Praxis Precision Medicines Inc (PRAX) 2021 Q3 法說會逐字稿

Good day, and welcome to Praxis Third Quarter 2021 Update Call. As a reminder, this call may be recorded.

I would now like to turn the call over to Alex Kane, Vice President of Investor Relations and Corporate Communications.

Thank you. Good morning, everyone, and thank you for joining us today to discuss Praxis Third Quarter 2021 Corporate Update.

With me on today's call is our President and Chief Executive Officer, Marcio Souza; our Chief Medical Officer, Bernard Ravina; and our Chief Financial Officer, Tim Kelly. Please note that today's prepared remarks will focus on recent business and pipeline progress, along with a brief update on our third quarter 2021 financial results. We will be referring to supplement slides throughout today's prepared remarks, which are posted on the Events and Presentations section of our Investor Relations website. So please access them now if you have not already done so.

Before we proceed, I would like to remind you that during today's call, we will be making certain statements that are beliefs, forward-looking, and subject to various risks and uncertainties. Any statements made during this call that are not statements of historical or current facts are intended to be forward-looking statements pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.

We want to emphasize that such forward-looking statements reflect our current expectations, assumptions, and currently available data regarding, among other things, our business operations, development efforts, and regulatory strategy and are neither predictions nor guarantees of future events. Actual results could differ materially from those stated or implied by these forward-looking statements due to risks and uncertainties associated with our business. For additional detail on the risk factors associated with our business, I encourage you to consult the detailed forward-looking statements disclaimer on Slide 2 of the supplement slides as well as our SEC filings.

I will now turn the call over to Marcio. Marcio?

Thank you, Alex, and good morning, everyone. Thanks for joining the call today. It's great to be here, and we are glad to share our recent progress and what's to come with all of you. Last month, Praxis celebrated its 1-year anniversary as a public company on the NASDAQ Stock Exchange. Looking back at where we were a year ago, it's natural to take inventory for how far we have come. As a company, we've been able to make significant progress towards the goal of bringing a number of CNS drugs to people in needs and have positioned Praxis to be able to do it over and over again. We have a saying here at Praxis and one that you'll hear more and more in the coming months, "dare for more ".While we are proud of how far we've come in the past year, we dare for more in every aspect of what we do, from ourselves, and our everyday work, to the patients we are working so hard for, and across the portfolio we are building and advancing every day.

Praxis foundational approach to drug development is the key to our ability to advance multiple programs so efficiently. This foundational approach is based on 4 pillars, which you'll see on Slide 3, and they underlie each one of our programs. First, we validate targets through genetics. While these principles apply to all our programs, our lead preclinical program and ASO candidates, PRAX-222, provides an ideal example. PRAX-222 targets mutations in the SCN2A gene, which can cause a rare and devastating epileptic encephalopathy. The second pillar draws upon the genetic findings and leverage translational tools such as electroencephalogram, or EEG, which help inform developments by, for example, supporting dose selection and indicating whether the drug is reaching its targets. Bernard will highlight this more in-depth later when he reviews the initial EEG findings from our PRAX-562 program.

The third pillar leverage these learnings and apply them to rigorous and efficiently executed development paths to proof of concept. The recent positive trial results for PRAX-114 provide a strength signal in perimenopausal depression or PMD, supporting our decision to move forward with the Phase IIb study in women with menopausal and mood symptoms. Finally, the fourth pillar is about implementing patient-guided development strategies. Ultimately, this encompass everything we do at Praxis, from early-stage research into late-stage developments and eventually commercialization. Patient-guided developments is particularly evident in our lead programs, PRAX-114 in MDD, and PRAX-944 in essential tremor, which could both address significant unmet needs for people living with these disorders.

