Praxis Precision Medicines Inc (PRAX) 2021 Q4 法說會逐字稿

Good day, and thank you for standing by. Welcome to the Praxis Precision Medicines 4Q and FY 2021 corporate update Q&A call. (Operator Instructions)

I would now 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 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 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 on your questions to provide additional perspective on the updates provided earlier. (Operator Instructions)

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?

(Operator Instructions) And our first question will come from the line of Yasmeen Rahimi from Piper Sandler.

We really like the new format of prerecorded 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 is in the last stretch of enrollment completion and you're looking at the patient population, can you give us an idea of how homogeneous is the patient population that you've gotten into Aria? I know, Bernard, you made some remarks earlier, but if you could just allude a little bit more what you see, what's the standard deviation just in HAM-D17 baseline scores among these populations? Any color that you could see on the baseline that could be helpful?

Yasmeen, thank you so much for the call, for calling in, and I appreciate the feedback as well on the format. So I'll hand over to Bernard, but maybe my quick remark there is it's spot on what we are expecting with a lot of blood, sweat and tears to get there because there was a lot of controls we 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?

Yes, a little bit of color. So our eligibility was HAM-D17 of 23 or higher, right? Typically, people come in a couple of points just above that cut off. And 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, were really working. If we hadn't had those, we would have had a lot of people who either didn't have MDD or didn't have adequate severity. And in terms of standard deviation, so what you really look for is like the change from baseline is the key for the standard deviation for powering, and that's right around where we expected it to be about 7 points. So overall, it looks like the processes and the assumptions that we had when we initially set up the study and powered the study seem to be holding true.

And then 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 on or quite low in response? So I guess what I'm trying to see is, as you're looking at these two curves, placebo and treatment, you're seeing probably a difference between them. But how do we -- how confident can we be that maybe some of those lower HAM-D scores, whether that they would be not -- that they were actually on treatment, not on placebo? So just some commentary around that would be really helpful.

Yes. So yes, if you look back, let's call, the last 30 or so controlled trials ran in moderate to severe major depressive disorder patients, right? And we've got -- going to have [to split] 3 or 4 that have no valid data on the like 2 weeks mark. They are all pretty tight actually on the 2 weeks -- on 1 week, 2 weeks, 3 weeks and so on. the -- 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 HAM-D17 scores, as you just said.

So it is tight. Like we are only looking to blind the data at this point in time. So it's like anything I say here or Bernard says, is going to be pure speculation to be perfectly honest, right? We set up the trial to do something, which is separate that they get seen with an effect size of around 0.4, which would be 3 points on the HAM-D17 adapt on the primary endpoints. We have a target for a number of patients that are required. We're in very good shape for that, completers at day 15 at this point in time. So we feel really good about it.

So historically, as we compare, as we simulate, as we resimulate, historically, we feel really good about it. And that is not a large proportion of patients deviating from the central tendency here, if you were to look. Again, some rare exceptions on trials that we don't consider to be valid, but the majority of that, right? Bernard, anything to add?

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

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

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 4-week window? And then the second question, and I apologize -- thanks for releasing the prepared remarks as well ahead of time. That was wonderful. You discussed some of the changes -- or I'm sorry, some of the changes you saw in the Phase 2a study with respect to HAM-A. And I'm wondering if you could just elaborate a little further on your expectations in Aria for impacts or potential impacts on anxiety. What's your sense in terms of the proportion of patients in the study that might have concomitant anxiety?

We expect -- when you get a population like this that truly has moderate to severe depression, roughly half or so will have high levels of anxiety. There are a couple of different ways to look at it is that you can measure it on HAM-A. Then we had seen was about a 50% improvement or so in HAM-A on average. So I think that's probably a similar expectation.

The other way to look at it, though, is within the DSM, the DSM-5, there's kind of a subcategory for people who suffer from anxious distress as part of their depression. So we've been looking at that all the way along in our Phase 2a study, it 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. And 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 HAM-D in and of itself nicely reflects that in terms of anxiety items and sleep items. So there are a number of different ways to get to that construct. But fundamentally, like anxiety levels in moderate to severe depression are just intrinsic part of it.

