see in June, once we report the results, but there is, I would say, a very reasonable chance that you're going to see not only a separation that is numeric, but also one that is statistical significance at day 29, which we're going to report. We're going to report MD-17 at day 15, at day 29. global impression on day 29, obviously the safety profile or the visits, how the patients went, and everything else that we have in the queue, if we have time to process that, we're going to be showing as well. But those are the key things we're planning to show at that day. We should give a very comprehensive feel of the drug viability and enable conversation for us with the agency. and it starts in phase three later this year, second registration trial later this year, that that's where we are aiming for the program.

Richard, it's a good point to reiterate, too, that we're talking about maintenance of effect on treatment. And in our experience in our phase 2A study, we tried both stopping treatment after two weeks as well as continuing it for the full four weeks. And what we saw very clearly is when you discontinue, you do get You lose, you know, a point and a half, two points over the subsequent two weeks versus maintaining the effect when we treat it over four weeks. So really, you know, just speaking about the active arm, we look to see continued levels of reduction from baseline. And we do think that's important. You've got to continue the drug and be able to treat through an episode.

Got it. Thanks for taking the questions. I'll hop back at the queue.

Thank you. Our next question comes from Tazeen Ahmad from Bank of America. You may begin.

Okay. Thank you for taking my question. Maybe I'll focus on essential tremor. So you've got the Essential One study that's reading out this year, the Phase II top line. Can you just talk us through that? what information, you know, we should expect to see when that dataset does come through. And, you know, as far as the three doses that you're studying, 20, 60, and 100, you know, is it your expectation that you will see dose-dependent efficacy? And, you know, is there a chance that after looking at the data, you might narrow your focus of doses? And then I might have a follow-up. Thanks.

Thank you so much, Suzanne. Like, there are three readouts for essential tremor right now, right? That what we're coming up with the final cohort for the phase two with the randomized withdrawal, which are going to be reporting in May. Then the 114 is studying essential tremor and essential one. And I know your questions were centered on essential one. So I'm going to hand over to Bernard to talk about our expectations and why we designed that way. What is the key objective here that is really to move to a phase three shortly thereafter?

Yeah, so essential one is really designed to do just that, to provide the data so that we can select a dose or a couple of doses for subsequent phase three or phase threes as needed based on regulatory discussions. The key things we'll look at, of course, safety and tolerability. We talked about how important that is. for this population. In terms of efficacy, we've talked about how, you know, what we'll look at there, and that landscape has been evolving. The focus is on activities of daily living, along with the modifications, the scoring that the agency has suggested. We will, of course, look at measures of tremor, and we talked about the importance of objective measures of tremor. given that there's some challenges in just the visual inspection of floor effects the way it's done in the Tetra. So if you look at all of those, in terms of expectations for a dose response, we selected our doses based on our Sigma band biomarker. We do think there will probably be a dose, you know, ranging a dose response on efficacy on those measures we talked about, Whether or not it will be linear or it will cap out at around 60 milligrams, we don't know. But that's really the question for the trial. We know sigma band tells us mechanistically about dose response, but we don't know how that translates into tremor reduction and function. So that's honestly exactly the question we'll answer. And I think we'll be really well positioned with the data we'll get out of Essential One.

Okay. You are pursuing 114, as Marcia mentioned, as well in Essential Tremors. So, you know, what is your long-term strategy in ET? Are you going to pick one over the other, or do you think that both can exist for different parts of the markets?

It's an awesome question because the way we look into the market, right, and well, the way we look, the way the market is right now when we talk to physicians, to patients, that is such a huge amount of needs. And because it's so large, there are different needs within the essential tremor markets, like younger patients that have familial AKs, about 30% to 50%, by the way. It's not a small number. which would know to progress and would like to start, like, from the gap goal, having some control of the tremor, versus a little bit more. I don't like calling mild because I think it's debilitating. Tremor is never mild. But one could argue a little bit less severe, whereas what you hear from patients, a very significant amount as well, is they just need that for a couple hours in the day when they're performing given tests. And then you have the more progress in disabilities that need that all the time. So there are really three major opportunities for us here. 114S for some of those patients were like, I need this either chronically or just as an on-demand drug for when it's most needed. Like it acts very fast. We get to TMAX around two hours or so. So it's predictable, going to have a reduction of the tremor, going to feel better and move on, or you can stay on the drug if that's the case. Then you have 944 that requires titration. It's a more long-term treatment. It's for someone that has decided to stay longer. And something we have not pursued right now, but we intend to, is to combine those treatments. So now we have three potential options. Our estimation is about 3 million patients. We are the only company with multiple mechanisms. On this, we understand the market, which seems better than pretty much anyone else out there. So it allows us to have like a franchise, really, as we see around essential tremors. So it's not either or. It's really developing both of them. Now, going back to the discipline on how we develop this molecule, the trial for... PRAX 114, inessential tremor, is really designed to answer one key question, right? Can we come up with a dose, which we believe we can, that reduce tremor but does not cause daytime somnolence? And that is the key for that trial. If it is a positive, if we can do that as we believe we can, we're going to move on, we're going to continue, we're going to develop. If we cannot, you have our assurance that you're going to move on from the molecule as well. And then we have 944 for that matter.

