Praxis Precision Medicines Inc (PRAX) 2020 Q4 法說會逐字稿

Ladies and gentlemen, thank you for standing by, and welcome to the Praxis Precision Medicines Fourth Quarter and Full Year 2020 Conference Call. (Operator Instructions) Please be advised that today's conference is being recorded. (Operator Instructions) I would now like to hand the conference over to your speaker today, Alex Kane, Head of Investor Relations. Thank you. Please go ahead, sir.

Thank you, Shannon. Good morning, and thank you for joining us today to discuss Praxis' Fourth Quarter and Full Year 2020 Corporate update. With me on today's call is our President and Chief Executive Officer, Marcio Souza; and our Chief Medical Officer, Bernard Ravina. Additional members of the management team, including our Senior Vice President of Regulatory Equality, Alyssa Wyant; and our Vice President of Finance, Lauren Mastrocola, will be available for questions following the prepared remarks.

Please note that today's prepared remarks will focus on recent business and pipeline progress. Detailed fourth quarter and full year 2020 financial results can be found in the press release issued this morning. We will be referring to supplement slides posted in the Events and Presentations section of our Investor Relations website throughout today's prepared remarks. 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 1955. 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 and our SEC filings, including our annual report on Form 10-K being filed today. I will now turn the call over to Marcio. Marcio?

Thank you, Alex, and good morning to everyone joining us today. We are thrilled to be speaking with you during our very first update call as a public company. Oftentimes, in calls like this, or 1-on-1 that we have, you heard me saying that I'm living the dream, when asked how I'm doing. Let me be clear, this is no hyperbole. It's a reflection of how fortunate I feel to be at Praxis, leading a company and an incredible team working every day to bring novel treatments to patients.

At this moment, as it seems that we are starting to turn the page, following an extremely challenging global period, and we start to look forward to the future, it's critical that as a company and a society we do not advert our attention away from the escalating rates of depression, which are expected to be long-lasting.

In the United States, depression symptoms have increased by more than 3 fold during COVID and the prevalence of depression globally has increased equally. Notably, the most dramatic increase have been seen in severe depressive symptoms, which have increased by a staggering 7.5 fold. Even with many treatment options available for people suffering from depression, a clear unmet need still remains. There is a clear need for faster acting, safer options, displaying high rates of remission and durable efficacy relative to standard of care.

Ideally, those will be complemented by simple patient-centric dosing. With that, we're excited that earlier today, we announced that study 213, our mono-therapy Phase II/III trial of PRAX-114 for the treatment of major depressive disorder will start recruiting later this month. We are incredibly determined and eager to continue to advance this program. We believe that 114 has the potential to be a highly differentiated option for people living with depression. I would like to now take a moment to review the upcoming trial and touch upon the registrational path for 114 in MDD. Please turn to Slide 3.

As I just mentioned, we are operationally ready and plan to start the trial in the following weeks. Following positive interactions with the FDA, we have submitted a proposal to the agency that included available preclinical data. The FDA agreed with our proposal and cleared the IND for 114 late last week, which allowed us to initiate the trial. Study 213 is designed to enroll approximately 200 participants randomized one-to-one to receive nightly dose of either a 40-milligram tablet of 114 or placebo.

Participants will receive study drug for 28 days in a full outpatient setting with an additional 2 weeks follow-up. The primary efficacy endpoints will be the change in the HAM-D 17 at day 15, with a key secondary endpoint being the change in HAM-D 17 at day 28. Historically, placebo effect in psychiatry trials tends to be maximal near the end of treatment. As such, the continuation of treatment beyond the primary endpoint is a key component of this trial design.

Importantly, the design of the Phase II/III trial was completed with both acute and maintenance treatment in mind and was done in consultation with the FDA and other stakeholders.

The primary endpoint at day 15 allows for assessment of the speed of onset and robustness of response, which is expected from this class. The key secondary endpoint at day 28 allows for assessment of durability of effect. If approved, this would allow for a dosing paradigm which is consistent with the duration of depressive episodes, typically lasting several months and would allow for flexible treatments based on physician discretion, being easily integrated into standard clinical practice.

