Thank you for standing by. Welcome to the Praxis Precision Medicines Essential1 topl ine results call. At this time, all participants are in listen-only mode. After the speaker's presentation, there'll be a question-and-answer session. To ask a question during this session, you will need to press star one one on your telephone. You will then hear an automated message advising you your hand is raised. To withdraw your question, please press star one one again. Please be advised that your conference is being recorded. I would now like to hand the conference over to your speaker today, Alex Kane, Vice President of Investor Relations and Corporate Communications. Please go ahead.
Hi, everyone. Good day. Thank you for joining us. We are pleased to be with you today to discuss the top line results from the ulixacaltamide phase II-B Essential1 study for the treatment of essential tremor. With me on today's call is our President and Chief Executive Officer, Marcio Souza. We will be joined by additional members of the Praxis management team for a live Q&A session following today's prepared remarks. Please note that today's remarks will reference the press release issued earlier this morning and the slide deck accessible through the Investors and Media section of our corporate website, which was posted in conjunction with the call. We will be making 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.
I will now turn over the call to Marcio. Marcio?
Thank you, Alex. Good day to everyone joining us today. It's great to be here to share the results from the Essential1 study assessing ulixacaltamide in patients with moderate to severe ET. Before reviewing the topline data, I want to take a moment to acknowledge and thank the patients with essential tremor who participate in this important study. Without their sacrifice and dedication, we could not be standing here today. My gratitude extends to all the investigators and study personnel involved in the conduct of Essential1, as well last, but not the least, the outstanding team at Praxis. We believe that ulixacaltamide has the potential to transform the treatment of essential tremor. Today's results reinforce our perspective. Essential1 demonstrated a profile for ulixacaltamide or PRAX-944 that has us, together with the essential tremor community, excited about progressing this program to phase III.
Essential tremor patients have waited more than 50 years for a new treatment for their disease and have never had the benefits of a precision medicine targeted for ET, such as ulixacaltamide. We are working urgently to deliver a potential treatment for the more than 2 million patients in the United States diagnosed with essential tremor. Looking at the effect efficacy data in aggregates, we observe placebo-adjusted improvements in multiple endpoints that have direct functional relevance for patients, which give us confidence in the drug effects. We also continue to observe a well-tolerated safety profile that is clearly differentiated relative to existing options. We learned important information throughout this study as well, giving us a clear understanding on the path forwards.
As you hear, the results inform our perspective on exposure and dose for phase III on endpoints, trial design, patient stratification, and other finds that we believe will be critical to running a successful registration study and ultimately getting ulixa to patients in need. Turning to the study, as seen on slide three, Essential1 is a randomized, double-blinded, placebo-controlled trial evaluating the efficacy, safety, and tolerability of once-daily treatment of ulixa compared to placebo after 56 days. Patients meeting eligibility requirements for Essential1 were randomized 1:1:1 to receive 60 or 100 mg of ulixa or placebo, taking orally once daily in the morning. The primary endpoint was the pooled analysis for the change from baseline to day 56 in the mADL scores for ulixa-treated patients relative to placebo.
We also assess the safety, PGI and CGI, as well as additional sub-items in the TETRAS scale. Following study unblinding, post hoc, we explore the impacts of treatment in the mADL without the addition of the TETRAS performance scale items, as well as potential prognostic factors which could be relevant to the population studied. We expect this post hoc analysis will be relevant for our phase III plans. Patients in Essential1 were required to have a clinical diagnosis of ET for at least three years and be considered moderate to severe in nature. Concomitant propranolol use was allowed as long as patients remained on stable dose. On slide six, you see that a total of 132 patients were randomized and treated in this study. Of those, 116 matched the criteria for the primary analysis, which we refer to as the mITT population.
