Good day and thank you for standing by. Welcome to the Praxis Precision Medicines for Q and FY2021 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. .

And I like to hand the conference over to your speaker 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 of 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 Ravina, and our Chief Financial Officer, Tim Kelly.

Following the press release and video update issued earlier this morning, we will focus today's call and 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 SEC filings, and in particular, our 10-K filed 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 our first question will come from the line of Yasmeen Rahimi, from Piper Sandler. You may begin..

Good morning, team. Thank you so much for taking my questions and we really like the new format of pre -recording them remarks. The first question that I had for you that we get quite a bit from clients is, now as the studies already have completed, or 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 populations that you've gotten into Aria? I know Bernard, you've made some remarks earlier, but if you could just have alluded a little bit more, what you see, what's the standard deviation? Just an HMD 17 baseline course among these populations.

Any color that you could see on the baseline that could be helpful..

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 remarks areas, it's a spot on what we're expecting with a lot of blood, sweat, and tears you get there, because there was a lot of controls are putting place, as Bernard remind as all of us earlier today. We're very happy where we are, but Bernard why don't you expand on that..

Yes, a little bit of color, sure. Our eligibility was handy 17 of 23 or higher at -- typically people come in and a couple of points just above that cut off.

I think 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, the review processes, we clearly say for that we set up, we're really working.

If we hadn't had those, we would've had a lot of people who either didn't have MDD or didn't have adequate severity. Then 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, looks like the processes and the assumptions that we had when we initially set up the study in powered the study seem to be holding true..

Thank you team, and if I may ask one other question is, when we look at historical studies, MDD studies, have you looked at what percentage of treated population actually really run quite high or quite low in response.

So I guess what I'm trying to see is as you're looking at these two curves, placebo on treatment, you're seeing probably a difference between them.

But how do you -- how confident can we be that maybe some of those lower HMD score it's whether -- that they would be not -- that they were actually on treatment and not on placebos? So just some commentary around that would be really helpful. And thank you for taking my questions..

Yeah. So if you look back, let's call the last 30 or so controlled trials ran in moderate to severe major depressive disorder patients. And you've got -- going to have two, three or four that's have known balanced data on the, like two weeks’ mark. They are all pretty tight spectrally on the two week. One week, two weeks, three weeks, and so on.

The -- so the separation that we see that we expect to see year by drive like, mechanistically, better quantify of sleep, like anxiety, last quarter fresh and pretty early. We are in a matter of days and then maintained throughout should be pretty clear. Without really that expansion of the 17 scores as you just said.

So it is tight, we only look into blinded data at this point in time. So it's like anything I say here or Bernard says is going to be pure speculation to be perfectly honest, right? What -- we set up to try to do something is to separate that they could see with an effect size of around 0.4, which would be three points on the HEMT 17 at that.

On the primary endpoints, we have a target for number of patients that are required. We're in very good shape for that. Completers are 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 starkly, 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 that, right Bernard anything to that?.

We don't know recovered in terms of like, retention rates at here. And adverse event at brave, those all look as we predicted. So as Mark said, it's all blood based on blinded data, review, aggregate data.

So we can't tell you how the groups will separate the way un -blind, but it just means that the assumptions overall in the planning stages appear to depend on that..

Thank you Bernard, and thank you, Marcio..

Thank you..

Our next question comes from the line of Laura Chico from Wedbush. You may begin..

Good morning, guys. Thanks for taking my 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 off. That was wonderful.

You discussed some of the changes, or I'm sorry, some of the changes you saw in the Phase 2a study with respect to. 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..

We expect -- If you get a population like this, that truly has moderate to severe depression, you roughly have or so will have high levels of anxiety, there are a couple of different ways looking into that. You can measure it on MA and we've seen was about a 50% improvement or so in EMA on average. So I think there are probably similar expectation.

The other way to look at it though, is within the DSM 5, there's a subcategory for people who suffer from anxious distress as part of their depression. We've been looking at that all the way along in our Phase 2a study. Those are pretty high proportion of patients, but we expect that to be around 50% or so who fit that sub-category.

So 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 for all the reasons, hitting extra synaptic, antidepressant, as well as synaptic, they're not cleanly divided like that, but we do expect a lot that moving forward, we'll have antidepressant and anxiolytic effects, in that, the MD 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 or just intrinsic part of it..