We have selected the 40 milligrams at target dose for the registrational studies and potential commercial use. This was based on data from our PK bridging study, where the overall PK profile of the tablet was found to be comparable to that of the suspension. But administration of the tablets generated more consistent exposure than the suspension, and we have observed accumulation of 1.3 fold. We expect that nightly dose with 40-milligram tablets will generate exposures resulting in beta power of approximately 170%, which is above the expected efficacy thresholds. The 40-milligram tablet allows for more predictable therapeutic exposures consistently at or slightly higher than previously seen with the 45-milligram suspension.

Based on the quantitative EEG, the preliminary efficacy from part A, the PK bridging study and accumulated safety data, we believe that this dose offers an optimal benefit risk to move the program forward. As an extrasynaptic GABAA receptor preferring positive allosteric modulator 114 has unique properties compared to other molecules in development in this class. We believe that these properties supports 114 profile to date, including the wide therapeutic window, and achieving high levels of Gabaergic activation with an advantageous tolerability profile.

Earlier today, we shared additional results from Part C of the 114 Phase IIa trial. This trial is important in that it was the first time at GABAA has been studied for the treatment of MDD with daily dosing for 28 days. And this data, along with other study learnings were informative for designing our upcoming Phase II/III trial.

As a reminder, our Phase IIa study included 3 parts: Part A, which has been completed, Part B, which is currently enrolling patients with perimenopausal depression and Part C, which was intended to evaluate the safety of 4-week outpatient dosing and explore durability of effect from day 15 to 28. In Part C, 13 patients with moderate to severe MDD were enrolled. 114 was generally well tolerated and no change in safety profile was observed when compared to previous clinical experience.

While the sample size itself is too small to draw an efficacy conclusion, we see the same trends produced previously with 114, leading to a rapid and marked improvements in HAM-D scores that remained stable through the end of the active treatment periods. For reference, Part C was conducted in Australia from mid- to late last year. This timing corresponds with a highly restricted public health lockdown due to the COVID-19 pandemic. As a result, we were required to make change to the trial conduct. Those changes included the use of telehealth for the study visits, mailed self report assessment and delivery of study drug to participants via courier.

The change ended up being fortunate since they served as learnings and have now been integrated into the design and operational plans for the upcoming Phase II/III clinical study. Let me quickly touch upon the registrational path for 114. The upcoming Phase II/III study, if positive, is intended to serve as 1 of the 2 monotherapy MDD registrational trials required by the FDA to support clinical efficacy.

We expect to report top line data from this trial in the first half of next year. We also expect to initiate a second Phase II dose range finding trial for 114 in adjunctive treatment setting in the third quarter of this year. This trial will provide information about lower dose and supporting data in adjunctive setting for MDD. Together with a long-term safety follow-up study, those trials would represent the expected registration of 114 as both monotherapy and adjunctive as both acute and maintenance treatments.

I now would like to highlight some key operational controls that we have put in place to further attempt to minimize variability in the upcoming trials. Please turn to Slide 4. Rigor and discipline in clinical conduct is essential across each of our programs. For our upcoming Phase II/III trial, we have implemented several measures that have historically helped mitigate variabilities and placebo effects. Those can be broken down into 3 distinct areas: one, rigorous patient selection; two using only high-quality sites; and three, ensuring optimal trial design and execution.

Let me take a minute to further define these measures. In relation to inclusion criteria, the 114 clinical program requires that patients have had at least one prior episode of MDD. This is important in the current environment, where acute stressors may cause mood and anxiety symptoms which could mimic MDD as a diagnosis. Also, we have implemented the SAFER screening process, which provides for a second level of independent clinical interviews to confirm patient inclusion and diagnosis.

In addition, we are working closely with sites that have proven track records of generating high-quality data. We have also integrated a placebo control reminder scripts for patients at every visit. Finally, we're using AIcure, a smartphone-based compliance monitoring system to ensure adherence. Combined we believe that this degree of rigor in clinical conduct will result in maintenance of data integrity and minimization of placebo effect.