And on the compliance part, Laura, that you asked, right? So we use like a number of things. First, it starts with getting the right patient. One of the key -- we talked a lot about the #1 reason why patients [and gaps to] after the trial, like that was failure to confirm for the severity for HAMD-17. But shortly thereafter, was the assessment by the investigator that patients wouldn't comply with this schedule, which is quite important, talked about how our investigators, the ones that are really like in the field helping us make this trial a reality, were taking that so seriously.

So it starts there. Then throughout the study, that is a number of like parameters and systems we put in place. Now this is a relatively long study when you think about [GABA-A PAM], right? So we're talking about 28 days of dosing, another week of observation after that. So I 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 standard 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. They customized the version with 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 had 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 are confident with the patient population. But it's not one thing. It's a constellation of different parameters here to drive good compliance to drug and to procedures because it has to be both of them.

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

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

Sounds good. So thanks. There's a number of things here, right, that we have to consider. Maybe I will start with the safety part. So when we chose the 40 milligrams to go on a daily dose nightly, our hypothesis then, which [affirms] on a number of things that we did internally, is drive beta power, which is the best surrogate we have here for the drug being in the brain. And it's still like not creates that state of sedation or somnolence that is incapacitating. That is next day or is really the patient cannot stay functioning. So that was a key thing for us. We're, again, very happy with what we are seeing so far, it seems to be panning out and you're going to see in a couple of months, I guess, the results.

In terms of the effects, when you put all those controls in place, when you believe the drug works as we do, then you should expect that the trial is going to behave as it should behave, that means placebo will decline like between 0 and whatever time point at the end is, in a controlled way, not on a like erratic or discontrolled way. And that means that the expectation is 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. Because we expect drug to be much larger decline, while the expectation from the FDA on the conversations we have and from ourselves, it's not that it would necessarily maintain statistical significance at day 29. It's quite possible it will.

And because like everything we're seeing, what 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 there's, I would say, a very reasonable chance that you're going to see not only a separation that is numeric, also one that is statistical significance at day 29, which we're going to report. We're going to report HAMD-17 at day 15, at day 29, global impression on day 29, obviously the safety profile or the visits, how the patients went and everything else that we have in the queue if we have time to process that, we're going to be showing as well. But those are the key things we're planning to show, that they should give a very comprehensive feel of the drug viability and enable conversation for us with the agency and starting a Phase 3 later this year, second registrational trial later this year. That's where we are aiming for the program.

Ritu it's a good point to reiterate too that we're talking about maintenance of effect on treatment. And our experience in our Phase 2a study, we tried both stopping treatment after 2 weeks as well as continuing it for the full 4 weeks. And what we saw very clearly is when you discontinue, you do get -- you lose 1.5, 2 points over the subsequent 2 weeks versus maintaining the effect when we treat it over 4 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've got to continue the drug and be able to treat through an episode.

Our next question comes from the line of Tazeen Ahmad from Bank of America.

Maybe I'll focus on Essential tremor. So you've got the Essential1 study that's reading out this year, the Phase II top line. Can you just talk us through what information we should expect to see when that data set does come through? And as far as the 3 doses that you're studying, 20, 60 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.

So thank you so much, Tazeen. Like, there are 3 readouts for Essential tremor right now, right? What we're coming up with the final cohort for the Phase II with the randomized withdrawal, which we're going to be reporting in May, then the 114 study in Essential tremor and Essential1. And I know your questions were centered on the Essential1. 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 3 shortly thereafter.

Yes. Yes, so Essential1 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 3 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 -- what we'll look at there in that landscape has been evolving. The focus is on activities of daily living, along with the modifications, the scoring that the agency has suggested. We will, of course, look at measures of tremor. And we talked about the importance of objective measures of tremor given that there's some challenges in just the visual inspection and floor affects the way it's done in the TETRAS. So we'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 ranging, a dose response on efficacy on those measures we talked about. Whether or not it will be linear or it will cap out at around 60 milligrams, we don't know. But that's really the question for the trial. We know sigma band tells us mechanistically about dose response, but we don't know how that translates into tremor reduction and function. So that's honestly exactly the question we'll answer. And I think we'll be really well positioned with the data we'll get out of Essential1.

