Q4 2021 Praxis Precision Medicines Inc Earnings Call

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Yeah.

Operator: 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.

Good day, and thank you for standing by and welcome to the practice precision medicines for Q.

In FY, 2020 , one corporate update Q&A call.

All participants are in a listen only mode. After the Speakers' brief presentation there'll be a question and answer session to ask a question. During this session you will need to press star one on your telephone.

Operator: After the speaker's brief presentation, there will be a question and answer session. To ask a question during the 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 our speaker today, Alex Kane, Vice President of Investment Relations and Corporate Communications, for a very brief presentation. Please go ahead. Thank you. Good morning, everybody.

You require any further assistance. Please press star zero, Oh, and I like to hand, the conference over to screen today, Alex Kane, Vice President of Investor Relations and corporate communications for a very brief.

Presentation. Please go ahead.

Alex Kane: 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.

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 Chief Medical Officer, Bernard You know and our Chief Financial Officer, Jim 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.

Alex Kane: Before we proceed, I would like to remind you that during today's call, we may make certain statements that are 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 10K file today. With that, I will now pass the call over to the operator to open up the line for Q&A. Operator?

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 their business I encourage you to consult our SEC filings and in particular, our 10-K filed today with.

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 one on your telephone.

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 Yasmeen Rahimi on Piper Sandler. You may begin. Yes, good morning, team.

And our first question will come from the line of Yasmin Rahimi.

From Piper Sandler you may begin.

Yasmeen Rahimi: 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 that the study 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 the patient populations that you've gotten into ARIA are?

Yes. Good morning team. Thank you so much for taking my question and we really liked the new format of prerecorded.

Thanks.

The first question that I had for you that we get quite a bit from clients.

Now as the studies are.

How complete it.

And the last stretch of enrollment completion and Youre looking at the patient population can you give us an idea of.

Homogeneous patient populations that you've gotten into our yeah.

Yasmeen Rahimi: I know, Bernard, you've made some remarks earlier, but if you could just allude a little bit more, what you see, what's the standard deviation, just in HMD-17 baseline scores among these populations, any color that you could see on the baseline, that could be helpful. Hey, Yazen, thank you so much for the call, for calling in, and I appreciate the feedback as well in the format. So I'll hand over to Bernard, but maybe my quick remark there is, it's spot on what we were expecting, with a lot of blood, sweat, and tears to get there, because there were a lot of controls that were 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.

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 H M D 17th baseline scores among these population.

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

Yeah.

Thank you so much for the call are calling in and I appreciate that feedback as well on the formats. So I'll hand over to Jean Bernard but maybe my my quick remark there, yes, it's a spot on the wall.

Are you expecting with a lot of blood sweat and tears to get there because that was a lot of controls are put in place that's Bernard reminded all of us today.

Very happy where we are but its Bernard why don't you expand on that.

Marcio Souza: So our eligibility was HAM-D17 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 that 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 the appropriate severity.

A little bit of color. So are our eligibility was a ham D 17 of 23 or higher.

Right.

Typically people would come in a couple of points just above that cutoff.

I think the key for US was as we mentioned 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 or really work if we hadn't had those.

We would have had a lot of people.

Either didn't have M D D or didn't have adequate severity in terms of the standard deviation. So if you really look for is like.

Marcio Souza: And in terms of standard deviation, so what you really look for is the change from baseline, which is the key to the standard deviation for powering. And that's right around where we expected it to be, about seven points.

Change from baseline is the key for the standard deviation of Repowering and Oh, that's right around where we expected it to be about seven point. So overall it looks like the processes and the assumptions that we had.

Bernard Ravino: 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 all true. Thank you, team. And then, if I may ask one other question, when we look at historical studies, MDD studies, have you looked at what percentage of the 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 on treatment, you're probably seeing a difference between them.

When we initially set up the study and powered the study seems to be holding true.

Thank you team and then if I may ask one other question is when we look at historical historical studies.

Studies M D D studies.

Have you looked at what percentage of treated population.

Actually really run.

Quite high online were quite low in response, so I guess, what I'm trying to see is as Youre looking at these two car play seaborne treatment, you're seeing probably a difference between them, but how do we how confident can we be that maybe some of those.

Bernard Ravino: But how confident can we be that maybe some of those, you know, lower HMD scores, whether or not they would be true if they were actually on treatment, not on placebo? So just some commentary around that would be really helpful.

You know.

Lower H M D score whether that that they would be not that they were actually on treatment.

Hey, Bob So just some commentary around that would be really helpful and thank you for taking my question.

Yasmeen Rahimi: And thank you for taking my question. Yeah, so, yes, if you look back, let's call the last 30 or so control trials ran in moderate to severe major depressive disorder patients, right? And we're going to have to include three or four that have known valid data only, like, the two weeks mark. They are all pretty tight, actually, on the two-week mark, one week, two weeks, three weeks, and so on.

So yes, if you look back.

It's called the last 30 or so controlled trials ran in.

Moderate to severe major depressive disorder patients right and we've got I'm going to have to it for three or four that's happened on salads.

Data on the like two weeks Mark.

They are all pretty tight actually own the only 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 bedroom quantify sleep plasma side see Laskhar depression pretty early on like the matter of days and then maintained.

Marcio Souza: So, the separations that we see that we expect to see here by drive, like 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. Tides, like we are only looking to blind the data at this point in time.

<unk>.

It should be pretty clear.

Without really that expansion off of the Ham <unk> scores as you just said so it is.

Marcio Souza: 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 a day 15 with an effect size of around 1.4, which would be three points on the MG17 at that on the primary endpoint. We have a target for the number of patients that are required, and we're in very good shape for that, with completers on day 15 at this point in time, so we feel really good about it.

Sites like we only look at you're blinded data at this point in time. So it's like anything I can say here Bernard and say, it's going to be pure speculation should be part of Madonna strikes well, we set up to try to do some things just separate that they could see with an effect size of <unk>, four which would be three points on the.

<unk> been seeing out that on the primary end points, we have a target for a number of patients are required.

Very good shape for that.

Theatres that they've just seen at this point in time, so we feel really good about it. So historically as we compare as we accumulate as you re stimulate start we feel really good.