I'll now turn the call over to Bernard to discuss recent progress with our second clinical program, 944, a T-type calcium channel inhibitor, which are in development for essential tremor. Bernard?

Thanks, Marcio. I'd like to echo Marcio's comments about how excited we are to start the PRAX-114 Phase II/III trial in the coming days. We're equally enthusiastic about the progress we have made in our PRAX-944 program for essential tremor and the work yet to come. To set the stage, we're currently conducting a 2 cohort Phase IIa open-label trial of PRAX-944 in patients with ET. We expect top line open label safety, tolerability and efficacy data, for the high-dose cohort in the middle of this year. We also anticipate initiating a Phase IIb dose ranging, randomized, placebo-controlled trial of PRAX-944 in ET later this year.

On Slide 5, you'll see data from 6 participants in the low-dose cohort of our Phase IIa trial. This cohort included daily morning dosing of PRAX-944 at 20 milligrams during the first week, followed by 40 milligrams in the second week and then wash out. The chart on the left shows change from baseline in the TETRAS score, both in the total performance scale and the upper limb subscore. For the primary efficacy outcome, we're using change from baseline in the upper limb items of the TETRAS because all patients suffer from upper limb tremor and these items are rated reliably. The chart on the right displays these data as percent change in tremor amplitude.

A reduction of greater than 40% in upper limb tremor amplitude compares favorably to pharmacologic standard of care such as Propranolol. Similar patterns of improvement were observed in accelerometry scores. There's also a strong correlation between the TETRAS site Investigator Ratings and central ratings. This concordance among various approaches to rating tremor gives us confidence in the reliability of the observed effect. Importantly, 5 of the 6 participants remained on Propranolol during this study. This suggests that PRAX-944 could be efficacious as both an adjunctive treatment and as monotherapy. Based on the observed safety profile and the preliminary efficacy shown in the low dose cohort, we believe that PRAX-944 is a titratable drug with a wide therapeutic range.

As such, we added a second cohort in which up to 12 ET patients will be titrated up to 120 milligrams per day. On the following slide, Slide 6, we've provided a schematic of the trial design for Part B. Part B will include an open-label titration period over 28 days, followed by 2 weeks on a stable high dose, after which there'll be a 2-week randomized withdrawal. The randomized withdrawal stage is intended to assess the durability of effect for this key mechanism of action and will provide blinded ratings to confirm the effects from the open label portion.

ET affects up to 7 million people in the U.S. alone and a new pharmacologic option for these patients hasn't been approved for more than 50 years. What often gets missed with understanding the burden of ET is that Tremor limits function and impairs social interactions throughout the entire waking day. ET manifests in upper limb action tremor that impacts everyday activities, such as writing and typing, eating and drinking and getting dressed.

Patients are looking for a treatment option that reduces tremor, improves their function and has a tolerability profile that won't interfere with their daily activity. Current pharmacologic standard of care has limitations in both efficacy and tolerability, leading to an estimated 80% discontinuation rate. With this in mind, the initial efficacy data and observed safety data for 944 give us confidence as we move forward. We're optimistic that PRAX-944 allows for convenient once-daily dosing with the potential to control tremor throughout the day without clinically significant sedation.

We haven't observed any SAEs or severe AEs, and the majority of observed AEs have been mild, transient and resolved without any intervention. We believe that the tolerability and prolonged exposure of the MR formulation currently being used in our Phase IIa study are well suited to the treatment of ET. Before we wrap up the prepared remarks and open the call to questions, I wanted to pass the call back to Marcio to briefly touch on the new collaboration we announced this morning with the Florey Institute. Marcio?

Thanks, Bernard. As a CNS focused company deeply ruled in genetics of epilepsy. It's very important for us that we continue to lead in this area. The research collaboration announced earlier today with the Florey allow us to do just that with the addition of 3 novel ASO targets to our pipeline. Under the collaboration, research will be conducted by the world-class team at the Florey Institute, an Australian-based medical research entity that specializes in neuroscience.