Okay. You are pursuing 114, as Marcio mentioned as well, in Essential tumor. So what is your long-term strategy in ET? Are you going to pick one or 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 look into the market, right, and one of 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 a familial cases 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 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 are very significant amounts as well as they just need that for a couple of hours in a day when they're performing given tasks. And then you have the more progressed in disabilities that need that all the time.

So there are really three major opportunities for us here. 114 is 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. We get to Tmax around 2 hours or so, so it's predictable. You're going to have a reduction of the tremor, you're going to feel better and move on or you can stay on the drug if that's the case.

Then you have 944 that requires titration. It's a more long-term treatment. It's for someone that has decided to stay longer. And something we have not pursued right now but we intend to is to combine those treatments. So now we have three potential options, right? The markets -- currently, our estimation is about 3 million patients. We are the only company with multiple mechanisms on this. We're going to -- we understand the market, we're seeing better than pretty much anyone else out there, so it allows us to have a moat -- 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 on how we develop these molecules. 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 believe we can, we're going to move on, we're going to continue, going to develop. If we cannot, you have our assurance that we're going to move on from the molecule as well. And then we have 944 for that matter.

Okay. And maybe to wrap it up, Marcio. For Essential1, what type of a TETRAS score would you consider to be clinically meaningful?

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

Yes. Yes. And then a couple of different points in terms of what tremor is meaningful, what we see. It varies a lot, patient to patient. But what we see just in terms of eligibility, and we think of this similar way as we talk about HAM-D 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, two things: they tend to have a lot of impairment in their activities of daily living. And we also, in the data we presented in Part B and in Part A, so far, we see those people have pretty robust improvements because they have enough tremor they can reliably measure change. So as Marcio said, like how much improvement is important? It 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.

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

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

Yes. Myles, it's actually fairly consistent. But obviously, it varies a little bit here and there. But we are not seeing like one site screen fading like 95% and the other one, 5%. That's for sure. The -- it's a little bit unusual. I would even say that from the feedback from the sites, it's a little bit unusual on 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 of their symptoms and they're obviously not getting it.

But makes us -- bring some resolution to the thought of, are we getting the right patients on the trial, as we mentioned before. So it's both sides of the coin here. But there is no major discrepancies amongst any of the sites that we're seeing, right, Bernard?

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

Yes, makes sense. Let's go on to the next question. This one I get a lot. Obviously, your peers out there sort of putting 11 to 13-point placebo response rates on the HAM-D17. And you're -- it sounds like you're very confident you're going to get much closer to those historic 6 to 8 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 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?

Great question, Myles. So it always starts with getting real patients in the trial. I think that's maybe the most important thing, right? So it sounds very simple, very basic. But when we get patients that are -- when we're talking about inflation of HAM-D17, we're not talking about inflation by a few points, talking about a very huge inflation, one could call, and I think it's been called, in the industry like there's a lot of professional patients in psychiatry trials, right?

So we want to make sure they don't participate in ours. They regress to the mean very 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 7 or 8 points, and they're all very recent and they're all from the same sponsor.

So I would call that outliers versus like norm. The -- when you look into everything else we did, probably the idea of having a second confirmation drives like 30%, 40% reduction in control. So you would get easily 3, 4 points just 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 is a verification in the site and then a SAFER interview. So that's probably the second most important. But in multifactorial analysis, we can never tell...

Yes. 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, Myles, but it's having the right people at the table. And so like when you have really experienced high-quality sites, you worry less about rater 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.

Our next question will come from the line of Douglas Tsao from H.C. Wainwright.

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

Yes. Doug, a super important question as well. So maybe we'll start with what we know here, and I'll go back and forth with Bernard, right? The -- we're going to need 2 or 3 half lives at least to start seeing something. Our first data point for Aria is on day 4. You've got to remember that when you get very early days in any trial, you enter into something that is very rarely discussed or debated publicly, there's a window in, meaning there is only so many days patients can be assessed to be, considered in the window.