Okay. And maybe to wrap it up, Marcio, for essential one, what type of a Tetra score would you consider to be clinically meaningful? Thanks.

Yeah. And I'm going to hand over to Bernard in a second. But one of the key things that we are moving away from, I would say, based on the agency or the FDA advice is just the raw PETRA score. So there are two ways we're going to be looking to this. The rescoring of the ATLs, as they suggested, makes any change in the ATL meaningful. And we believe that's why the agents suggested that, because now we're talking about any points that change, they are clinically meaningful. And by going through, like, accelerometry, for example, as Bernard mentioned on the highlights today, Now we're going to be able to see the true amplitude of the tremor changing. So we believe like 20% or so there would be something quite meaningful. But Bernard, why don't you chime in?

Yeah, yeah. A couple different points in terms of what tremor is meaningful, what we see. It varies a lot patient to patient, but what we see just in terms of eligibility. And we think of this similar way as we talk about HAMD and depression. Like, you need to verify that the score is right. So we have, you know, visual confirmation by video, by an independent rater, same kind of thing. What we see is when people come in with tremor scores in the upper limbs in the 10 to 12 range, two things. They tend to have a lot of impairment in their activities of daily living. And we also, in the data we presented in Part B and in Part A so far, we see those people have pretty robust improvements because they have enough tremor that you can reliably measure change. So, you know, as Marcio said, like how much improvement is important may be easier to measure by ADLs, but typically people think 20% to 30% tremor improvement is about where you need to be or more. But for baseline tremor, you probably need upper limb scores in the 10 to 12 range to really be able to measure anything.

Okay, that's helpful. Thank you.

Thank you. Our next question comes from Miles Mentar from William Blair. You may begin.

Hey, everyone. I'm just curious as to the 50% screen-out rate. Is that consistent across all sites in ARIA, or are you seeing some sites that are screening out a huge amount and others that are incorporating more?

Yeah. Hey, Miles. It's actually fairly consistent. Obviously, it varies a little bit here and there, but we are not seeing like one site screen failing like 95% and the other one 5%. That's for sure. It's a little bit unusual. I would even say even from the feedback from the sites, it's a little bit unusual on their field, but it makes us not happy because there are the patients out there that are desperate to participate in trials. They want to get relief of their symptoms, and they're obviously not getting it, but makes us bring some resolution to the thoughts of are we getting the right patients on the trial, as we mentioned before. So it's both sides of the coin here, but there is no major discrepancies amongst any of the sites that they were seeing, right, Bernard? Yeah, yeah.

And Bob, these are all really experienced sites that our team has worked with before. And so it's not like there's, you know, there's not a skew of sites driving what are kind of inappropriate screenings across the board. And a lot of the sites have commented that the COVID environment is just different and they're their screen fail rates are higher than what they've previously seen. It just goes back to emphasizing the importance of doing this and having that eligibility review process in place.

Yep, makes sense. Let's go on to the next question. This one I get a lot. Obviously, your peers out there sort of putting 11 to 13-point placebo response rates on the HAMJ-17. and it sounds like you're very confident you're going to get much closer to those historic six to eight points there. So when you look at your most important mitigators built into the trial, so placebo reminder scripts, the safer protocol, prior episode MDD patients, have you actually done work to quantify on a ham D17 point basis what each of those actually contributes to a placebo response? Or is it more just a fact of, collectively, we're just getting a better, more uniform patient population. And ultimately, that's what's going to get us into the historic placebo response category. Thanks.