Each of the 3 programs focus on rare epilepsies with very high unmet needs and limited or no research and development ongoing. Quite importantly, efforts on all these problems have been underway. The lead program from this partnership is an ASO for the treatment of SCN2A loss of function, which is the leading cause of genetically associated autism. Together with PRAX-222, our ASO program for the treatment of SCN2A gain of function patients, we have demonstrated our commitment to the SCN2A community and continue to build a leadership position in sodium channel research.

As a company, we now have 6 distinct epilepsy programs, including four ASOs. In the past several months, we have seen promising advancements in our 2 lead rare disease programs. Earlier this year, the FDA granted both rare pediatric and orphan drug designation for PRAX-222 for the treatment of SCN2A-DEE. We have ongoing IND-enabling tox studies for 222 and expect them to be completed by the end of the year with an IND to follow in early 2022.

The FDA also granted rare pediatric designation for PRAX-562 for the treatment of SCN2A and 8A DEEs. For 562, our most advanced small molecule rare disease program, we completed the single ascending dose stage of the Phase I study and have advanced to the multiple ascending dose. The SAD stage was completed up to the maximum planned dose with no dose-limiting toxicities. We are currently at the highest preplanned dose in the MAD phase, which are reaching exposures that exceeds the predicted therapeutic concentrations in animal models of seizure and epilepsy. We intend to escalate those further if the drug continues to be generally well tolerated.

We expect to initiate the first proof-of-concept trial for 562 in the second half of this year, which will be in rare adult cephalgias. We recently expanded the scope of this upcoming trial to include trigeminal neuralgia in addition to SUNCT and SUNA patients. We believe that 562 has broad potential in rare disease, and we choose to follow a deliberate approach to clinical development. We intend to expand next into a range of rare pediatric epilepsies.

As you can see on Slide 7, Praxis has built a novel, diversified pipeline with multiple potential value-creating milestones in the next 12-plus months. We look forward to continuing to report our progress and to interact with all of you throughout the year. With that, we're now going to open the call for questions. Operator?

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

Marcio, I want to make sure I understand correctly. The day 28 secondary endpoint, that key secondary endpoint, if the trials don't reach statistical significance at day 28, will you be moving forward or will FDA require you to move forward with the sort of episodic day 14 indications similar to Sage's? Or even if you have trends, can you be talking about a chronic label? And then I've got a couple of follow-ups.

Ritu, I hope all is good. The conversation with the FDA in relation to 28 day, it's really, as we mentioned, as a key secondary endpoint, right? So that would be by definition, an additional claim. We see as a huge opportunity actually to have the 15, as you mentioned on the prepared remarks as the primary since that would be what would declare the trial of positive or not. Now it's all dependent, as always, of the FDA reviewing the results and so on. We fully expect that, that's going to be maintenance of effect at day 28 and then would have both claims.

As a reminder as well, as we discussed previously, the FDA did insist that we follow these patients for more than 15 days on drug in order to qualify for monotherapy label in MDD. So it caps a number of topics, right? So 1 is serving as a secondary endpoint, is obviously quite important, but also serving as a determination of like the safety of looking to these patients for more than 15 days and securing with the trial being positive with a second trial being positive to support the label. So a number of things, but maybe going more simplistically, I believe that if there was a small change there on day 28, and for some reason, something happened, that would still be a path forward with the claim of day 15 very clearly.

Got it. Okay. And then the 40 milligram, is that -- based on your beta power studies, is that the top of the dose response curve? I may have forgotten to write it down in my notes, but the Phase II dose-ranging that you're doing later this year, are you planning on going up or down in doses there?

Yes. So the beta power that we are seeing with the 40 milligrams with the tablet formulation is around 1.7x. So 170%, right, since baseline is normalized to 1. That is far more than what we would expect for the effect here. Now for the DRF trial, I'm going to hand over to Bernard to explain how we are thinking about that, why we are doing that and the dose range that would be exploring. Bernard?