And on the compliance part, or that you asked, right? So, we use like a number of things, first starts with getting the right patients.

One of the key -- we talked a lot about the number one reason why patients uncaps to after the trial, like there was failure to conform or this average for having G-17, but shortly thereafter was the assessment by the investigator that patients wouldn't comply with this schedule, which is quite important thoughts about how our investigators, the ones that aren't really like in the fields helping us make this trial reality, what take NetSol series of it.

So it starts there, then throughout the study, there is a number of parameters and systems we would put in place. Now this is a relatively long study when you're thinking about our GABAA gap, right? So we're talking about 28 days of dosing, another week of observation after that.

So wanted to make sure the patients are engaged, but not so engaged, that would drive unintended consequence here. So we work with AiCure, not with their standard version. I think what we learned in the process is the extended version did not have the what we call Praxis reaction time.

We want to know immediately if something happens, so we can intervene. So they were very good as they customized the version with us. Our team like -- there 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 ideas 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 no one thing. It's a constellation of different parameters here to drive our good compliance to drug into procedures because it has to be both of that..

Thank you, guys..

Of course..

And our next question will come from the line of Ritu Baral from Cowen. 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 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 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..

So thanks. There's a number of things here I said, 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 then, which is firms on a number of things that we did internally as drives beta power, which is the best surrogates we have here for the drug being in the brain. And it still not creates that state of sedation or that is incapacitating.

That is next day or is it really the patient cannot stay functioning. So that was a key thing for us. We are again, very happy with what we're seeing so far. It seems to be panning out and you're going to see in couple of months, I guess the results. In terms of the effects when you put all those controls in place.

But we believe that drug works as we do. Then you should expect that it drives going to behave as it should behave. That means placebo will decline, by between 0 and whatever time points at the end it is in a controlled way, not in on a like erratic or just controlled way. And that means that's 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 on phone ourselves, it's not that route necessarily maintaining 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 are right on the mark.

So again, we're going to see in June, once we report the results, but it ends up -- I will say a very reasonable chance that you're going to see not only a separation that's numeric. Also one that is statistical significance at day 29, which we're going to report to report MD 17, at day 15, at day 29, global impression on day 29.

Obviously, the same profile, on the gen sets, how the patients aware them. 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 that they would should give a very comprehensive feel of the drug, viability and enabled a conversation for us with the agency, and is starting a Phase III later this year, second registration trial later this year, but that's where we are aiming for the program..

Ritu, it's a good point to reiterate too.

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 a point and a half, 2 points, over the subsequent two weeks versus maintaining the effect when we treated over four weeks.

So really just speaking about the active arm, we look to see continued levels of reduction from baseline. And we do think that's important. You got to continue the drug and be able to treat through an episode..

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

Our next question comes from the line of 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 Essential1 study that's reading out this year, the Phase 2 top line. Can you just talk us through what information we should expect to see when that dataset does come through, and as far as the three doses that you're studying, 2060 and 100.

Is it your expectation that you will see dose dependent efficacy? And 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 Tazeen, like there are three readouts for essential tremor right now, right step, what we're coming up with, the final cohorts for the Phase II with the randomized withdrawal, which are going to be reporting in May then the 114, for instance show being 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 in why we designed that way.

What is the key objective here that is really to move to a Phase III shortly thereafter?.

So central one is really designed to do just that, to provides the data that we can select a dose or a couple of doses for subsequent Phase III or Phase 3s as needed based on regulatory discussions. The key things we'll look at, of course, safety and tolerability. And we talked about how important that is for this population.

In terms of efficacy, we've talked about how we'll look at there in that landscape has been a fall being the focus is on activities of daily living along with the modifications to scoring that the agency is suggested. And we'll of course, we'll 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 Tetris. So if you look at all of those, in terms of expectations for dose response, we selected our doses based on our Sigma band biomarker.

We do think there will probably be a dose 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 Bain tells us mechanistically about dose response, but we don't know how that translates into tremor reduction in function. Honestly exactly the question will answer and I think will be really well-positioned with the data will get out of central one..

Okay. You are pursuing 114 as Marcio mentioned as well, and essential tremors. So 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 market?.

It's an awesome question because the way we're looking to the markets and one of the way we look, the way the markets, if are right now, when we talk to physicians, to patients, there is such a huge unmet needs.