In the mITT population, 78 patients were randomized to ulixa and 38 to placebo. In terms of baseline demographics, the groups were generally well balanced, with the population randomized to ulixa exhibiting characteristics is slightly different than placebo in family history and background propranolol use. The key parameter used to assess efficacy, the TETRAS-ADL, was well balanced between the groups. It's important to notice that since the ADL is composed of several items, modifications to the items or how they are assessed influence the aggregated baseline and eventual changes. The unmet need in essential tremor is not only for effective drugs, but ones that are well-tolerated. In Essential1, patients treated with ulixa experienced rates of treatment-emergent adverse events consistent with the previous profile of the drug. No drug-related serious adverse events were observed, and the AE profile were generally mild to moderate in severity.
Discontinuations due to AE were 12% in the ulixa group and mostly occurred during the first month of treatment. As you can see on slide nine, there was no pattern associated with those discontinuations. I now would like to focus on the efficacy analysis for the primary population. As noted, the primary endpoint for Essential1 was the change from baseline to day 56 on the modified ADL. We'll also discuss the effect on clinical and patient global impression, as well as subscales of the TETRAS. As a reminder, as seen on the left side of the slide, the TETRAS-ADL subscale is composed of 12 measures directly impacting the ability to function for patients with a total possible score of 48 points.
The modified ADL scale in Essential1 excluded social impact, one of the original items in the ADL scale, and included two items from another scale, the TETRAS Performance Subscale, specifically the handwriting and spirals items. The modified ADL is also scored differently, with transformation resulting into a maximum score of 42 points. We have included feedback received from the FDA in relation to endpoints for the ET trials in our public filings with the SEC today. We can more fully appreciate the advice we received from the agency in the past. Moving on to the analysis of the ADL items. As you can see in slide 13, we did not achieve the level of statistical significance the study was designed to meet in the primary endpoints.
The numerical change from baseline was in favor of ulixa-treated patients, with patients improving their mADL score by 3 points and placebo patients improving by 1.44 points, the P value for comparison between groups was 0.126. We will make reference to P values in other analysis and endpoints throughout today's presentation. They should all be considered nominal. When examining the change in the untransformed TETRAS ADL scale on the right-hand side of the slide, we observe a difference of more than 2.5 points in favor of ulixa, which is considered clinically meaningful. When observing the distribution of individual patients on drug and placebo in the waterfall plot in slide 14, you note a large proportion of patients with improvements in the ulixa arm compared to placebo.
In order to better understand the change between the two scales, we plotted the difference between each item, as you can see here in slide 15, for the ADL and the mADL scales. It becomes clear that the effect was diluted by the addition of the performance scale items, predominantly the left-hand spirals. Of note, more than 90% of patients in this study were right-handed. The performance scale items have been historically unreliable to assess patients' progress in clinical trial settings. While we expected that our enrichment criteria, careful site selection, and eligibility review would have resulted in a more reliable measure, the data indicated that our assumptions were incorrect. As you reflect on the next steps for the program, we believe that the feedback we previously received from the agency would be supportive of removing the performance scale items from assessments in clinical trials.
We intend to make this proposal to the agents in a forthcoming end of phase II meeting. When the performance scale items are removed, one can observe a clear and consistent response to treatment with ulixa in the ADL items. We reference these endpoints as mADL 11. Those results are supported by the improvements noted by both patients and clinicians in the Global Impression Scales, PGI-C, and CGI-S, as reflected in slide 16. After reviewing this data internally and with support of key opinion leaders in the fields, we have concluded that there is a clear signal of efficacy for ulixa, warranting advancing the program. Because we intend to focus moving forward on the 11 items in the ADL scale for which we previously received feedback, I would now like to discuss the change in those items in the mITT population.
As displayed in slide 19, we observed a clear and consistent change in the mADL 11 for this population, not only at day 56, but throughout the course of treatment. As you can see in slide 20, the effect was consistent with the expected exposure response to ulixa, starting when patients reach therapeutic drug levels and maintained during the course of treatment. The effect was not dependent on whether patients were randomized to Regimen 1 or 2 of treatments. As part of our post-hoc exploration of this study, we conducted a review of additional prognostic factors which could have influenced the performance of patients in our study. One such factor was the presence or not of intention tremor, which is described in slide 22. This clinical manifestation was assessed in addition to the diagnosis of essential tremor for the patients in this study.