Marcio Souza: 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 in trials that we don't consider to be valid, but the majority of them. Right, Bernard? Anything there?

About it and that is not a large proportion of patients deviating from from the central tendency here. If you were to look again.

Some rare exceptions, all drivers that we don't consider to be valid.

But the majority of that like were not that anything to add no no I think.

Bernard Ravino: No, no, I don't think you covered that. In terms of retention rates, adherence, and adverse event rates, those all look as we predicted. So, as Marcio said, it's all based on, you know, blinded data review aggregate data, so I can't tell you how the groups will separate the way I'm blind, but it just means that the assumptions... Overall, and the planning stages appear to be panning out. Thank you, Bernard. And thank you, Marciu. Thank you. Our next question will come from Laura Chico, or Chicho, sorry, from Wedbush.

He covered it in terms of.

Like retention rates of adherence adverse event rates those all look as we predicted so.

As Marcio said, it's all blood based on blinded data review aggregate data. So I can't tell you how the groups we'll separate so blunt.

But it just means that the assumptions are overall in the planning stages appear to be paying in that.

Thank you Bernhard and thank you might you.

Yeah.

Thank you.

Our next question will come from the line of Laura Chico Tito sorry from Wedbush you may begin.

Laura Chico: 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.

Hey, good morning, guys. Thanks for taking my questions.

I, just have two and I'll stick with ARIA as well.

Laura Chico: 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.

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 then I apologize. Thanks for release in the prepared remarks as well ahead of time that was all that was wonderful.

Can you discuss some of the changes or I'm sorry, some of the changes you saw in the phase Iia study with respect to hem, a and I'm wondering if you could just elaborate a little further on your expectations and are you 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.

Bernard Ravino: You discussed some of the changes, or I'm sorry, some of the changes you saw in the Phase 2a study with respect to HAM-A. And I'm wondering if you could just elaborate a little further on your expectations for 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.

<unk>.

Really what we expected.

Bernard Ravino: Yeah, we do expect when you get a population like this that truly has moderate to severe depression, roughly half or so will have, uh... high levels of anxiety. There are a couple of different ways to look at it. You can measure it on MA, and we saw about a 50 percent improvement or so on MA on average, so I think that's probably a similar expectation. The other way to look at it though is within the DSN, The We've been looking at that all the way along in our Phase 2a study.

A population like this truly has moderate to severe depression, roughly half or so will have.

High levels of anxiety, there a couple of different ways looking into that you can measure it on M&A and we had seen was about a 50% improvement or so in PMA.

So I think you know that.

Probably similar expectation the other way to look at it though is within the D. S N.

The DSM five there's a kind of a sub category for people, who suffer from anxious distress as part of their compression. So we 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.

Bernard Ravino: That was a pretty high proportion of patients, but we expect it to be around 50% or so who fit that subcategory. So we'll look at that. It's not part of the primary analysis, but we'll look at that as well. We do expect, mechanistically, for all the reasons, hitting extrasynaptic antidepressant as well as synaptic. They're not cleanly divided like that, but we do expect that 114 will have antidepressant and anxiolytic effects and that the HAMD, in and of itself, nicely reflects that in terms of anxiety items and sleep items. There are a number of different ways to get to that construct, but fundamentally, anxiety levels in moderate to severe depression are just an intrinsic part of it.

Who fit that subcategories. So we'll look at that it's not part of the primary analysis, but we will look at that as well and we do expect Mechanistically you know for all the reasons hitting extra synaptic anti depressant.

Well its synaptic theyre not clearly divide it like that but we do expect a law that wound for all have anti depressant in anxiolytic effects in there.

You know the Ham D in and of itself nicely reflects that in terms of anxiety anxiety items and sleep item. So there are a number of different ways to get to that construct but fundamentally like.

Zaidi levels and moderate to severe depression, or just intrinsic part of it.

Marcio Souza: And on the compliance part, Laura, that you asked, right, so we do like a number of things. First, it starts with getting the right patient. One of the key things we talked about a lot was the number one reason why patients then get to, after the trial, like there was failure to confirm or severity for Mg17, but shortly thereafter was the assessment by the investigator that patients wouldn't comply with this schedule, which is quite important. We talked about how our investigators, the ones that are really in the field helping us make this trial a reality, we're taking that so seriously. So it starts there.

And on the compliance parts or all of that that you asked right. So we use like a number of banks for us it starts with getting the right patients one of the key and we talked a lot about the number one reason why patients M gaps to Oxford, a trial like that wont stay there to conform arbitrate merits for having to 17, but shortly.

Thereafter, well.

The assessment by the investigator that patients would have to comply with the schedule, which is quite important talked about how our investigators the ones that arent really like in the fields, helping us make this trial, a reality or take pencils here isn't it. So it starts there than throughout the study that is a number.

Marcio Souza: Then throughout the study, there are a number of parameters and systems we put in place. Now, this is a relatively long study when you think about GABA-A-PAP, 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 they would drive an extended consequence here. So we work with AI cures, not with their standard version.

Like parameters and systems were put in place. This is a relatively long study what do you think about a guy by that right. So we're talking about 28 days of dosing on all the week of observation after that so wanted to make sure. The patients are engaged but not so engaged that will drive.

Intended consequence so.

So we wanted to stay on cure Norwich their standard version I think what we learned.

Marcio Souza: I think what we learned in the process is that if the standard version did not have what we call Praxis Reaction Time, we want to know immediately if something happens, so we can't intervene. So they were very good.

In the process.

Based on their version of it did not have the what we call practices reaction time, we want to know immediately if something happened. So we can't intervene. So they were very good they customize diversion with.

Ritu Baral: They customized the version with our team, like that is someone that is looking at it 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 were confident about the patient population. But it's not one thing; it's a constellation of different parameters here to drive good compliance with the drugs and with procedures, because it has to be both of them. Thank you, guys, of course. And our next question will come from the line of Ritu Baral from Caled. You may begin. Good morning, guys.

Our team like that if someone is looking to this all the time.

And that became like a keep.

So 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 have constant what's the patient population.