And because it's so large, there are different needs within the essential tremor markets like younger patients that had a familiar case above 30% to 50%, by the way, it's not a small number which would know to progress and will like to start 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 they're very significant amounts as well as they just need that for a couple of hours in the day when they're performing given tasks.

And then you have the more progressed in disability that needs that all the time. So there are really three major opportunities for us here. 114F for some of those patients were like, I need this either chronically or just as our own demands, a drug for when is most needed.

Like it acts very fast, we've got your t-max around two hours or so, so it's predictable, you're going to have a reduction of the tremor or you're going to feel better and move on, or you can stay on the drug if that's the case.

We have 944 that requires titration, it's a longer 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 the potential options. The markets currently, our estimation's about 3 million patients.

We are the only company with multiple mechanisms on this, we're going to -- we understand the market would seem better than pretty much anyone else out there, so it allows us to have a -- like a franchise really as we see around essential tremor. So it's not either or, it's really developing both of them.

Now, going back to the discipline of how we develop this molecule. The trial for PRAX -114 in Essential 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 be if 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 is 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 Essential1, what type of the Tetris score would you consider it to be clinically meaningful? Thanks..

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 advise is just the raw praxis score. So there are two ways I'm going to be looking to this. The risk collaring walk of the ATLs, as they suggested, makes any change in the ATL meaningful.

And we believe that's why the agent's suggested that. Because now we are talking about any points that change their clinically meaningful. And by going through accelerometer for example, as Bernard mentioned the highlights today, now 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, a couple different points in terms of what tremor's meaningful, what we see, it varies a lot of patient-to-patient. But what we see just in terms of eligibility. And we think of this similar way as we talked about EMD and depression.

Like you need to verify that the score is right, so we have 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, few 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 as Marcio said like, how much improvement is important, maybe easier to measure by ADLs, but typically people think 20-30 percent tremor improvement is about where you need to be or more buffer baseline tremor. You probably need upper limb scores as 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 the line of Myles Minter from William Blair. You may begin..

Hey everyone. I'm just curious as to the 50% screen outright.

Is that consistent across all sites in Aria or are you saying in some sites that are straining out a huge amount and others that are incorporating more?.

Yeah. Hey Myles. It's actually fairly consistent for obviously, it varies a little bit here and there, but we're not seeing one side screen failing like 95% and the other one 5%. That's for sure. The -- it's a little bit unusual. I would even say even for the feedback from the sites.

It's a little bit unusual on their view but 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 obviously not getting it.

But makes us -- brings some resolution to the thoughts of are we getting the right patients on the trials we mentioned before, so it's both sides of the coin here, but there is no major discrepancies amongst any of the sites that we're seeing, right, Bernard?.

Right. And Myles these are all really experienced sites. Their team has worked with before, so it's not like there's not a SKU of sites driving what are inappropriate screenings. It's across-the-board and other sites have commented that the COVID environment is just different and their screened fail rates are higher than what they previously seen.

It just goes back to emphasizing the importance of doing this and having that eligibility review process in place..

Yes. Makes sense. Let's go on to the next question is one I get a lot. Obviously, your peers out there putting ALIF anticipating point per se very response rights on the hand they save a name. And your -- 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 mitigated built into the trial, sir, to stay very remind us scripts, the cypher product call product insight MDD patients.

Have you actually done work to quantify on a hand Day 17-point basis, what each of those actually contributes to a placebo response, or is that 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.

It sounds very simple, very basic, but when we get patients that are -- when you're talking about inflation of HAM-D17, you're not talking about inflation by a few points, you're talking about a very huge inflation, one could call, and I think it's been called in the industry, there's a lot of professional patients in psychiatric trials.

So we want to make sure they don't participate in ours. They regress so they may vary quickly when they are like that. And that's when you see these abnormalities. 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'd call that outliers versus norm. The -- when you look into everything else we did, probably the idea of having a second confirmation drive like 30%, 40% reduction control, so you would guess easily 3, 4 points based on that on using safer. And we talk a lot about Safer.

We have a lot of respect for the forth MS general that do this with us, but it's not only Safer, there's a verification in this site and then a Safer interview. So that's probably the second most importance but in multifactorial analysis, we can never separate the factors..