So we have to force a window, which we don't like to do for those early days. But we should expect to see separation pretty early. That's mechanistically what happens. I think that's what others have shown as well with a similar mechanism, right? Less extrasynaptic, so not exactly the same, but similar mechanisms here.

And as Bernard mentioned in one of the questions, once you start going down like the road of like treating these patients, there is no condition, preclinically or clinically, that you're seeing or anyone to our knowledge that says that by treating with a GABA-A PAM that is partially or very extrasynaptic preferring change biologically the structure, the physiology of the brain.

So it means that we have to continue dosing for as long as the patient needs. Like it should be pretty obvious based on some recent trial results that those curves go back together. And therefore, there's no maintenance on that case. Our hypothesis has been from day 1 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 3 and 6 months.

And if that's what we're going for, as we are, then we should show that we can treat those patients for a prolonged period of time. So in that regard, we don't believe on removing the drug until those patients feel like stable, until their investigators or their treating physicians, in the case of going to market, 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. 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, this is the #1 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 if it's going to be treating for long, we are -- I would say we're on lucky side that we can. We have no restrictions to treat these patients for as long as we are treating right now, and our sales profile supports it.

And Doug, the way we designed Aria was really because speed of onset, rapid acting antidepressant and durable effect, they're both important. That's why we've got the primary at 2 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. So the first in-person is at 1 week.

As Marcio said though, there's like there are windows around those. And if you're not tight about the window, it's like 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.

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 particularly predominant? And two, when -- do you anticipate starting a PTD study? And do you have timing on that?

Yes. So we do, right? We're looking to this. Basically, our team look into that every day. Bernard and I and the rest of the leadership team look into this every few days in the week. By far, by a large margin, what the screen failure rate is driven by HAM-D17 not being able to be confirmed, which is against, I would say, for how we've been doing this.

And then the second is like compliance with protocol or inability to comply. 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 percent, I would say, by a disproportional amount in HAM-D17, which reinforce everything we've been talking about, expansion on placebo in other trials and so on if they are not careful on doing that.

And your second question about perimenopausal depression, we're looking to this market kind of in 2 ways. So one, originally, we show very good proof of concept in our view on PMD. It is, by all definition, a subsets of patients with moderate to severe depression that happens to be on a period of life that is prolonged, right? About 7 years in duration in average where really women suffer like quite a lot about that change.

But then when you start looking to the market, there are 2 key parameters here. One, they don't identify with the depressive parts of this stage, but much more with the menopausal part of the condition, which drives to different treaters, which drives to different potential regulatory pathways. And the second is there is a constellation of symptoms there or in the moods parameters that we believe we can attack quite nicely with 114.

And it goes from 3 million or so women per year market in the U.S. for PMD to about 9 million to 10 million if we consider these other symptoms. So from a market perspective, it's quite interesting. We finalized those analysis. We have a go-to in terms of how we are looking to develop. Then we got to look into ourselves in the mirror, to the markets out there and ask the question about capital 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 are allocating capital here. And hopefully, shortly after Aria, we are going to be able to restart the trial.

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

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

Yes. The -- Acapella is designed, I would say, almost purely to answer a question from a conversation we had with the agency. When you look into this class and specifically about 114, but I would say this is more of a class effect, you increase the exposure in the brain. You don't necessarily decrease the symptoms of either anxiety or resolution of insomnia or core depression. But we do for certain increase the number of side effects.

So that is a quasi-dose proportion or concentration proportion, I would call, increasing the ease, 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 they're really, really clean? So what do we know? We go back to the [healthy] volunteers and we dose 10 milligrams, 20 milligrams so on, very clean even during the beta. And that's why we're using those doses for Essential tremor, by the way, with 114. So incredibly clean in terms of the dose response.