Yes, so right. The 40-milligram gets us to data power, on average, about 1.7. And we had said based on the accumulated data and our preclinical data that we want to be around 1.5, 1.6 or above. So we think this is getting a full pharmacologic effect at those exposures. The -- for that dose range finding trial, we are planning on going to lower doses as far down as 10 and 20, and we believe we'll still maintain pretty significant beta power in that dose range. That's the main part of the curve we want to explore because as you saw with the open-label data in Part A, looks like we're at the plateau of the dose response.

We do expect, however, to include a higher dose as well and that offsets any risk in terms of diminishing efficacy in the lower part of the dose range.

Got it. And then just the fact that, that trial is adjunctive? Are you going to be investigating any, I guess, any cohorts that look at adjunctive versus non-adjunctive to sort of tease apart any potential effect? And are you going to be investigating like what are your competitors sort of simultaneous combination initiation of treatment?

So that trial, which we call study 214 is solely in adjunctive setting. And the benefit here is 1 that a clean set, the second is really operational enrollment, right? We're going to be doing this trial virtually in parallel with study 213, that is the Phase II/III in monotherapy and it gives an alternative for the sites to screen patients for both trials really and to like select them to the trial that makes the most sense. Bringing both in 1 trial, it's normally more of a confounder effect than not and we wanted to make sure whatever result together, on the other hand, is interpretable, and we can clearly express that.

Our next question comes from Laura Chico with Wedbush Securities.

Congrats on the progress. I guess I just wanted to circle back 1 more time on the dose selection for 114 and just with regards to kind of all the data, putting it together, the beta power of the accumulation. Just to clarify, would the 40-milligram dose be analogous to one of those suspension doses that you already covered in the part A study? I guess I'm trying to just contextualize what the 40 mg tablet is equivalent to?

Yes. No, absolutely. And Laura, good to hear from you. The suspension dose right that we tested before, just to recall, they did not show any differentiation in terms of the effect we're seeing. But the was, as we escalated the dose more prevalence of AEs, not necessarily severity on that. And what we are looking is to stay above the 1.4, 1.5 in the beta power in general, as we are guiding dose, right, since we are using quantitative EEG. The tablet profile, what we've seen was a number of things, right? So the general profile were very similar, which was good. We learned a little bit more about the time of day dosing, as Bernard mentioned, but one thing that was quite important is the variability is reduced. So we drive exposures that are at or higher than the 45 on the previous suspension trial and that's where the overlap part of your question is.

But because the variability is smaller on the exposure, we end up getting more patients. Our prediction is that we're going to get basically all patients to the beta power we are expecting. And therefore, on the efficacious range there. So you could look into between the 2 lower dose that we did for the Phase IIa, so between 45 and 60, I would say, as a surrogate in terms of the exposure there. But we are consistently seeing on the 40 in the tablets at or higher than 45 for the previous one.

Okay. That's helpful, Marcio. Of course. Okay. And then maybe a follow-up question here. Just -- well, maybe 2 follow-ups, sorry. On 114 for the registrational path, I just wanted to clarify, with the initial plan then to be pursuing both monotherapy and adjunctive labels at the same time for the initial filing? And then on 944, also kind of clarifying there, I guess, you're looking to do the separate titration study with the Phase I work. Would that be a gating factor to starting that Phase IIb study as well as 944 and any thoughts on whether -- on how you would handle patients already on propranolol?

Absolutely. So maybe I'll get the first question on the 944 question to Bernard, and then we can go back and talk a little bit about the registration path for both of them. Bernard, why don't you talk a little bit about that?

Yes. So for 944, right, we've -- we now understand that we can get up to 120 milligrams in healthy volunteers. We're going to explore that now in the Part B study in ET patients. And really, the goal there is to make sure that in that generally older population of ET patients are taking a bunch of concomitant medications that they can tolerate that as well. So we'll be having those data around midyear, we'll get a sense in that pool of subjects up to about 12, what kinds of treatment effects we're seeing in ET.