For PRAX-114, the potential of a fast-acting antidepressant that takes days, not weeks or months, to show the effects, combined with improved tolerability relative to the existing therapies, would certainly be meaningful for people suffering from depression. For PRAX-944, the potential of a new treatment option, ideally developed to be given at daytime when tremor impacts patient activities the most, holds significant promise. The foundational approach has led to a diverse pipeline that is quickly progressing and growing as you can see on Slide 4. I will point out each of our 3 clinical programs that's current and/or soon to be in trials in multiple indications, which highlights the considerably expansion possibility within our existing portfolio.

In addition, our preclinical pipeline is advancing, and we anticipate the first inpatient trial of PRAX-222 to initiate in the first half of next year, which would add a fourth program to our portfolio. The maturation of the portfolio is well represented by the following slides, which shows how we expect to have 6 placebo-controlled trials active by the end of 2021. This includes the ongoing PRAX-114 registration trial, Aria, in monotherapy MDD and a dose-ranging Acapella Study; and PRAX-944 Essential1 Study in ET that recently initiated. This quarter, we expect to initiate Phase II studies for PRAX-114 in essential tremor and PTSD, as well as Phase II first-in-patient studies for our third clinical program, PRAX 562, which will focus in rare adult cephalgias.

Slide 6 clearly illustrates what this foundational approach has led to, a catalyst-rich period with readouts upcoming for each of our clinical-stage programs in the coming year. Bernard will discuss these trials in-depth momentarily. Prior to passing the call to Bernard, I wanted to share that we'll be hosting a Movement Disorder Day in New York City on Friday, December 17th. As you can imagine, with multiple programs and trials ongoing in essential tremor, the focus will be on our efforts there.

We're also going to highlight the opportunities for PRAX-944 as a nondopaminergic treatment for the motor symptoms in Parkinson's disease and discuss why this is just the beginning for our movement disorders franchise. For ET, you can expect a comprehensive view of our clinical results today and a look into our market assessments. You'll hear more about the burden faced by people living with essential tremor and will also provide updates on the developments and regulatory paths for our ongoing efforts with both PRAX-944 and 114. We're excited to be leading the first advanced in pharmacological treatment for essential tremor in over 50 years.

Following our Movement Disorder Day in December, we'll be hosting a Rare Disease Day and Psychiatry Days in the first half of next year. While there is much to look forward to in the remainder of this year, 2022 result is shaping up quite nicely to deliver on our promise to patients and all stakeholders. In the first half of the year, we expect topline results from our ongoing PRAX-114 trials in depression and anticipate starting a Phase III study in MDD later next year. We'll also share topline results in the first half of 2022 for the PRAX-562 ASSR biomarker study, which is currently dosing in the United States. Furthermore, in the first half of '22, we plan to initiate a Phase II study for PRAX-944 in Parkinson's disease and a Phase II trial for PRAX-562 in DEEs, marking the second indication for each one of those programs.

Finally, we expect to restart the Phase I/II trial for PRAX-222 in the first half of next year, which will be the first inpatient study for this program and would be the first ASO in Praxis portfolio to reach the clinical stage. In the second half of 2022, we can expect topline results from PRAX-114 in PTSD and ET. Also, we plan to provide topline results from our ongoing PRAX-944 Essential1 Study in ET, which would allow us to initiate a PRAX-944 Phase III trial in ET before the end of 2022. As you can see, we fully intend to keep up the pace to progress throughout our portfolio.

I'll now pass the call over to Dr. Ravina to walk you through our ongoing and upcoming studies as well as provide a look into PRAX-562 Phase I healthy volunteer data, which we just completed. Bernard?

Thanks, Marcio. To echo Marcio's comments, it's great to be here with you. I'm looking forward to providing more perspective on our clinical studies and the progress we've made this quarter. On Slides 8 and 9, we've included the trial designs for the ongoing PRAX-114 Aria and Acapella studies. Both trials are currently enrolling, and we're confident in delivering topline results in the first half of next year. Most of you have seen these slides before. So instead of reviewing all the details, I wanted to briefly call out an important aspect of the trial design for both studies. As you can see, the primary endpoint for these trials is after 2 weeks, but the blinded treatment period continues out for 4 weeks.