But it's not one thing I'd say its a constellation of difference on parameters here to drive a good compliance to drug into procedures, because he has to be both of that.

Thank you guys.

Okay.

Yeah.

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

Marcio Souza: 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, and what you might report beyond day 29? And then you gave us very helpfully what your expectations were for somnolence. 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.

He can stay 29 or 30 Marcio I think you mentioned that you expect maintenance of effect does that mean, you're expecting maintenance.

Mystical significance and just sort of generally what you expect.

At day 29, what you might report beyond day 29, and then you gave us a very hopefully what you're expectations for somnolence lie.

Could you speak to how you expect the patient to come in.

That might be at the French I'll try that.

Thanks, and then I'll hop back in queue.

Marcio Souza: Good. So, thanks. There are a number of things here, right, that we have to consider. Maybe we should start with the safety part. So when we chose the 40 milligrams to go on a daily dose, nightly, our hypothesis, and which is based on a number of things that we did internally, drives beta power, which is the best surrogate we have here for the drug being in the brain. And it's still like not creating that state of sedation or somnolence that is incapacitated the next day or is really the patient cannot stay functioning. So that was a key thing for us.

Sounds good so thanks, Mike.

There's a number of things Youre right.

So maybe we start with safety apart. So we chose the 40 milligrams as you go in a daily dose nicely.

Our hypothesis, which is farms all not on a number of things that we did internally.

Drive beta power, which is the best summer games, we have here for the drug being in the brain.

And it's still like not create steady state of sedation or somnolence that is incapacitated.

Next day, or so really the patient cannot.

State functioning so that that was a key thing for us where I get very happy with what we're seeing so far it seems to be panning out and you're going to see a couple of months I guess their results in terms of the effects. When you put all those controls in place when we believe the drug works as we do.

Marcio Souza: We're again very happy with what we are seeing so far. It seems to be panning out, and you're gonna see the results in a couple months, I guess. In terms of the effects, when you put all those controls in place, when you believe the drug works as we do, then you should expect that the trial is gonna behave as it should behave. That means placebo will decline between zero and whatever time point at the end it is in a controlled way, not in an erratic or just controlled way, and that means that the expectation is that there 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.

Then you should expect that it drives going to behave as it should behave that means.

Placebo will decline like between zero and whatever five point that yes. It is.

In a controlled way not on a like erotic art just controlled way.

And that means doubts.

Is it the expectation as 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 getting a lot larger damn it.

Marcio Souza: Because we expect drugs to be much larger declines, while the expectation from the FDA based on the conversations we had and from ourselves is not that we would necessarily maintain statistical significance at day 29. It's quite possible we will.

Kosmos expects drugs to be much larger decline.

Why would the expectation from the FDA on the conversations we've had on phone ourselves, it's not that it would necessarily mean things statistical significance at day 29, it's quite possible we will.

Marcio Souza: And because, like 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. I, again, we're going to see in June once we report the results, but there's a, I'll say, a very reasonable chance that you're going to see not only a separation that is numeric but also one that is statistically significant at day 29, which we're going to report.

And because like everything we're seeing what's Bernard sadow or sounds like aviation so far it's actually right on the Mark.

The kind of patients that came in right on the Mark So.

I guess I'm Gonna see June once we report the results, but it ends up I would say a very reasonable chance that youre going to see not only a separation that was all about.

Also one that is statistical significance at day 29, which we're gonna reports within reports, having just 17, a day 15 day 29 global impression.

Marcio Souza: We're going to report MD-17 at day 15, at day 29, and global impressions on day 29. Obviously, the safety profile of 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 that as well. But those are the key things we're planning to show on that day, which should give a very comprehensive feel for the drug viability and enable conversation for us with the agency, and it starts in phase three later this year, the second registrational trial later this year, but that's where we are aiming for the program.

All day on day 29, obviously, the safety profile of the visits how the patients are with everything else that we have in the queue. If you have time to process data wouldn't be showing as well, but those are the key things. We're planning to ensure that they would should give up their comprehensive feel off the drug via.

Let's see.

Enable conversation, whereas with the agency and starting a phase III later this year of seconds Registrational trial later this year, but that's where we are aiming for the product.

Marcio Souza: Ritu, 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 that when you discontinue, you do lose, you know, a point and a half, two points over the subsequent two weeks versus maintaining the effect when we treat it for four weeks.

Richard It's a good point to reiterate two that we're talking about maintenance of effect on treatment.

And in our in our experience and our Phase Iia study, we had a we tried both stopping treatment after two weeks as well as continuing it for the full four weeks.

We saw very clearly is when you discontinue you do get you lose you know point and a half two points.

Over the subsequent two weeks versus maintaining the effect.

When we treated over four weeks, so really don't just speaking about the active arm, we look to see continued levels of reduction from baseline and.

Bernard Ravino: 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.

And we do think that's important gotta continue the drug.

And you'd be able to treat through an episode.

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

Tazeem Ahmad: Thanks. Thanks for taking the questions. Our next question comes from Tazeem Ahmad from Bank of America. You may begin.

Cuba.

I know <unk> 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.

Tazeem Ahmad: 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 two top line. Can you just talk us through what information we should expect to see when that data set does come through?

This year too.

Top line can you just talk us through what information you know, we should expect to see when that date, if it does come through.

Bernard Ravino: And, you know, as far as the three doses that you're studying, 20, 60, and 100, 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. So thank you so much, Suzeen.

You know as far as the three doses that you're studying 2060 and 100. So is it your expectation that you will see a 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.

So thank you so much so seems like there are three readouts for essential tremor right now right is that what we're coming up with the final cohort for the phase two with the randomized withdrawal, which I'm gonna be reports may Dan. The 114 is studying essentials.

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

In essential tremor and essential wanted I know your questions were sent through all that central 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 phase III. Shortly thereafter, so central was really designed to do just that.

Bernard Ravino: 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, are safety and tolerability. And we talked about how important that is for this population. In terms of efficacy, we talked about how, what we'll look at there, that landscape has been evolving. The focus is on activities of daily living along with the modifications and scoring that the agency has suggested.