In parallel with that, we're going to explore some different titration schemes, and we'll be looking to see if we can titrate up a little bit faster and what kind of increments we can go in and then putting those 2 pieces of information together. I think we'll be very well positioned to (inaudible) RCT towards the end of the year. But both of those pieces of information are going to be informative for a well-designed RCT.

And going back to your 114 question. So the base plan here is to get to a monotherapy label with the phase II, III that we are starting in the next couple of weeks and a second Phase III after that. We are starting study 214, as we mentioned, for adjunctive as well based on the results of that study, would have a conversation with the FDA on whether or not an additional study for adjunctive would be necessary. I think it's largely on their hands in terms of that. They might require another one. I feel pretty good based on precedents that the adjunctive with 2 positive trials in mono might be possible to be, but it's very hard to guide right now to -- or exactly what the label would be. But the base case is, monotherapy, which shortly thereafter or in parallel has an adjunctive in the label.

Our next question comes from Tyler Van Buren with Piper Sandler.

Congrats on the progress definitely an unusual amount of clinical activity for recent IPO. I have 3 for you. Forgive me for asking another beta power question. But when you talk about the consistent exposure, if I look at the prior beta power qEEG data, that spike that occurs, appears to last for about 1 to 2 hours, if I'm not mistaken. So is that increase in beta power over a longer period of time? And is it possible to quantify that for us at the 40-milligram tablet dose?

And then the second question is just you mentioned kind of maxing out on efficacy, but also having the ability to improve tolerability can you just confirm that you've never seen any sedation at kind of these levels at these doses relative to, I guess, the equivalent of the suspension dose or that has been very low. And then also what the kind of rate of somnolence has been because clearly, those 2 things are quite different as I understand.

And then the third 1 is on the essential tremor. I believe you said data from 6 patients in this slide. I think we had 5 recently. So could you just comment on that 6 patient? And also your confidence in clinical trials moving forward with respect to people who respond or don't respond and any sort of placebo response?

Yes. So I'll try to unpack, Tyler, good to hear from you as well to unpack like the 100 questions you got there, but I appreciate the nice attempt. So unpack a bunch of them. So Beta Power, so maybe to clarify that, right? So the way we're looking into Beta Power and actually would guide you guys towards our Form 10-K that was just posted at the SEC website because we're talking about the first time about the alpha bands as well in the quantitative EEG in relation to 114. So something that might be interesting for some of the follow-up calls. But we are looking to that is whether or not, we're being able to expose patients to therapeutic dose. So it's a surrogate to whether or not we cross that threshold, right? So we believe that it's incredibly important that you have to do that with doubt the drawbacks that you talked about. So just to be exquisitely clear, we've never seen next day, somnolence, sedation or worse yet tremor.

So we haven't seen those things that might have been seen with the class or expected with the class on next day. So for us, it's incredibly important that because next day somnolence, for example, or sedation might be seen as depression by these patients. So we wanted to separate that. Now a hypnotic effect is expected and desirable from this. So we want the patients to feel at ease quote unquote, and hypnotic before going into bed without any requirements that they are in any given state of feeding or minds before going to just taking the drug and really being able to sleep and feel bad about their depression.

So the 40 milligrams with the tablet gives us the best possible to this day, as we just mentioned we are going to explore a lower dose profile that wraps the expected efficacy, which we're hopefully going to be seeing at the end of study 213 with our safest profile to date in terms of the rates of somnolence. And we haven't seen frank sedation, as we mentioned before, just going to reinforce that even at a much higher dose than 40, but definitely not a 40. That I answered the 114 part of the question.

Yes.

Sounds good. So on the key part for 944, right? So you might recall, at the time we filed the S1 late last year, we had 5 preliminary patients. The data was like coming hot off the press, we needed to basically do a number of things, like clean that up to the extent that was required, run the assessment for concordance with the other endpoints and then add any other patients. So we had 7 patients on the safety database, one of those patients did not complete any of the efficacy measures. So we are showing data for 6 patients on the efficacy measures.