This is critical for 2 reasons. First, we believe that 114 will work rapidly to resolve depressive symptoms, and that patients need to be treated through an episode of depression to ensure resolution and prevent relapse, whether that episode is several weeks or several months. The design was completed in consultation with the FDA, and we believe would allow for demonstration of both fast onset and support longer-term treatment with PRAX-114. Second, this design is expected to dampen the placebo effect and thereby help separate signal from noise. Placebo effect tends to be maximal towards the end of the treatment period, and in the case of the Aria and Acapella studies, the end of treatment period is 2 weeks after the primary endpoint.

Moving on to Slide 10. Consistent with our focus on psychiatry, we anticipate starting a Phase II proof-of-concept study of PRAX-114 for the treatment of PTSD in the fourth quarter of '21 with topline data to come in the second half of '22. PTSD impacts an estimated 11 million adults in the U.S. alone, and there is a marked and growing need that we believe could be addressed by 114. There's a strong rationale for 114 in this indication based on its mechanism of action and the clinical profile we've seen to date. And while we're well aware of the historical challenges in developing treatments for PTSD, we're confident in our approach here.

A natural role of neuroactive steroids like PRAX-114 is in mediating the response to stress. Deficits in GABA and neuroactive steroids have been documented in patients with PTSD and correlate with clinical symptom severity. Also, PRAX-114 has shown benefits in stress-induced preclinical models of depression and PTSD. Finally, the rapid onset antidepressant and anxiolytic effects, as well as the improvement in sleep seen with 114 in depression, would be clinically very important if replicated in PTSD.

Next, I'd like to discuss our PRAX-114 essential tremor study. We believe that people with ET need a medication that is well tolerated so they can function throughout the day. The goal of this trial is to determine if 114 can improve tremor without tolerability issues when taken during the day. Our preclinical data in the harmaline model of tremor and EEG measures in humans suggests that exposures that correspond to human doses of 10 and 20 milligrams may be effective for tremor. It's important to note that this dose range was well tolerated during the day in previous healthy volunteer studies. This trial is designed as a 3-way crossover of a single dose of 10 or 20 milligrams of 114 or placebo. And this study will allow us to select the dose and regimen of 114 for subsequent trials.

We're fortunate to have 2 distinct mechanisms to address the large ET population, which has a range of treatment needs. In our lead movement disorders program, PRAX-944, we've made good progress across 3 clinical trials for ET. We previously reported dose-related pharmacodynamic effects of 944 on EEG from about 5 to 120 milligrams, suggesting a broad therapeutic range. In Part A of our Phase IIa PRAX-944 study in ET patients, which assess doses of 20 and 40 milligrams, we saw a reduction in tremor amplitude in the arms of over 40%.

We'll report preliminary open-label ET data from Part B later this year, assessing doses of up to 120 milligrams titrated over about 4 weeks. Complete data from the open-label and the randomized withdrawal period of Part B will be released in the first half of '22. In parallel to these studies, we've assessed the safety and tolerability of up to 120 milligrams of PRAX-944 in a faster 10-day titration regimen in healthy volunteers in the Phase I study. This faster titration regimen confirmed the previously reported safety profile with no SAEs or dose-limiting toxicities. And we believe the results of this study will support flexibility in dosing for ET patients going forward.

Based on the overall safety profile, pharmacodynamic effects, and encouraging preliminary efficacy, we've initiated the Essential1 Phase IIb trial. Essential1 is a randomized, double-blind, placebo-controlled dose-ranging trial that will assess the safety, tolerability, and efficacy of 20, 60, and 120 milligrams of 944 in patients with moderate to severe ET. We expect topline data from this study in the second half of next year, which will support the design of our Phase III trials expected to start before the end of '22.