Intention tremor has the potential to make assessments like the ADL more variable and harder to assess over time, since it could directly interfere with the measured task, and therefore it's important to consider its impact. Removing essential tremor patients presenting with intention tremor generated a more homogeneous group in the analysis, which also resulted in an improved ability to observe drug effects. We will continue to evaluate how to control for the presence of such patients in future trials. In slide 24 and 25, we'll be able to observe the trajectory of this group of patients over time when treated with ulixa adjusted to placebo, as well as their ADL profiles for the 11 items previously described. It's certainly reassuring to see that in a more homogeneous group, the effect is even more clear with ulixa.
In summary, we have learned a lot with Essential1, remain excited to move the program forward. While the primary endpoint did not formally achieve the expected significance level, the effect of the drug in this population, in our view, is very clear. We additionally achieved important objectives for this phase II study, gaining significant insights into the use of these scales in essential tremor, as well as key elements to progress the drug to phase III, including dose, safety, and the ability to define a better population. We plan to meet with the FDA shortly in an End-of-phase II meeting and advance the program to phase III by the end of this year. I'll now turn the call back to Alex to cover Q&A with the operator. Alex?
Thank you, Marcio, and thank you to everyone for listening today. For the Q&A session, we would ask that you limit yourself to one question initially. If you have follow-up questions, please feel free to return to the queue. With that, operator, please feel free to open up the line for questions.
Thank you. As a reminder, to ask a question, press star one one on the telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. Our first question comes from Yasmeen Rahimi with Piper Sandler. Your line is open.
Good morning, team. Thank you so much for all the color. I guess the first question that on everybody's mind is based on the KOL discussion and interactions that you have had since this data, like what is the probability that the FDA will grant you the green light to move forward with the ADL without the PS scoring? Then two, why did initially the FDA really insist on changing it to that modified definition and including it? Then maybe the third one is just any kind terms of how soon you're going to get details on how you plan on communicating it with the Street?
Hey, Yas, good morning. Thanks for the questions. They are quite important, so I appreciate starting with that. I'll break that on the three buckets, right, that you put there.
Key opinion leaders view, the ones that represented independence to our view, they gave us the advice that this is clearly a drug they would clearly use on the majority of their patients. What they're seeing in the clinic, what is reading back from these patients' lives, are really the ability to conduct tasks, right? Not like, necessarily a clinical examination. That is quite positive on that regard, and I'm sure we're gonna hear the same when we talk to them. I encourage you and everyone else to read the full feedback that we posted with our Form 8-K with the SEC today, in relation to the FDA response to our question.
The reason why we wanted to give the full context, as you're gonna note it there, they are very clear about the 11 items on the ADL, and also very clear in our understanding and our interpretation that that could be used as the endpoints. The other answers there, what I mean, are in relation to the question we asked that was originally in relation to the performance scale. They did not oppose to do the handwriting. The handwriting assessing the clinic versus the handwriting as impact to the patient's life because there are two of them, as you know, and to the spirals, although they're less inclined to rely since they spirals, as you're gonna read yourself. When you look into the feedback, becomes again quite clear that we went with the most comprehensive version.
We're looking into how these patients behave. What we learned here, is that the assessment, neurological assessment in the clinic is just not reliable. I think we've seen this in other clinical trials in this space, both in neurology at large and specifically in essential tremor, made this assumption based on the data stats we had before, where being a smaller data stats, maybe less size, was a little bit more stable. Our, our degree of confidence is very high, and that's based on the feedback we have from the FDA to date, they wanna encourage you to take a look at. In terms of the timing, we're gonna be meeting with them ASAP. As you know, it's a special type of Type B request.
The end of phase II meeting, 70 days from the time of the request that is granted. We're working diligently to put the package together to submit to the agents. That's why we gave the 100 days- ish, deadline there. We're gonna be communicating to all of you shortly thereafter on their understanding, which we, again, strongly believe is gonna be in agreement with us.
Thank you, Marcio. I'll jump back into the queue.
All right. Thanks.
Thank you. Our next question comes from Myles Minter with William Blair. Your line is open.