To provide the data so that we can select a dose or a couple of doses or subsequent phase III or phase threes as needed based on regulatory discussions. The key things. We will look at of course safety and Tolerability and we talked about how important that is for this population.

Sure.

In terms of efficacy we've talked about how you know what we'll look at there that that landscape has been a fall being the focus is on activities of daily living along with the modifications to scoring that the agency has suggested we will of course look at measures of tremor.

Bernard Ravino: We will, of course, look at measures of tremor. And we talked about the importance of objective measures of tremor, given that there are some challenges with just the visual inspection of floor effects the way it's done in the Tetra. So if you're looking 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 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 mechanistic information about dose response.

And we talked about the importance of objective measures of tremor.

Given that there's some challenges it just the visual inspection at Florida effects. The way it's done in the in the Tetra. So if you're looking 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.

You know ranging of 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 well, we don't know, but that's really the question for the trial are we know SYGMA band tells us.

Ines Stickley about dose response, but we don't know how that translates into tremor reduction.

Function. So that's honestly exactly the question won't answer and I think will be really well positioned with the data we will get out of a central one.

Marcio Souza: 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 that gets out. Okay. You are pursuing 114, as Marcio mentioned, as well, an essential trimmer.

Okay.

You work with doing 114, as Mike mentioned as well and it's been September or so.

Marcio Souza: 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 in different parts of the market? It's an awesome question. Because the way we look into the market, right? And while the way we look, the way the market is, right now, when we talk to physicians, to patients, there is such a huge unmet need. And because it's so large, there are different needs within the essential tremor markets, like younger patients that have familial RK, it's 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 get-go, having some control of the tremor versus a little bit more. I don't like calling it myos because I think it And then you have more progress in disabilities that need that all the time.

What is your long term strategy any P are you going to pick one over the other or do you think that both can make sense.

Parts of the market.

So now some question.

Because the way we are looking to their markets right.

Well the way, we look the way the markets, yes, right now when we talk to physicians to patients there.

It is such a huge unmet needs. It because it's so large there are different needs within the essential tremor markets like younger patients that's happened Emilio arcade the bulbs, 30% to 50% by the way, it's not a small number which woods.

No to progress it will like to starts like from the GAAP goal, having some control of the traveler for Suez a little bit more I don't like calling miles because I think it's debilitating travelers never miles, but one could argue a little bit last severe whereas what do you. What do you hear from patients that are very significant.

Amounts as well is they just need that for a couple of hours in the day when theyre performing given desks and then you have the more progress and just to be honest that needs that all the time.

Marcio Souza: So there are really three major opportunities for us here. 114S, for some of those patients who are like, I need this either chronically or just as an on-demand drug for when it's most needed. Like, it acts very fast.

So there are really three major opportunities for us here 114 as for some of those patients were like I need steps, either chronically or just on demand drug for when it's most needed spike it acts very fast we got Ya <unk>.

Marcio Souza: We get to Tmax in around two hours or so, so it's predictable. We're gonna have a reduction in the tremor, we're gonna 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 three. So now we have three potential options, right?

Around two hours or so so it's predictable gonna have a reduction of the turmoil 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.

A more long term to meet demands as for someone that has decided to stay longer and something we have not pursue right now, but we dance too is to combine those treatments.

Now we have three potential auctions by the markets currently our estimation is about 3 million patients.

Marcio Souza: The market currently, our estimation is about 3 million patients. We are the only company with multiple mechanisms for this. We understand the market, which seems better than pretty much anyone else out there. So it allows us to have a franchise, really, as we see around the central tremor. So it's not either or; it's really developing both of them.

We are the only company with multiple mechanisms.

On this we're going to we understand the market would seems better than pretty much anyone else out there. So it allows us to have a more like a franchise really is we see around the central tremor, so its not either or it's.

Marcio Souza: Now, going back to the discipline of how we develop these molecules, the trial for Prax114 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 reduces tremor but does not cause daytime somnolence?

It's really developing both of that now going.

Going back to the discipline on how we develop this molecule.

Oh for <unk>.

Perhaps 114 in essential tremor is really designed to answer won't keep last year right.

Can we come up with a dose, which we believe we can.

That reduce tremor.

But it does not cause date times somnolence.

Marcio Souza: And that is the key to that trial. If it is 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.

And that is the key for that.

If it is a positive if we can do that that would be if we can move on.

Change is going to develop if we cannot you have our assurance that it's going to move on from that molecule as well and then we have mined or for that matter.

Marcio Souza: Okay, and maybe to wrap it up, Marcio, for Essential One, what type of TETRA score would you consider to be clinically meaningful? Thanks. Okay, and I'm gonna hand over to Bernard in a second.

Okay, and maybe to wrap it up marcio for essential one what type of the tetra or would you consider to be clinically meaningful.

Yeah.

I'm going to handover to Bernard in a second but one of the key things that we are moving away from I would say.

Marcio Souza: But one of the key things that we are moving away from, I would say, based on the agency's or the FDA's advice is just the raw Tetra score. So there are two ways we're going to be looking into this. The rescoring of the ATLs, as they suggested, makes any chance in the ADL 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.

Based on the agency or the FCA advise is just the raw Catherine score. So there are two ways of going to be location deaths.

Scoring walk off the Atl's suggests that makes any challenge in J D. L meaningful and we believe that's why the agent's suggested that because now we're talking about any points that change they are clinically meaningful.

Marcio Souza: And by going through like accelerometry, for example, as Bernard mentioned in the highlights today, now we're going to be able to see the true amplitude of the tremor changing. So we believe that by 20% or so there would be something quite meaningful. But Bernard, why don't you chime in?

By going through like a seller Amit III for example that Bernard I mentioned on the <unk>.

Highlights today.

Be able to see the true amplitude of the time, we're changing so we believe like 20% or so there would be something quite meaningful but Bernard why don't you chime in yeah yeah.

Bernard Ravino: 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 in a similar way as we talk about HMD 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 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.

A couple a couple of different points in terms of.

You know what tremors meaningful what we see it varies a lot of patients patient, but what we see just in terms of eligibility and we think of this similar way as we talk about Ham D and depression like you need to verify that the score is right. So we have visual confirmation by video by an independent.