Moving on to our rare disease portfolio, we've completed the Phase I SAD, MAD and food effect studies for PRAX-562. Consistent with the mechanism of action and our preclinical data, 562 was well tolerated. Over 14 days of dosing, there were no drug-related SAEs or severe AEs. Over 90% of the treatment-emergent adverse events were mild, and they were generally transient around the time of Cmax. PRAX-562 showed generally dose-proportional PK. Peak concentrations were seen 2 to 3 hours after dosing when we observed the half-life of 4 to 5 days with no appreciable food effect. The highest single dose of 562 studied was 150 milligrams and the highest multiple dose was 120 milligrams for 14 days. Importantly, we achieved exposures that are well in excess of those needed for efficacy based on the preclinical data in epilepsy models. Additionally, we saw a dose-related trend and over 50% reduction at the highest dose of 562 on our exploratory biomarker of auditory steady state response.

As with our other programs, we've used EEG to measure effects on ion channels. And in this paradigm, we measured the EEG response to an auditory stimulus. These clinical findings on ASSR are consistent with our preclinical data, where ASSR changes tended to occur at exposures well above the EC50 in epilepsy models. We've started a follow-up healthy volunteer study in the U.S. intended to confirm and extend the ASSR pharmacodynamic findings over 4 weeks of dosing, which will approach steady-state concentrations for 562. We expect to report topline results from this trial in the first half of '22.

The Phase I data and the ongoing follow-up study give us confidence in the safety and tolerability profile of 562 in what we believe is a therapeutic dose range. Based on these encouraging data before the end of this year, we plan to initiate a Phase II trial in adult cephalalgias with a cohort of SUNCT and SUNA patients and a cohort of trigeminal neuralgia patients. We also plan to start PRAX-562 Phase II trial for the treatment of developmental epileptic encephalopathies or DEEs in the first half of '22. As you've heard, there's been tremendous progress across our portfolio. We're excited to report our continued progress in the coming months as we read out a number of these trials.

I'll now turn the call over to Tim for an update on the financials for the quarter. Tim?

Thanks, Bernard, and good morning, everybody. I'm glad to join you all today. I will focus on the key financial updates for the third quarter and would refer you to this morning's press release and our 10-Q on file with the SEC for a comprehensive review of the third quarter financial results. As of the end of the third quarter, Praxis had $314 million in cash and investments, which is expected to fund operations into the second quarter of 2023 and through the trials and data readouts discussed on today's call. This compares to $339 million as of the end of second quarter of 2021, a quarter-over-quarter decrease of approximately $25 million. With the breadth of portfolio that Praxis has developed, one way that we dare for more is through leveraging our strong cash position efficiently and effectively to advance the quickly growing pipeline.

Operating expenses for the third quarter were approximately $44.8 million, an increase of roughly $8.3 million from the prior quarter, which is in line with our internal assumptions on expense growth as our portfolio advances. The quarter-over-quarter increase in operating expenses was primarily driven by higher R& D expenses during the third quarter related to ongoing and soon-to-be-initiated clinical trials. These R&D expenses comprised roughly 75% of third quarter operating expense and approximately 89% of the growth from the second quarter, with the remainder being G&A expenses. The difference in operating expenses and cash and investments quarter-over-quarter was primarily due to an increase in R&D accruals as well as non-cash charges for stock-based compensation expense.

I'll now turn the call back to Alex to cover Q&A with the operator.

Thanks, Tim, and thank you to everyone (technical difficulty) today. (Operator Instructions) With that, operator, please feel free to open up the line for questions.

(Operator Instructions) Our first question comes from Ritu Baral with Cowen.

I wanted to ask about how you're looking at some of the other endpoints in the Aria and Acapella study. You guys did walk us through why you're anticipating placebo being mitigated. But one of the other GABA agents has decided, in a different trial design, to elevate day 3 as well. Are you going to be considering elevating day 3? Does that make sense given the chronic treatment paradigm and these 2 studies? How do you think about those sort of ultra-fast early time points?

Thank you, Ritu. Thank you so much for the question, and nice to hear from you. So let's maybe go back and remind everyone about what's the expectation here, right, for these trials. From our perspective, we've been pretty consistent on how we see the development of GABA agents for depression. So we expect them to start acting fairly fast. So in that regard, it makes sense to see -- as we discussed on the prepared remarks, just see an action pretty fast, like in a matter of days. But we do expect that effect to maximize anywhere around like 7 to 10 days or so, as we've seen before.