Great question, Myles. So it always starts with getting real patients in the trial. I think that's maybe the most important thing, right? It sounds very simple, very basic. But when we get patients that are, when you're talking about inflation of MG17, you're not talking about inflation by viewpoints. Talking about a very huge inflation, one could call, and I think it's been called in the industry, like there's a lot of professional patients in psychiatry trials, right? So we want to make sure they don't participate in hours. They regress to the mean very quickly when they are like that. And that's when you see this abnormality to our knowledge, there's only really one group of trials that show placebo north of like seven or eight points. And they're all very recent and they're all from the same sponsor. So we'll call that outliers versus like norm. When you look into everything else we did, probably the idea of having a second confirmation drives like 30%, 40%. reduction control. So you would guess easily three, four points based on that, on using SAFER. And we talk a lot about SAFER. We have a lot of respect for the folks at Mass General that do this with us. But it's not only SAFER. There's a verification in the site and then a SAFER interview. So that's probably the second most important. But, you know, in multifactorial analysis, we can never separate the factors.

It is true. There's certainly the most data on SAFER, right, by far. And then I do think it's, like, not to be trite, Miles, but it's having the right people at the table. And so, like, when you have really experienced high-quality sites, you worry less about radar training and things like that. and, you know, their own imprint on placebo effects. So I think it's both the right site personnel as well as the right patient population, I think. Eligibility and site selection are probably the most important.

Okay, cool. We'll jump back in the queue. Thanks.

Thanks. Our next question is Douglas Sal from HC Wainwright. You may begin.

Hi, good morning. Thanks for taking the questions. Just a first one for me. Obviously, there is another competitor that has really emphasized the rapidity of benefit. You obviously, you know, of their drug, and you have sort of emphasized sort of their ability to treat the entire episode. I'm just curious how you're thinking about some of the short-term games and what we might see in the early days, and what's the first time point that you're going to be measuring improvements in the handy?

Yeah.

Hey, Doug, super important question as well. So maybe we start with what we know here, and I'll go back and forth with Bernard, right? We're going to need two or three half-lives at least to start seeing something. Our first data point for ARIA is on day four. We've got to remember that when you get very early days in any trial, you enter into something that is very rarely discussed or debated publicly. There's a window in, meaning there is only so many days patients can be assessed to be considered in the window. So we have to force a window, which we don't like to do for those early days. But we should expect to see separation pretty early. that's mechanistically what happens. I think that's what others have shown as well with a similar mechanism, right? Less extra synaptic, so not exactly the same, but similar mechanisms here. And as Bernard mentioned in one of the questions, once you start going down, like, the road of, like, treating these patients, there is no condition preclinically or clinically that you've seen or anyone to our knowledge that says that by treating with Agava-8, that is partially or very extra synaptically preferring, changes biologically the structure, the physiology of the brain. So it means that you have to continue dosing for as long as the patient needs. It should be pretty obvious based on some recent trial results that those curves go back together and therefore there's no maintenance on that case. Our hypothesis has been from day one that you need to treat throughout the episodes. It's a shared hypothesis with the FDA when they told us that they see an episode of depression between three and six months, and if that's what we're going for, as we are, then we should show that we can treat those patients for a prolonged period of time. So in that regard, we don't believe in removing the drug until those patients feel like stable until they are investigators or they're treating physicians in the case of going to markets, believe that they are to that stage. Now, depression is not a chronic condition. I know we call this chronic, but depression is an episodic condition. And that's why we see some patients resolving and going down in terms of their symptoms over time. Treating the episode or not treating properly an episode is the number one reason why patients have problems afterwards. So we're very committed to not getting patients to just relapse on their treatment. So our paradigm is and is going to be treating for long. We are, I would say, on the lucky side that we can. We have no restrictions to treat these patients for as long as we're treating right now, and our SAIT profile supports it.

And the way we designed ARIA is really because speed of onset, rapid-acting antidepressant, and durable effect, they're both important. That's why, you know, we've got the primary at two weeks. As Marcio said, you know, we have the first post-baseline assessment at day four, which is done virtually because we try not to have too many visits which drive placebo effect up. So the first in-person visit is at one week. As Marcio said, though, there are windows around those, and if you're not tight about the windows, these bleed into each other. So we try and be real tight about those and get assessments really right at around those time points. But the way we've designed ARIA is really to reflect rapid onset, and then assess the durability of ongoing treatment. So I don't think we're choosing in this design, and clinically both are very important. Okay, great.