Or the same kind of thing we see is when people come in with tremor scores in the <unk>.

Her limbs and the 10 to 12 range do things they tend to have a lot of impairment of their activities of daily living and we also in the data we presented are being 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.

Bernard Ravino: So, you know, as Marcio said, 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.

You know as Marcio said like how much improvement is important may be easier to measure by adl's, but typically people think 20% to 30% tremor improvement is is about where you need to be or more buffer baseline tremor, you'll probably need upper limb scores in the 10 to 12 range to really be able to measure it.

Okay.

Miles Mentor: Okay, that's helpful. Thank you. Our next question comes from Miles Mentor on behalf of 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 aren't?

Okay. That's helpful. Thank you.

Kip.

Our next question will come from the line of Myles Minter from William Blair You may begin.

Marcio Souza: Screening out a huge amount and others that are incorporating more. Yeah, it's actually fairly consistent. So obviously, it varies a little bit here and there. But we're not seeing like one side screen failing like 95% and the other one 5%. That's for sure. Then it's a little bit unusual.

Hi, everyone I'm, just curious as to the 50% screen out right is that consistent across both thoughts in ARIA or you're saying some thoughts that are.

Training out a huge amount and others that are incorporating mall.

Yes.

Yeah.

It's actually fairly consistent for obviously it varies a little bits here and there, but we are not seeing like one five screen phase in like 95% and the other one 5% that's for sure.

The it's a little bit unusually I wouldn't even say even from the feedback from the sites, it's a little bit unusual under review, but it makes us.

Bernard Ravino: I would even say, even from the feedback from the sites, it's a little bit unusual from their view, 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 from their symptoms, and they are obviously not getting it. But it makes us bring some resolution to the thoughts of are we getting the right patients on the trial, as we mentioned before.

Not happy because that aren't the patients out there that arent that spreadsheet participating trials, they want to get really bumped their symptoms and they obviously not getting its ah but makes us.

Bricks bring some resolution two to the thoughts off or are we getting the right patients on the trial as we mentioned before so it's a it's the both sides of that point here, but there is no major discrepancies amongst any of the sites that they were seeing a ride we're not yeah. Yeah. It bothers us. These are all really experience sites there.

Bernard Ravino: So it's both sides of the coin here, but there are no major discrepancies amongst any of the sites that we're 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 deriving what are kind of inappropriate screenings across the board.

<unk> worked with before and so it's not like Oh.

There's.

There's not a SKU of sites driving.

What are kind of inappropriate screenings across the board in all of them.

Bernard Ravino: And a lot of the sites have commented that the COVID environment is just different, and there are, you know, 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. Yeah, makes sense. Let's go on to the next question. This one I get a lot.

<unk> commented that the Covid environment is just different and there there's no screen fail rates are are higher than what they previously seen.

Goes back to emphasizing the importance of <unk>.

Doing this and having that eligibility review process.

Place.

Yeah makes sense.

Now, let's turn to the next question. This one I get a lot of it.

Miles Mentor: Obviously, your peers out there are sort of putting 11 to 13 point placebo response rates on the HAM-D17, and it sounds like you're very confident you're gonna 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, like 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 that, collectively, we're just getting a better, more uniformed patient population and, ultimately, that's what's going to get us into the historic placebo response category? Thanks. Great question, Miles.

So your peers out there sort of putting 11 to 13 point placebo.

Response rates on the Ham D seven nine.

And your it sounds like you're very confident you're going to get much closer to the historic six to eight points. There sorry. When you look at your most important media guide is built into the trial start to shape out or remind us scrapes the safer protocol prior ecocide M today patients like.

Have you actually done work to quantify on a Ham D 17 point basis, what <unk> actually contributes to a placebo response or is it more just the 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 let's say for a response.

Category. Thanks.

Great question. So it's always starts with getting real patients.

Marcio Souza: 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 for MG17, you're not talking about inflation by viewpoint; you're talking about a very huge inflation. One could call it, and I think it's been called in the industry, like there are a lot of professional patients in psychiatric trials, right? So we want to make sure they don't participate in ours.

In the trial I think that's maybe.

The most important thing is it sounds very simple very basic.

But when we gas basins that are when theyre talking about inflation of <unk> 17, or we're not talking about inflation, Mike do you want.

Talking about a very huge inflation, one could call and I think it's been calls.

The industry like Theres, a lot of professional patients and sometimes it drives Brian so want to make sure they don't participate in hours.

Marcio Souza: 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 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 I would call that outliers versus like norms.

They've regretted it means very quickly when they aren't like that.

That's when you see this abnormalities.

Our knowledge there was 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 call that outliers versus like norm.

Marcio Souza: 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 easily guess 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 on the site and then a SAFER interview.

<unk>.

Well when you're looking through everything else, we did probably the idea of having a second confirmation drive like 30, 40% reduction controls. So you would guess easily three four points based on back on using safer and without.

A lot of I'll say, because we have a lot of respect for the folks at mass general that doing this with us, but it's not only statements.

Irrigation in just fine.

And then a safer interview so that's probably the second most important.

Marcio Souza: So that's probably the second most important factor. But you know, in multifactorial analysis, we can never separate the factors. Yeah, 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. When you have really experienced, high-quality sites.

But he's already multi factorial and Amazon, we can that we're sometimes wait the factor.

It is it is true that there is certainly the most data on safer right, but 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.

Do you worry less about rate or training and things like that drift in.

They are their own.

In print 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 are probably the most important.

Yeah.

Okay cool jump back in the queue. Thanks.

Thanks.

Our next question on Sunshine of Douglas Tsao from H C. Wainwright you may begin.

Bernard Ravino: You worry less about radar training and things like that, drift, 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. I'll jump back in the queue, thanks. Our next question on the front line is from Douglas Tsao from H.C. Wayne Wright. He may be

Douglas Tsao: Thanks for taking the questions. Just a first one for me, obviously, there's another competitor that has really emphasized the rapidity of benefit. You obviously, you know, of their drug, and you sort of emphasize 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 those in the early days.

Hi, Good morning, Thanks for taking my questions just a first one for me obviously.