But quite importantly, we also expect that patients will only benefit, truly benefit, or holistically benefit, if I may, if we keep then on drug for longer, right? And that's what Bernard discussed a little bit on his part of the script today. In terms of going for this 4 weeks as our trial, and that would allow us to actually dose for even longer in the commercial setting, if we ever get there. Hopefully, we will. So we don't have any plans to maybe to be a little bit more pointed on your question. We don't have any plans to change the endpoints right now. Those were based on the preclinical and clinical data we have and on the treatment rationale. They were well discussed with the FDA, and we believe they are the right way to treat depression. We're not trying to salvage this trial. We're trying to guess that to be registrational and to help patients in needs.

Our next question comes from Yasmeen Rahimi with Piper Sandler.

Team, maybe a good place to start would be just to understand sort of what -- as you pointed out, in the Aria study, your key secondary endpoints are going to be at day 29 as well. So patients are dosed for over a month. I guess, what do we know about sort of the cadence of somnolence and sedation when we look between treatment duration at week 2 versus continued duration over to 1 month? And I think that's going to be really important because a lot of investors might be taking the data from Aria and compare to maybe other classes that are currently in developments. So if you could just provide some commentary how we should be thinking about it, that would be very helpful.

Absolutely. And yes, I'm going to ask Bernard to discuss the safety profile that we see on 114 and address your question.

Yes. Thanks for the question, Yas. Yas, as you've seen before, we have a very well-tolerated profile overall, and we believe that's due to the relative preference at extrasynaptic GABAA receptors versus synaptic. We really have not seen anything like next-day somnolence in our depression population or in the healthy volunteers who were dosed. So it's been very well tolerated across the board. There is a little bit of a hypnotic effect at nighttime, which is desirable, but it's short-lived around Cmax. In terms of where it occurs, with respect to the dosing interval, it's variable. In general, we tended to see people experiencing somnolence if they were going to upfront, but it can recur overnight. So we don't see any tolerization to treatment effect. So again, it generally occurs upfront if people are going to have that side effect, but it can last through the dosing period. I think we certainly have not seen any pattern of accumulation or worsening as people continue to take it.

And then I apologize. Just a quick follow-up in regards to the upcoming open-label cohort from 944 that's expected in this quarter. Is -- just kind of remind us, right, like how many patients -- what type of data should we be seeing? What -- how should we be looking at this upcoming data set? Are we looking for consistency versus the 6 patient data that we have seen so far? So if you could just orient that ahead of this catalyst could be very helpful for us.

Yes. Thanks a lot. So we'll be presenting data from the open-label portion of Part B, so up to 120 milligrams. And then in the first half of next year, we'll have the complete data set of the randomized withdrawal. So there'll be some placebo comparator there. What we'll be looking for and what we'll be presenting is really the same kind of data you saw from Part A with a focus on upper limb tremor. We think that's the most important aspect of tremor and the most reliably measured. In terms of what we are looking for out of the data, this was really overall meant as a safety check for us in terms of titration on higher doses. We've seen -- what we have seen at 40 milligrams was really very robust improvement of tremor control in the hands, just over 40%. We may or may not see more than that in a small cohort like this. But certainly, 40% or in that ballpark, similar to what we saw with 40 milligrams would be very consistent and certainly enough to move forward with.

And maybe, Yas, just to add for part of your question about the patient numbers that we expect. So as we mentioned before, we expected to enroll 12 patients in this cohort. Like it's probably obvious that we did, and we're like moving these patients along to get the results later in the year to discuss on November -- December, apologies for that, December 17, New York. We're going to give a comprehensive view about the program, including any other data that we might have at that point in time to inform -- I just want to go to that part of the question saying we're incredibly pumped about this. We're super excited about 944 and the potential it has.

Great. We're looking forward to seeing you in New York.