It is true. There is certainly the most data on safer right, by far and then I do think it's like not to be tried, Myles, but it's having the right people at the table and when you have really experienced high quality sites, you worry less about radar training and things like that, drift and their own imprint on placebo effect.

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. Let's jump back in the queue. Thanks..

Thanks..

Our next question will come from the line of Douglas Tsao from H.C. Wainwright, you may begin..

Hi. Good morning. Thanks for taking the questions. Just a first one from me, obviously, there is another competitor that has really emphasized the rapidity of benefit. You obviously their drug and you have emphasized their ability to treat the entire episode.

I'm just curious how you're thinking about some of the short-term gains and what we might see in those -- in the early days. What's the first time point that you're going to be measuring improvements in the Hamed..

Hey, Doug (Ph). Hi. Super important question as well. So maybe to start with what we know here and I will go back and forth with Bernard. The -- we're going to need two or three hop lives that at least to start seeing something. Our first data points for Aria is on day four.

Got to remember that when you get very early days in any trial, you something that is very rarely discuss or debated publicly. There's when, when to when. Meaning that there's only so many days’ patients can be assessed be considering the window. So we have to force or window which we don't like to do for those early days.

But we should expect to see separation pretty early. That mechanistically will happen. I think that's why others have shown as well with a similar mechanism, labs, extrasynaptic. So not exactly the same, but similar mechanisms here.

And as Bernard mentioned in one of the questions, once you start going down the road of treating these patients, there is no condition pre -clinically or clinically that you've seen or anyone to our knowledge, that says that by treating with GABAA ATMs that it's partially or very extrasynaptic referring change biologically.

They structure the physiology of the brands. So it means that we have to continue those 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 is 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, that we should show that we can treat those patients for a prolonged period of time.

So in that regard, we don't believe on removing the drug until those patients feel like stable, until their investigators, or their treating physicians in the case of going to markets, believe that they are at that stage now. Depression is not a chronic condition. I know we call this chronic, but depression's an exotic 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 paradigms is, and is going to be training 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 you are treating right now and our safety profile supports it..

The way we designed Aria was really because speed of onset, rapid acting anti-depressant and durable effect. They're both important, that's why we've got the primary at -- at two weeks.

As Marcio said, we have the first post baseline assessment at Day 4 which is done virtually because we try not to have too many visits which drive placebo effect up to the first in-person visit is at one week.

As Marcio said though, there's like -- the windows around those and if you're not tight about the windows like these -- 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?.

Yeah..

Just a couple of 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 particular predominant? And two, when do you anticipate starting at PPD study and do you have timing on that?.

Yeah. So we do it. We're looking to this basically our team look into that every day. Bernard and I and the rest of leadership team look into this every few days in the week. By far, by a large margin, what is the screen failure rates is driven by MG 17 not being able to be confirmed. Which is again, I would say for how we've been doing this.

And then the second is compliance with protocol or inability to comply, certain drug abuse, unfortunately is very prevalence in mental health in general. One more reason to have good drugs to treat these patients. But those are smaller percent’s, I would say by a disproportionate amount is MG 17.

Which reinforces everything, we've been talking about expansion on placebo in other trials and so on if they're not careful or at home doing that..

Tim your second question about our perimenopausal depression, we're looking to this markets in two ways. So one originally we showed very good proof-of-concepts in our view on PMG.

It is by all definition of subsets of patients with moderate to severe depression that happens to be on our period of life that is prolonged, right about seven years in duration in average where a really this -- women suffer like quite a lot about that that changed. But even when we start looking to the markets, there are two key parameters here.

one, they don't want to identify with the depressive parts of a stage but much more with the menopausal parts of the condition which drives to different traders who drive through different potential Regulatory pathways.

And the second is, there is a constellation of symptoms there or in the moods parameters than we believe we can up back quite nicely with one on four. And it goes on a 3 million or so women per year markets in the wells for PMG to about 9-10 million, if we consider this other symptom. So from market perspective is quite interesting.

We finalized those analysis, we have a go to in terms of how we are looking to develop, though we got to look into ourselves in the mirror, to the markets out there and ask the question about capital allocation.

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 of months to be responsible to how we're allocating capital here, and hopefully shortly after Aria we're going to be able to restart the trial..

Okay. Great..

Our next question comes from the line of Ritu Baral from Cowen. You may begin..