There is another competitor that is really to emphasize the rapidity of benefit you. Obviously, you know of their drug and you are sort of emphasize 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.

The first time point that youre going to be measuring improvements tonight in the handy.

Marcio Souza: And are you, what's the first time point that you're going to be measuring improvements in the in the hand case? Yeah. Hey, Doug, super important question as well. So maybe we start with what we know here. I'll go back and forth with Bernard, right?

Yeah, Hey, Doug fly Super important question as well so maybe just start with what do we know with your and I'll go back and forth with Bernard right.

<unk>.

Marcio Souza: The We're gonna need two or three half lives at least to start seeing something. Our first data points for ARIA are 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 are only so many days patients can be assessed, and should 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 on because that's mechanistically what happens.

We're gonna needs two or three hop lives at least to start seeing something our first data points for ARIA as on date for it.

<unk> got to remember that when he gets very early days in any trial you you enter into something that is value rarely discuss our debates publicly there's windowing.

Meaning there is only so many days patients can be SaaS to be confident in the windows that 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 already.

That is mechanistically what happens I think that's why others have shown much law with a similar mechanism right lads extra synaptic so not exactly the same but but similar similar mechanisms here.

Marcio Souza: I think that's what others have shown as well with a similar mechanism, right? Less extra synaptic activity, 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 like creating the space, There is no condition, preclinically or clinically, that we've seen, or anyone to our knowledge, that says that by treating with Agava-8m, that is partially or very extrasynaptic-preferring, changes biologically the structure or the physiology of the brain.

And as Bernard mentioned in one of the questions. Once you start going down like they rolled off like treating these patients that is no competition pre clinically or clinically that you've seen on any one to our knowledge that say staffed by treaty with hung out by age that is partially arbitrary extras.

Boring chain.

Chains biologically the structure of the physiology of the brands. So it means that we have to continue dosing for as long as the patient needs.

Marcio Souza: So it means that we have to continue dosing for as long as the patient needs it. But it should be pretty obvious, based on some recent trial results, that those curves go back together, and therefore there's no maintenance in 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.

Should be pretty obvious based on some recent trial results that those commscope back together and therefore, there's no medicines in that case, our hypothesis has been from day one.

Needs to three 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 that's why we're going for as we are that we should show that we can treat those patients for a prolonged period of time.

Marcio Souza: 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 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 is an episodic condition.

In that regard, we don't believe on removing the drug to those patients feel like stable until their investigators are theyre treating physicians in the case of Orange markets believes that they are at that stage and all that.

<unk> is not a chronic condition I know, we've called this chronic but depressions and episodic condition.

Marcio Souza: 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 it properly 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 it's going to be training for a long time, 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 treat right now and our safety profile supports it.

And that's why we see some basins resolving them going down in terms of their sometimes overtime.

Reading the episode or not reading property and that's so this is the number one reason why patients have problems. Afterwards, so we're very committed should not getting patients.

To just relax.

On their treatment. So our paradigms is and is going to be drilling for long we are.

I would say on the luxury side that we can we have no restrictions to treat these patients for all for as long as we're trading right now in our safety profile supports it.

Marcio Souza: And that's the way we designed ARIA, really because speed of onset, rapid acting, anti-depressant, and durable effect are both important, and 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 drives the placebo effect up, so the first in person is at one week. But as Marcio said, though, there's like, there are windows around those, and, you know, if you're not tight about the windows, like these bleed into each other.

Okay.

Doug.

The way we've designed ARIA is.

Really because speed of onset rapid acting antidepressant.

In durable effect, they're both important and that's why you know we've got the primary yet.

Two weeks as Marcio said, you know we have the first post baseline assessment.

Dave for which is done virtually because we try not to have too many visits which drive placebo effect up so the first in person visit.

It is at one week as Marcio said, though there's like their windows around those and you know if you're not if you're not tied about the windows like these these bleed into each other so we try and be a real tight about those and get the.

Assessments really right at around those time points, but the way we've designed area is really to reflect.

Rapid onset and then assess the durability of ongoing treatment. So I don't think we're we're choosing in this design and clinically both are very important.

Okay, great and.

Hello.

Yes.

Douglas Tsao: Yep. Oh, 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?

Oh, just a couple of quick follow ups, one just in terms of screening I'm just curious do.

Do you have data in terms of what the cause of most screen failures or is there something that's particular predominant and two when do you anticipate starting a P. P. D study and do you have timing on that.

Marcio Souza: And two, when 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 looks into that every day. Bernard and I and the rest of the leadership team look into it every few days during the week. By far, by a large margin, the screen failure rate is driven by MT17 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, like, compliance with protocol or inability to comply.

Yeah. So we do a rights. We're looking today is basically our team looking to that every day 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 is driven by <unk> 17, not being able to be components.

Which is again.

Would you say or how it's been doing this and then the second just like.

Compliance with protocol or in a village to comply.

Marcio Souza: Some drug abuse, unfortunately, is very prevalent in mental health in general. One more reason to have, like, good drugs to treat these patients. But those are, like, smaller percents, I would say, by a disproportional amount, which reinforces everything we've been talking about, expansion of placebo in other trials and so on if they're not careful about doing that. And your second question about perimenopausal depression. We're looking at this market kind of in two ways.

Drug abuse, Unfortunately is very prevalent.

It'll help me in general one more recent you'll have like good drugs to patients, but those are like smaller percent I'll say by disproportionate amounts of 17 17, I want to reinforce that many people have been talking about expansion on placebo and other trials in saltwater and still not careful on doing that.

And your second question about upper Menopausal depression with.

We're looking to to this markets kind of in two ways. So one recently, we showed very good proof of concept in our view on PMT. It is by all definition of subsets of patients with moderate to severe depression that happens to be on a period of life.

Marcio Souza: 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 on average, where really these women suffer quite a lot about that change.

That is prolonged right about seven years in duration and average where really this women suffer like quite a lot.

About that that changed but didn't want to start looking to the markets. There are two key parameters here one day.