Likewise.

Our next question comes from Laura Chico with Wedbush Securities.

I guess I'll stay on the 114 track. One question for you on the Acapella Study, and I apologize if I missed this in the opening remarks. But could you remind us kind of more about the powering assumptions here? And what would be a positive outcome from Acapella?

So Acapella is not powered for efficacy. And I want to be clear about that, and maybe we were not that clear in the past, right? So the way we're looking to this program maybe to give a general overview as Aria as a Phase II/III. It's our first registrational trial. When we talk to the FDA, they did agree with us that we could explore lower dose in a different trial. And that's what we are doing in Acapella. And basically, the going assumption there is that there might be a lower dose than 40 milligrams per day of PRAX-114 that generate similar or the same effects, but with lower side effects. And that's kind of the going assumption there. So looking for trends in terms of a dose-ranging, kind of a more typical Phase II dose-ranging study. Obviously, we are putting all the controls in place, all the quality measures. We're using like eligibility, verification, and so on. So we should be able to trust the data comes out of that. But the real, I would say, efficacy best is on 213 or Aria that is coming up further in the year.

Our next question comes from Myles Minter with William Blair.

Just on 944 and the faster titration Phase I study you conducted. Can you just sort of frame for us what the nausea rates were and whether they were sort of titration limited there relative to the titration schedule that you're using in the upcoming open-label data that you're going to disclose? And are you using this faster titration schedule in the Essential1 Phase II trial?

I'll go, Myles, and I'll start and I'll hand it over to Bernard. So the easiest part of the question is, no, we are not using this schedule. The way to look into the fast titration study that we did is when you're planning for like a blockbuster type of drug, as we are thinking about 944 to be, going to like look ahead several years and ask how physicians are going to use, what is the expectation in terms of a patient shows up to the clinic, what is going to be important for them, and that's where the fast titration works for us. You have a younger cohort and an older cohort on that study. So younger and older than 55 years of age.

And we've seen very comparable safety. We're able to dose up to 120 on both cohorts in fairly fast. So in that regard, check all the marks that you wanted there. Essential1 had started. As you know, we're trying to run this program in parallel like and accelerate as much as possible. Should be clear through our press release, but we do have that trial started in the US. We do have patients enrolled on that trial. So it's moving quite nicely. So we don't expect to slow that down for the new titration. Now, we might come back or even for the Phase III that we expect to initiate next year and implement that, but not for Essential1 right now. Now I hand over to Bernard to talk a little bit about the safety profile in general.

Yes. Myles, the safety profile we saw with the faster titration was really very similar to what we saw with the original titration that 944 105 study, where we titrated over about a month. So what it overall tells us is that, as we said before, people tend to have nausea and dizziness when they start out and then they don't seem to really have issues as they titrate up. So we'll unpack those data a bit more at the Movement Disorders Day in December. But overall, the profiles are looking the same with the longer or the shorter titration. So the big picture, like Marcio was getting at is, it's going to allow people flexibility for how quickly they want to or need to get up to higher doses.

And I have a follow-up with Ritu Baral with Cowen.

I wanted to move to PTSD and the rationale for 114 in PTSD. Especially Marcio and Bernard, you were talking about anxiety. How is the -- how is anxiety sort of moving into the CAPS-5? I know there's various domains, but it's not -- I feel like there's anxiety components to certain questions and certain subdomains and not others. I'm just wondering if there are certain subdomains that you think 114 could improve the most within the CAPS-5.

Yes. So the -- we're really excited about PTSD. I think the rationale is particularly strong for the GABAA PAM, especially one with an extrasynaptic preference, given that benzos don't work particularly well in PTSD, and a lot of people actually avoid them as part of the treatment regimen. So the overall rationale, though, is, right, endogenous neuroactive steroids like allopregnanolone are involved in modulating the response to stress and modulate the HPA axis. There's really good experimental data. And you get reductions in GABA and allopregnanolone in PTSD and it actually correlates with clinical symptom severity in some studies. So in terms of what we're expecting to see, the CAPS-5 is the 30 item scale. It's actually pretty complicated in terms of the different factors I cut across there.