Hello? Yep. Just a couple quick follow-ups. One, just in terms of screening, I'm just curious – Do you have data in terms of what the cause of most screen failures are? Is there something that's particularly predominant? And two, do you anticipate starting a PPD study? And do you have timing on that?

Yeah. So we do, right? We look into this. Basically, our team look into that every day. Bernard and I and the rest of the leadership team look into this every few days in the week. By far, by a large margin, what is the screen failure rate? driven by MT-17 not being able to be confirmed, which is a gift, I would say, for how we've been doing this. And then the second is compliance with protocol or inability to comply. Some drug abuse, unfortunately, is very prevalent in mental health in general. One more reason to have good drugs to treat these patients But those are like smaller percents. I would say by a disproportional amount is MG17, which reparts everything we've been talking about, expansion of placebo in other trials and so on, if they're not careful on doing that. Then your second question about perimenopausal depression, we're looking to this market kind of in two ways. So one, originally we showed very good proof of concept in our view on PMG It is, by all definition, a subset of patients with moderate to severe depression that happens to be on a period of life that is prolonged, right, about seven years in duration in average, where really these women suffer quite a lot about that change. But then when you start looking to the market, there are two key parameters here. One, they don't identify with the depressive part of a stage, but much more with the menopausal parts of the condition, which drives to different treaters, which drives to different potential regulatory pathways. And the second is there is a constellation of symptoms there or in the moods parameters that we believe we can attack quite nicely with one-on-four. And it goes from 3 million or so women per year markets in the U.S. for PMT to about 9 to 10 million if we consider this other sentence. So from a market perspective, it's quite interesting. We finalized the analysis. We have a go-to in terms of how we are looking to develop. Then we got to look into ourselves in the mirror, to the markets out there, and ask the question about capital allocations. is this the right thing to do in advance of ARIA with the amount of trials we have? So we decided to just hold back for a couple months to be responsible to how we are allocating capital here, and hopefully shortly after, ARIA will be able to restart that trial.

Okay, great.

Our next question will come from Ryan Ove. Rachel Baral from Calend, you may begin.

Hey, guys. Thanks for taking the follow-up. I just wanted to ask about the strategy behind having a second dose that you're pursuing in acapella. First, do you anticipate that it will be a lower dose or a higher dose based on what you have seen preclinically? And second, like, if you just forgot about the preclinical data and just answered that from a commercial perspective, where do you think the biggest need is, just given psychiatrists are used to titrating all day long, so how do you think they want to approach this?

Yeah, the acapella is designed, I would say, almost purely to answer a question from a conversation we had with the agency. When you look into this class, and specifically about 114, but I would say this is more of a class effect. You increase the exposure in the brain. You don't necessarily decrease the symptoms of either anxiety or resolution of insomnia or core depression, but we do for certain increase the number of side effects. So that is a quasi dose proportional or concentration proportional, I would call, increase in AEs but not necessarily a benefit. So rightly so, the question we get is, can you go lower and still have the effect, but no side effect, like be really, really clean? So what do we know? We go back to the health volunteers and we dose 10 milligrams, 20 milligrams, so on, very clean, even during the day. And that's why we're using those dose for essential tremor, by the way, with one on four. So incredibly clean in terms of the dose response. So It made sense for us to go down there. Now, if we extrapolate from the beta power data we have, below 20 milligrams or so, we shouldn't really have much of an effect, if at all, for depression dosing the night before as it does on MDT. So that should be the limit there for us or the limit for us. Then we're going up to the 40th, right, just to confirm, make sure everything is like looking as it should. And because this is a mixed population, a little bit lower, hamsi, it was appropriate to go up to 60 as well and to confirm the hypothesis that the side effects are going to be proportional but not necessarily any additional effect. So it's a true exploration of the dose range. As Bernard mentioned on his prepared remarks this morning, there is no expectation of a statistical powering for this trial. We should be able to see those trends. But let's call, like, let's say the 20 milligrams is actually active and similar to 40. We believe we're going to be pushed to actually add that on a second trial. That would be very transparent with all of you, as we always are. That's the reason for the trial.