Marcio Souza: But then when you start looking at the markets, there are two key parameters here. One, they don't identify with the depressive parts of a stage but much more with the menopausal parts of the condition, which leads to different treatments, which leads to different potential regulatory pathways. And the second is that there is a constellation of symptoms there or in the mood parameters that we believe we can attack quite nicely with one on four.

They don't identify will stay depressed if part of this stage, but much more with the minimum Basel parts.

The off the condition, which drives two different readers, who drives to a different potential regulatory pathways.

And the second is that he is a constellation of symptoms there.

Or in the moods, alright, emitters, and we believe we cannot back quite nicely with one on <unk>.

Marcio Souza: And it goes from 3 million or so women per year in the US for PMZ to about 9 to 10 million if we consider this other symptom. So from a market perspective, it's quite interesting. We finalized our analysis. We have a goal in terms of how we are looking to develop. Then we have to look in the mirror, at 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 money we have?

And it goes from 3 million or so women per year markets in the last four P. M C.

<unk> nine to 10 million if we consider this other symptoms so from a market perspective is quite interesting.

We finalized the analysis, we have a go to in terms of how we are looking to develop it doesn't kind of looking to ourselves in the mirror to the markets out there.

And asked a question about capital allocation is the right thing it should do in advance of ARIA with the amount of prize. We have so we decided to just hold back for a couple of months.

Marcio Souza: So we decided to just hold back for a couple months to be responsible for 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 the line of Ritu Baral from Calen.

She'll be responsible to how we're allocating capital here and hopefully shortly after our RVO would it be able to respond to that product.

Okay great.

Yeah.

Our next question will come from the line of Ritu <unk> from Cowen you may begin.

Ritu Baral: 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 with Acropala. 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, Acapella is designed, I would say, almost purely to answer a question from a conversation we had with the agency.

Hey, guys. Thanks for taking the follow up.

You asked about the strategy behind having a second dose.

Pursuing them.

First do you anticipate that it will be a lower dose or a higher dose based on what you had seen pre clinically and second like if you just forgot about the preclinical data just answered that from a commercial perspective.

Where do you think the biggest need.

Just given you know psychiatrists are used to titrate them all day long.

So how do you think.

Okay.

Yeah.

Palace is decide I would say.

They almost purely to answer a question from a conversation we had with the agency.

Marcio Souza: 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, 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 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 without any side effects, like be really, really close? 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.

What are you looking for this class and specifically at ball.

One four but I would say this is more of a class effect you increased your exposure in the brain you don't necessarily decrease the symptoms of either anxiety or our resolution of insomnia or card depression, what do we do for certain increase the number of side effects.

So that is a quasi dose proportional war concentration proportional with the call increasing aes, but not necessarily a benefit so rightly. So the question I've got is can you go lower.

Still have the effect, but no side effects like really really clean so what do we know go back to the help volunteers and we dose 10 milligrams 20 milligrams. So one very clean.

Even during the day and that's why they're using those those fourth central tower by the way with one month LIBOR so incredibly clean.

Marcio Souza: And that's why we're using those doses 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.

In terms of the dose response, so it made sense for us to bolt down there now if you extrapolate from the data our data we have.

Marcio Souza: 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, dozing the night before as it's dozed 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 looking as it should. And because this is a mixed population, a little bit lower HMD, 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 in his prepared remarks this morning, there is no expectation of a statistically significant powering for this trial.

Below 20 milligrams are so we shouldn't really have much of an impact if at all for depression dosing denied before as installs on M. D. G. So.

So that shouldn't be the anemia are there for hours are there limits for US then we're going up to the 40 right just to confirm make sure everything is like looking at as it should and because this is a mixed population.

A little bit lower Ham D. It was appropriate to go up to 60, as well and to confirm the hypothesis that dissatisfied is gonna 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 statistical powering for this trial, we should be able to see those trends.

Marcio Souza: We should be able to see those trends. Let's call, like, let's say the 20 mg is actually active and similar to 40. We believe we're going to be pushed to actually add that to a second trial. That would be very transparent with all of you, as we always are. That's the reason for the trial.

But last call like let's say the 20 milligram is actually active and similar to 40, we believe we're gonna be Bush to act on the ads data on a second trial would that'd be very transparent with all of you as we always box. That's the reason for the point that's right yes.

And and enter into the.

Bernard Ravino: As I said, expectations, most antidepressants don't have a dose response effect on efficacy, so it's typically more of a threshold effect. So no, we don't necessarily know that this will be, you know, real dose-related efficacy that would, that would be an advantage in terms of getting that clinical use. So psychiatrists currently do titrate up, but they have very limited data to support that, you know, higher doses across any class of antidepressants are more effective.

To set expectations, most anti depressants don't have a dose response effect on efficacy. So it's typically more of a threshold effect. So.

So we don't necessarily know that this will be you know real dose.

Dose related efficacy that would that would be an advantage in terms of getting that clinical use of psychiatrist currently they do titrate up but they're very limited data to support that higher doses across any class of anti depressants or more effective. So I think if we were to show that it would be.

Bernard Ravino: So I think if we were to show that it would be of tremendous benefit, very useful clinically for people to be able to have a starting dose and know there's more efficacy to gain as they go up. But they currently really are doing it on an individual patient basis.

This benefit very useful clinically for people to be able to have the starting dose and no theres more efficacy to get us that 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.

Ritu Baral: 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 Part B of the 9442A study, I'm just wondering what the definition of the response required to be randomized into the withdrawal portion of that trial is, considering the FDA is asking you to do not only tremor but also activities of daily life. Is it the composite of both of those measures on the Tetris?

I know that started one for a question star one.

Next question a follow up will come from the line of Myles Minter from William Blair you.

You may begin.

Hey, just on the pot Bay of the non full fourth two IDE study.

I'm just wondering what the definition if the response for quad is could be random Austin sort of withdrawal portion of that trial.

Considering the FDA is asking you to do not only trim up but it'll sorry activities. The daily lock is a composite of both of those measures on the Tetris.

Yeah.

Bernard Ravino: Yeah, so we didn't do the randomized withdrawal period of this to include everybody who was treated. And so we didn't do this as a responder group the way you would like for a phase three study. So the question, as we framed it up in our protocol, 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.