But cutting across many of the items are common features of anxiety, worry, and avoidance as well as like dysphoria, depressive symptoms and anhedonia. And so we're not focusing on any particular domain. We're looking at the overall CAPS-5. This is a Phase II exploratory study. So we'll learn if particular domains, as they're captured in the CAPS-5, come out. But I expect the benefit we'll see will kind of cut across the domains, and it'll show up in the overall score. The other factor in there is sleep. There are a whole range of different kind of sleep impairments from just regular insomnia to nightmares that might be improved with 114. So we're looking broadly, but we expect to learn a lot from this trial.

Got it. And what is the overall prevalence of sleep disorders within PTSD? And are there any sort of files of the sleep disorder that might, for whatever reason, contraindicate a GABA? You mentioned that benzos aren't really used for PTSD. And could you go into why?

Yes. It's incredibly prevalent, Ritu, in the PTSD. It's actually interesting as well. We have one of our clinicians in the company is a fellow for MGH. We have a fellowship program with them that focus on this lead or areas of leading [diseases] specifically. So it's something we've been looking quite closely. And obviously, the patterns change, depending on the patients and so on. But it's pretty dramatic, the impact it has. And to the point that we always discussed is about other conditions, other mood disorders is when this lead becomes primary to the condition versus secondary, right, like are you like tired all the time or have you more of this fear because you didn't sleep versus not sleepy because of that?

So that is central to the condition in our view and being able to really ease into it versus not feeling okay all the time, like Bernard mentioned, benzos here, I think that's the biggest problem there, right. They just don't do okay at any time with it. Seems to be a quite important differentiator for us simply. And I'll even go back to the preclinical models when you're talking about extinguishing fear. Just that is a huge rationale for us on this. But Bernard, anything to add there?

No. I would just say that the sleep connection and like kind of comorbid with depression, stress disorders like PTSD and conditions like perimenopausal depression, but it's very common. A lot of people actually think the sleep disorder starts first and are vulnerability. But it is -- that would be a good thing for us to follow-up on more and break it out in some more detail in terms of the different kinds of sleep disruptions. Maybe we can do that at our Psychiatry Day.

Our next question comes from Tazeen Ahmad with Bank of America.

Sorry, if this -- part of this question has already been asked before. But Marcio, as far as the essential tremor study is concerned, I think you're going to be releasing data in 2 tranches. I think you spoke a little bit about what to expect for this quarter. But for -- I'm assuming the bigger data release next year, what additional data should we expect to see in totality? And what's going to be your bar for what you think is good enough to move forward overall?

Absolutely, and thanks, Tazeen. So I'll break it down like this here, what we expect, right. As Bernard mentioned, there is not a lot more to be done in terms of tremor reduction when you look into amplitudes because that is a floor effect on the TETRAS. So when you look into the 40% or so that we had before, we think that that's like outstanding. And if you were there on the ballpark, that would be great for the next 12 patients or more that are going to be showing up in the next few months. The -- for next year, we're looking like a number of things, right? And this would be earlier in the year. So one is the more complete data sets like as many patients that have completed the trial at that point in time, the activities of daily living that we're also measuring.

We've been doing some work like exploring some like biomarkers, like digital biomarkers, and we want to talk a little bit more about that as well and how that would enable the Phase III program. And quite importantly, how much patients come back to baseline after discontinuation, right? And that's the randomized withdrawal phase of the trial, and that's why we need to wait a little bit longer to wrap that up. That part is blinded. So it requires a little bit different type of treatments and why we're going to be showing that at the beginning of the year. Our going hypothesis is that it's going to be a relatively slow coming back because these are more fundamental change to the network, right. So we're not simply reducing tremor. But again, our going hypothesis is that the oscillations are being "remodulated" and some more fundamental treatment for essential tremors like primordial, may I say, in terms of how they bring is wired.