And the good news here is, one, it's a very robust average reduction in the tremors as measured on this trial. But the second thing is that by the first time, and while we believe that our difficulties on measuring tremors using the current standards, a trial was able to show concordance between blinded central readings and the site readings. The site readings is the standard of care is what most goes to, there's a lot of validity there, but it was important for us as this is open-label to get that confirmation.

So we feel really good about the results we're having right now, and that's what led us to move and accelerate further to the previous question from Laura in terms of getting the next 2 trials running and starting the phase IIb by the end of the year. So it was eventful, as you said, between the IPO and now, it's definitely even more eventful for the next 6 months. So we're really looking forward to it.

Our next question comes from Ritu Baral with Cowen.

Sorry, I was muted on this. One protocol question, what's the placebo-controlled reminder script that you described as part of the depression study. I don't recall ever encountering that before? And then can you quickly -- and again, sorry, if understood, but you can you go over what you've seen to date on the side effect tolerability of 944 at the 40-milligram dose?

And given the mechanism of 944, what do you think is the side effect to watch when it comes to tolerability and compliance in like a real-world setting for the drug?

Yes. No, absolutely. The reminder script, Ritu, it's actually something that sounds very simple on the surface, but it's incredibly powerful. We have added the reference for that in a recent paper to our slides and in our SEC filings. So I recommend like take a look that afterwards, but it basically is a structured way to remind the patients in a very simplistic manner that they are in an experimental drug that is blinded and therefore, there should be no expectation of effect since there is a 50% chance, they are not on drug. By doing that systematically using a script in every visit, it has been shown to fairly significantly separates the placebo patients from us. So control for the placebo effect.

A lot of what we are doing is to make sure the trial is operationally sound is not only that we show a separation from 114 at the end, but then that we can control the placebo effect to historical rates in our controlled trials. So question is one to Bernard as well to talk a little bit more sense what his idea and his team idea to implement this so thoughtfully in this study. Bernard?

Yes. Like Marcio said, they're really nice data to support this. So basically, the placebo effect is driven by expectations and what the placebo reminder script is really not to do is kind of refocus people on expectations, remind them that they're in a clinical trial, that it is an experimental agent and it's not known to work yet. And so it just kind of sets expectations and reminds them that they are not in a treatment setting.

So it's this kind of approach has actually shown pretty robust effects in terms of maintaining less of a placebo effect. So it's been used in a number of -- this kind of approach has been used in a number of different kinds of psychiatric trials, pain studies and other places where placebo effects and expectation bias can really cause trouble for trials. So -- and our sites are experienced with using it.

The way it's implemented, Ritu, is that it's simply not read but presented to the patient kind of discussed prior to conducting the main assessment to the primary and key secondary assessment.

And then 944 tolerability.

Yes. And on the 944 tolerability, so that's been very, very good and right. So going into this, we knew what kind of AEs to look for. So the main AEs are around nausea, dizziness, lightheaded. And what we see is that yes, people may have those, but they tend to occur at the beginning of titration, and then they seem to tolerize. We know the EEG effects don't tolerize. But those AEs tend to. And so you see them upfront, they're mild, they're transient, really don't need to do anything in terms of any intervention. The main thing to do is just let people know that they will subside and just have the right expectations around that. And I think that's just part of the mechanism in getting started, but the key is they go away, and they do not increase with titration.

(Operator Instructions) And I'm currently showing no further questions at this time. I'd like to turn the call back over to Marcio Souza for closing remarks.

Thank you very much, operator, and thank you, everyone, for joining today. We're incredibly thrilled to be on this first public call with all of you. And most importantly, advancing all these therapies to patients. This is very close to our hearts at Praxis and what keeps us up at night sometimes and definitely very early in the morning, making sure we can advance, I believe you all would agree with me that in the last 5 months, since we became public, there is a tremendous amount of progress and operational promise from the company, moving each one of our programs and more towards the clinic or at the clinic to help those patients. So very proud of the team of people that are behind Bernard and I and others in this call really helping us move this to patients.

So thank you very much for supporting Praxis and everything we do and looking forward to talk to all of you.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.