So it made sense for us to go down there. Now if we extrapolate from the beta power data we have, below 20 milligrams or so, we shouldn't really have much of an effect, if at all, for depression, dosing the night before as it does on MDD. So that should be the linear there for us or the limits for us. Then we're going up to the 40, right, just to confirm, make sure everything is like looking 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 the side effect is going to be proportional but not necessarily any additional effect.

So it's a true exploration of the dose range. As Bernard mentioned on his prepared remarks this morning, there was -- there is no expectation of a statistical like powering for this trial. We should be able to see those trends. But let's call, like, let's say, the 20 milligrams is actually active and similar to 40. We believe we're going to be pushed to actually add that on a second trial. That would be very transparent with all of you, as we always are. That's the reason for the trial.

Yes. And I'd add, Ritu, to set 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 a dose-related efficacy. That would be an advantage in terms of we're getting that clinical use. So psychiatrists currently, they do titrate up, but they have 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.

(Operator Instructions)

Our next question or follow-up will come from the line of Myles Minter from William Blair.

Just on the Part B of the 944 2a study. I'm just wondering what the definition of the response required is to be randomized into the withdrawal portion of that trial, considering the FDA is asking you to do, not only tremor, but also activities of daily life. Is it the composite of both of those measures on the TETRAS?

Yes. So we did not -- the randomized withdrawal period of this will include everybody who was treated. And so we didn't do this as a responder group the way you would like for a Phase 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 to do a true responders randomized withdrawal in the future. And I think what we'd have to engage with the agency about what the responder definitions are because there aren't fixed definitions at this point.

Okay. So it's safe to say that 12 patients will be going into that randomization stage regardless of whether they responded or not? And I think, judging from what you've previously reported from Part B in the 9 patients, yes, it's like, what, a 40 -- no, higher than that, like a 50% response rate. So it's safe to say that 12 patients, some responding, some not, randomized? Okay.

Exactly. That's correct.

Okay. Cool. And then the final one for me is just I did notice for 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 to a bit more color about that decision? And if you do see decent data out of the trigeminal neuralgia studies, like is that an indication that you'd proceed with? Or you would just take that data and try and shape further epilepsy programs out of those assets?

Yes. So Myles, the foundation of how we screen drugs here, as we discussed before, right, in some of the calls like offline has been always used like genetics, epilepsy models. They are highly projected to efficacy in humans. And we have like a number of programs, as you saw in the pipeline, were a lot more comprehensive today than we were in the past, and we've been like brewing and they're coming to a point now, we're incredibly excited about them, and we believe they're viable.

So for a company our size, our resource, it made sense to pause and to ask what is the strategy here? What is the one that the market supports, the regulatory framework is clear, patients are all that it needs. So we direct towards epilepsies, including like common epilepsy right now. But most of those drugs can be used in several conditions. So we're not abandoning CNS. In general, we're just focusing the resource we have towards the highest probability and the highest impact. Now if the CN or trigeminal neuralgia [symptoms] trial is positive, I think there are different avenues. There is one that we would continue development. 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 to patients, to get for approval, get commercialized. If you have the right people to do that, great. If you're not, we're not going to be like greedy and try to keep that and not do a good job. And that's what the strategy is for.

Thank you. I'm not showing any further questions in the queue at this moment. I'd like to turn the 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. It was based on feedback a lot of you gave us. Maybe 2 remarks here. We're 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 it, continue to develop drugs for those rare conditions, continue to really use the rare disease framework -- or the rare disease regulatory framework to get these drugs approved.

But there's also a moment in the world that mental health is taking yet another dip. We have an active war in -- like in Europe as we all know. And that always impacts how we all feel, and specifically the ones and our brothers and sisters in Ukraine right now are fighting for their country. So I just want to remind that it is not a simple moment in time. Mental health is very important.

We are very committed to help a world where we recognize and we celebrate more the healthiness on the part of the mental health. And we're hopeful that in the near future, there are going to be no more like stupid wars happening here and there. And you're all going to be feeling a lot better about all of us, the humanity because that's what we are, just brothers and sisters everywhere.

So thanks again for joining, looking forward to talking to all of you.

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