So it might actually be that we create a more constant state of production, and that's why we are trying to explore on this trial. For the second one, for Essential1 that we used to call 944, 222 and now the name is Essential1, that is a more typical parallel design. So we wouldn't be able to explore on that trial. And that's why we're separating this two in terms of the learnings. But in the first quarter, in the beginning of the year, we should be able to see -- first or second quarter and the first half of the year should be able to see this patient and how much they returned. And we hope they didn't return much for the sake of the patients, but we do expect to see a nice separation there.

And I'll just add on the -- echo the point that Marcio mentioned, which is the roughly 40% reduction we saw in cohort A at 40 milligrams, that was on top -- most people were taking propranolol. So we've been mostly studying this as adjunct. There were a lot of people to come in on one medication. But the other key point is the floor effect in the TETRAS because you just -- it's almost impossible to get below a one where tremor is barely visible. So the only thing you can really do as you go up and dose is maybe have higher responder rates. But on a patient-by-patient basis, you'd have to make tremor basically invisible or go away, which -- so you run into these floor effects unless you have a better measure of tremor.

And I have a follow-up with Myles Minter with William Blair.

Just on the Phase II PTSD study design, what was the rationale for doing a potentially flex dose of 114 for patients that don't improve on the CAPS-5 in 2 weeks versus just running a separate 60 mg arm? I've been getting a few questions like we'd like to see more patients on the 60 mg, just given the disclosure that I think a perimenopausal depression patient had sedation at 60 mg. If you could just run me through the rationale for this, this would be great.

Yes. I will start with the last part of your question there, Myles. So the formulation that we're using right now is a lot tighter in terms of the exposure that it gets. So we don't expect to have much variability there. So that gives us some nice separation between 40 and 60. So you're not really seeing much before it varied a lot, as we discussed on the previous formulation. So that's one. The second one, we're looking to here, what did the first trial suggested? So we want to make sure we understand. Then we look into the actual PTSD patients in the domains and like how much they would tolerate like certain like exposures of a GABAA PAM or how much their brains would need or their bodies would need.

And that's why we thought that if they're going on the right direction, therefore, the ones that did not move to the 20% or so in the CAPS-5 would allow for under the discretion to go up to 60. It gives kind of the best possible way to explore in this Phase II trial. We do expect most of the patients are not going to go up there, but it gives us an extra understanding. And then we will run -- we're probably going to keep these patients for a few more weeks after that as well, is the current plan. The feedback we got from all the sites we've been talking to is to run an open-label right after that. And that's what we have in the docs being planned. So we're going to have a very nice exposure-response, understand the safety on this population and being able to hopefully discuss with the FDA what our registrational path will look like afterwards.

And at this time, I'm showing no further questions in the queue. I'd like to hand the conference back over to Marcio for any closing comments.

Thank you so much, and thanks again for everyone for joining and for all the questions. And on behalf of the team here at Praxis, right, there was a lot of work and there was a lot that we reviewed today, and we're quite pleased to share the progress. As you saw, there was a lot going on in our portfolio, and virtually everything advanced quite nicely, so a busy year for us. In just one year as a public company, we advanced like basically every program to the stage we wanted them to be through proof of concepts. We're bringing our first ASO to the clinic early next year, as we discussed. And that's, for us -- it's super exciting since we have a number of other ASOs to come in the near future. We more than doubled the number of Praxans, as we call our fellow colleagues here that work every day to deliver these therapies to patients, in the last 12 months as well.

We surpassed the 100 full-time employees in the company in the last few months. And we moved to our new headquarters in Boston. Actually, Bernard and Tim are sitting just next to me here in a beautiful weather in Boston. So -- and finally, we have, like all the personnel, all the funding that is necessary to continue to tag along and to deliver on this growth trajectory in a very practical and efficient manner. We're proud of how far we come, no doubt whatsoever on that. But we always say, we dare for more. And we look forward to having all of you right along with us daring for the patients in need. So thanks again for the support, and enjoy the rest of the day.

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