Hi guys, thanks for taking the follow up. I just want 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 pre -clinically, and second, if you just forget about the preclinical data and just answer 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?.

Yes. Acapella is designed, I would say almost purely to answer a question from our conversation we had with the agency. When you look into this class and specifically about our 114, but I will say this is more of a class effects.

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 there is quasi dose proportional or concentration proportion, 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 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 than if you -- 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 impact if at all, for depression, dosing the night before as it does on MDD. So, that should be the linear there for us or the limits for us.

Then, we're going up to the 40, just to confirm, make sure everything is looking as it should. And because this is a mix population, a little bit lower, MG, it was appropriate to go up to 60 as well and to confirm the hypothesis that the side effects facts are going to be proportional but not necessarily any additional effect.

So, it's up two exploration of the dose range. As Bernard mentioned on his prepared remarks this morning, there was -- there is no expectation of our statistical powering for this trial. We should be able to see those trends.

But let's call -- let's say the 20 milligrams is actually active and similar to 40 milligrams, we've been going to be pushed to actually add that on our second trial. That would be very transparent developed view as we always are. That's the reason for this point of trial..

And I'd add into the set expectations, most intended presence doesn’t have the dose response effect on efficacy. So it's typically more of a threshold effect, so we don't necessarily know that this will be real dose-related efficacy.

That would be an advantage in terms of we're getting at clinical use, so psychiatrist currently they do titrate up, but there's very limited data to support that higher doses across any class of antidepressants are more effective. So I think if we were to show that, it would be 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..

Our next question, a follow-up, will come from the line of Myles Minter from William Blair. You may begin..

Hi, just on the pop bay of the 944-2A Study. I'm just wondering what the definition of the response for Quad is to be randomized into the withdrawal portion of that trial, considering the FDA is asking you to do not only trim up, but also activities, the daily locus of the composite of both of those measures on the Tetris..

So we did not -- the randomized withdrawal period of this will include everybody who was treated and so we can do this as a responder group, the way you would like for a Phase 3 study. So the question as we've framed it up in our prepared remarks 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, Myles, give us the data to help us decide if we do want do a true responders randomized withdrawal in the future.

And I think what we -- 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 side-to-side 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 then on patients, yeah it's like 45 higher than that like a 50% response, right? Sorry..

Yeah.

It's safe to say that 12 patients, some responding, some not, randomized. Okay..

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 pediatric epilepsies, actually solidly dropping 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 neurology studies, is that an indication that you'd proceed with or you would just take that data and try and shape for the epilepsy programs out of those assets. Thanks..

Yeah, so Myles the foundation of how we screened drugs yes as we discussed before like offline as being always are used like genetics, epilepsy models that are highly projected to.

And we have rights like a number of broadens as you saw on the pipeline, we're a lot more comprehensive today than we are in the past that we've been brewing and they're coming to a points now we are incredibly excited about that and we believe they are viable.

So for our 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's support, the regulatory framework is clear. Patients are all there in needs, so we direct towards epilepsy including common epilepsy right now, but most of those risks can be using several additions.

So we're not abandoning CNS in general, just focusing the resource we have towards the highest -- probability in the highest impacts. Now, in or in trial is positive. I think there are different avenues. There is one that we would continue developments.

There is one that a partner would develop with us on those indications if it's more appropriate to that. So, we're going to continue to look into this and the best drugs are the drugs that make two patients to get for approval get commercialized. If you are the right people to do that's great.

If we're not, we all going to be like greedy and try to keep that and not do the job. And that's what this strategy is for..

Great. Thanks..

Of course..

Thank you and there are no any further questions in the queue at this moment. I'll just turn the call back over to Marcio Souza, President and CEO for any closing remarks..

Thank you very much everyone and I really hope you enjoyed this form as we think it's fairly efficient, was based on feedback of a lot of few gave us. Maybe two remarks, your incredibly excited about all the progress, much more to come in the coming months.

Today is Rare Disease Day, as I mentioned, we are very excited about its continued to develop drugs for those rare conditions, continued 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 in our brothers and sisters in Ukraine right now are fighting for their country. So I just want to remind that is not a simple moment in time. Mental health is very important.

We're very committed to have our 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 going to be no more like stupid wars happening here and there.

And you all going to be feeling a lot better about all of us as humanity, because that's what we aren't 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..