Yeah, and adding to the set of expectations, most antidepressants don't have a dose response effect on efficacy. So it's typically more of a threshold effect. So we don't necessarily know that this will be dose-related efficacy. That would be an advantage in terms of we're getting that clinical use. So psychiatrists currently, they do titrate up, but they're very limited data to support that. are more effective. So I think if we were to show that, it would be a tremendous benefit, very useful clinically for people to be able to have a starting dose and know there's more efficacy to get as they go up. But they currently really are doing it on an individual patient basis.

Got it. Thanks for framing that. Very helpful. Thank you.

And once again, as a reminder, that's star one for questions, star one. Our next question or follow-up will come from the line of Myles Mentar from William Blair. You may begin.

Hey, just on the part B of the 9442A study, I'm just wondering what the definition of the response required is to be randomized into the withdrawal portion of that trial. considering the FDA is asking you to do not only tremor but also activities the daily life is as a composite of both of those measures on the Tetris yeah so we did not

The randomized withdrawal period of this will include everybody who was treated. And so we didn't do this as a responder group the way you would like for a Phase III study. So the question, as we framed it up in our prepared marks, is really to understand how long the effect lasts. And so everybody who goes through this study and completes the open label will enter the randomized withdrawal, whether they've had a robust response or not. This will, however, give us the data to help us decide if we do want to do a true responders randomized withdrawal in the future. And I think we'd have to engage with the agency about what the responder definitions are. Because there aren't fixed definitions at this point.

Okay. So it's safe to say that 12 patients will be going into that randomization stage regardless of whether they responded or not. And I think judging from what you've previously reported from Part B and the nine patients, yeah, it's like what a 40, higher than that, like a 50% response rate. So... Yeah. It's safe to say that 12 patients, some responding, some not, randomised. Okay.

Exactly.

That's correct. Okay, cool. And then the final one from me is just I did notice for your earlier stage pipeline that you are looking to push more towards paediatric epilepsies, actually solely driving that focus, which I think is great. But can you just talk to... a bit more color about that decision. And if you do see decent data out of the trigeminal neuralgia studies, like is that an indication that you'd proceed with or you would just take that data and try and shape further epilepsy programs out of those assets? Thanks.

Yeah. So the foundation of how we screen drugs here, as we discussed before, right, some of the calls are like offline calls. has been always used, like genetics, epilepsy models that are highly projected to efficacy in humans. And we have a number of programs, as you saw on the pipeline, we're a lot more comprehensive today than we were in the past. And we've been brewing, and they're coming to a point now where we're incredibly excited about them. We believe they're viable. So for a company our size, our resource, it made sense to pause and to ask, what is the strategy here? What is the one that the market supports, the regulatory framework is clear, patients are all there in need? So we direct towards epilepsy, including like common epilepsy right now, but most of those drugs can be used in several conditions. So we're not abandoning CNS. In general, we're just focusing the resource we have towards the highest probability and the highest impact. Now, if the TN or the trigeminal neuralgia is positive, I think there are different avenues. There's one that if we would continue development, there's one that a partner would develop with us on those indications if it's more appropriate to that. So I'm going to continue to look into this. The best drugs are the drugs that make two patients to get for approval, get commercialized. If you're the right people to do that, great. If you're not, we're not going to be like greedy and try to keep that and not do a good job. And that's what this strategy is for.

Great, thanks. Of course.

Thank you. I'm not showing any further questions in the queue at this moment. I'm just trying to call back over to Maurice. Marcio Souza, President and CEO, for any closing remarks.

Thank you very much, everyone, and I really hope you enjoyed this format. We think it's fairly efficient. It was based on feedback a lot of you gave us. Maybe two remarks. We're incredibly excited about all the progress. Much more to come in the coming months. Today is Rare Disease Day, as I mentioned. very excited about it, continue to develop drugs for those rare conditions, continue to really use the rare disease framework or the rare disease regulatory framework to get these drugs through. But there's also a moment in the world that mental health is taking yet another deep. We have an active war in Europe, as we all know, and that always impacts how we all feel and specifically the ones and our brothers and sisters in Ukraine right now are fighting for their country. So I just want to remind that it is not a simple moment in time. Mental health is very important. We're very committed to help a world where we recognize and we celebrate more the healthiness on the part of the mental health and we're hopeful that in the near future there are going to be no more stupid wars happening here and there, and you're all going to be feeling a lot better about all of us as humanity because that's where we are, just brothers and sisters everywhere. So thanks again for joining. Looking forward to talking to all of you.

This concludes today's conference call. Thank you for participating. You may now disconnect. Everyone, have a great day.