Yeah. So we did not is it are the randomized withdrawal period of this will include everybody.

It 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 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 hover miles.

Bernard Ravino: This will, however, give us the data to help us decide if we do want to do a true responder 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.

Give us the data to help us decide if we do want it to be true responders randomize withdraw in the future and I think what we would have to engage with the agency about what the responder definitions are because there arent fixed definitions at.

This point.

Okay.

Bernard Ravino: 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 then nine patients, it's like, what a 40, higher than that, like a 50% response rate, so.

Okay, so its safe to say that.

12 patients will be gone into that randomization stage, regardless of what the dive responded or not and I think judging from what you've previously reported from pop a and then non patients.

Yeah, it's like.

40 <unk>.

Higher than that like a 50% response rate sorry.

Miles Mentor: It's safe to say that 12 patients, some responding, some not, ran out. Exactly. That's correct.

Yeah, it's safe to say that 12 12 patients some responding some not randomized okay.

Yeah, that's correct.

Miles Mentor: Okay, cool. And then the final one for me is just, I did notice in your earlier stage pipeline that you are looking to push more towards pediatric epilepsies, actually solely driving that focus, which I think is great. But can you just talk a bit more about that decision?

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.

Solely dropping that focus.

I think its great, but can you just talk to that a bit more color about that decision and if you do see decent diet or out of the touch eminent neuralgia.

Miles Mentor: And if you do see decent data out of the trigeminal neuralgia studies, like, is that an indication that you'd proceed with, or would you just take that data and try and shape further epilepsy programs out of those assets? Thanks. Yeah, so Miles, the foundation of how we screen drugs here, as we discussed before, right, some of the calls are like offline, have always been used, like genetics, epilepsy models, they're highly projected to efficacy in humans.

Studies like is that an indication that you would presage waste or you would just take that data and try and shape for the epilepsy program satisfies them out of those assets. Thanks.

Yeah. So the foundation of how we screen throughout this year as we discussed before writing some of the calls unlike offline.

Always I use like genetics lapsing models, they are highly project that to efficacy in humans.

Miles Mentor: And we have a number of programs, as you saw in the pipeline; we're a lot more comprehensive today than we were in the past, and they're coming to a point now where we're incredibly excited about them, and we believe they're viable.

And we have rights like a number of programs I just saw on the pipeline, we're a lot more comprehensive too.

Today than we were in the past that we've been like brewing and they are coming to a point now we are incredibly excited about that and we believe they are viable.

Marcio Souza: So for a company, our size, our resources, it made sense to pause and ask what the strategy here is. What is one that the market supports, the regulatory framework is clear, patients are all there. So we are focusing on epilepsy, including common epilepsy right now. Most of those drugs can be used in several conditions.

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 support that regulatory framework is clear patients are all day needs. So we to rack up warranted lapses.

Clothing like common epilepsy, right now but.

Most of those Roes can be using several conditions.

Marcio Souza: So, we're not abandoning CNS. In general, we're just focusing the resources we have towards the highest probability and the highest impact. Now, if the TN or the trigeminal neuralgia, sometimes, you know, the prior is positive, I think there are different avenues.

So we're not abandoning CNS in general we're just focusing the resource we have towards the highest probability of the highest steam back now if the T N or the tourism and a neurologist I'm concerned ill try. It is positive I think there are different avenues that is one that we would continue developments they want that partner.

Marcio Souza: There is one that if we continue development, there is 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 true patients. Get Approval, Get Commercialized.

Once developed with us on those indications if it's more appropriate to that so we'll continue to look into this and the best drugs are the drugs that make two patients to get for approval gas commercialized you've got the right people to do that great. If we're not we're not going to be like <unk>.

Marcio Souza: If you're the right people to do that, great; if you're not, we're not going to be greedy and try to keep that and not do a good job, and that's what this strategy is for. Great, thanks. Thank you. I'm not showing any further questions in the queue at this moment.

And try to keep that and not do a good job and that's what the strategy is sports.

Great. Thanks.

Of course.

Yeah.

Operator: I just want to call back over to Marcio Souza, President and CEO, for any closing remarks. So thank you very much, everyone. And I really hope you enjoyed this format. We think it's fairly efficient, was based on feedback from a lot of you who gave us maybe two remarks. You're incredibly excited about all the progress, and much more to come in the coming months.

Thank you I'm not showing any further questions in the queue at this moment.

Just trying to call back over to Maria Marcio, Souza, President and CEO for any closing remarks.

So thank you very much everyone and I really hope you enjoyed styled this format. We think it's a fairly efficient was based on feedback from a lot of you gave us a.

Maybe to remark here, we're incredibly excited about 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 continue to really use that rare disease framework.

Marcio Souza: Today is Rare Disease Day. As I mentioned, we're very excited about it. Continue to develop drugs for those rare conditions, and 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 where mental health is taking yet another dip. We'll have an active war in Europe, as we all know, and that's always, in fact, how we all feel, and specifically the ones who are our brothers and sisters in Ukraine right now are fighting for their country.

Or rather it is a regulatory framework to get these drugs through.

There's also a moment in the award that mental health is taking yes, another deep havent.

We have an active war.

In like in Europe , as we all know and that's always impacts how we all feel and specifically the wants and our brothers and sisters in Ukraine right now fighting for their country. So I just want to remind you that it is not a simple moments in time mental health is very important we're very committed to help.

Marcio Souza: So I just want to remind you that it is not a simple moment in time. Mental health is very important. We're very committed to helping a world where we recognize and celebrate the healthiness of mental health more, and we're hopeful that in the near future, there will 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 what we are, just brothers and sisters everywhere. So thanks again for joining us, and I look 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. [music]

Award where.

We recognize and we celebrate more b.

Healthiness on the part of the mental health and hope.

Hopeful that in the near future I'm going to be no more like stupid war happening here and there and you're all going to be sitting a lot better about all of us as humanity, because that's why we arent just brothers and sisters everywhere. So thanks again for joining looking forward to stock swallowed view.

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

[music].

Bernard Ravino: So we try and be real tight about those and get, you know, assessments really write them around those time points. But the way we've designed RIA is really, 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. And, hello?