Hey, thanks for taking the first question. I believe from the prior phase IIa that one of the signals that could have confounded not getting more responders was, like, dizziness and confusion. It does seem to be popping up again in this trial despite the slower titration. I just wanted your thoughts on whether you thought that those AEs impacted the ability of a trial participant to perform on those TETRAS-PS items that seem to be trending in the wrong way from the ADLs, and if the slower titration achieved the improvement in AEs that you were hoping for in this trial. Thanks.
Thanks, Myles. I'll start with the last part of your question there. These lower titration did not improve, I would say in general. I think what we learned, it's a little bit more idiosyncratic than necessarily titration related here. Definitely we shouldn't start with a high dose, but probably would have been fine to just start with 20 mg, for example, as before. The events of dizziness that you mentioned, they're very short in duration, and just a few of them led to discontinuation. It's actually lower than we're expecting, much lower than any other competitive trial in this space. We do not believe that there was that in general that affect the assessments. We believe the problem is with the assessments.
As you recall in another trial in this space that's being reported previously, the two different assessors had discordant views on the performance scale. As you're gonna read on the feedback from the agents that we posted with the SEC today, the FDA probably seen that as well and warns that that is more chance to unreliable assessments. When you look throughout the times, obviously you are looking for an aggregate number here at the very end. It's actually bounced back and forth a lot more inconsistently in terms of the PS assessments in general, which handwriting and spirals are part of, versus the activities of daily living were really clearly more on the impacts. I'll point it out to one specifically. The handwriting as assessed by the patients, right?
During the last seven days, the activities to write, and general tasks, general life, things that you and I do, taking notes and so on, was positive across all the analysis. When you look into the writing of the cursive name in front of the physician, the assessment was basically new. I don't believe that those things are the same. We don't believe those things are the same. They As you've seen now, as we learned from this trial, they have less sensitivity in general. So not putting too much emphasis on the side effect profile was very mild, but rather on the assessment itself.
Okay, cool. Just a quick follow-up. You measured both TETRAS PS, the entirety of that scale, and the entirety of the ADL, then back calculated the modified version of it. What was the data looking like for the entirety of the performance scale? Were the parameters all, like, not improved to worsening as you've shown with the three that we're seeing today, or did it paint a different picture? Thank you.
We included in the appendix of the slides that we posted on our website today, and I'll point you to slide 29 there, where the three items, the three ways to analyze the PS, right? We have seen no change on the performance scale in aggregates. The point estimate is really around 0 out there. We have seen no change on the combined upper limb. Same thing, high variability point estimates. A slight change on the upper limb, which as you recall we discussed before, was never deemed to be reliable. The overall, what I would call neurological examination that is assessed as an endpoint did not perform reliably here.
Okay. Thanks for the questions. Hop back in the queue.
Thank you.
Thank you. We have a question from Douglas Tsao from H.C. Wainwright. Your line is open.
Hi. Good morning. Good to see the data. Marcio, it sounds like it looks like there's a pretty significant discrepancy between the response patients with and without intention tremor resulted from ulixa. I'm just curious, it looks like about 18 patients had intention tremor in the study. Just curious, is that relatively reflective of the broader population of the essential tremor population at large? To confirm, would you be looking to exclude those in the phase III study?
Yeah. Thanks, Doug. Intention tremor, and maybe to be clear here, and I know you got it, but just like for the broader audience, right? All those patients in the trial had essential tremor for more than three years and so on. Since 2018, so it's like relatively recently, the Movement Disorder Society guideline included this other, like, specifiers in terms of other confounding tremors. We assess that. We, we check that at baseline, right, that screening, and we carry that to baseline. That's how we had the data to look. This is the first trial that collected data prospectively since it's the first one after 2018 that follows the MDS guideline here. I wanna make that point.
When you look into those patients, and we look into the literature, that is very scarce because there's not a lot of data being followed. What we're seeing is that the fact that the tremor amplifies towards the objects can confound the assessments. I think that's the point we're trying to make. We will exclude them moving forward from primary analysis. We still might include them in a trial side of a primary analysis. We do not believe we're harming these patients, right? We not believe that they wouldn't benefit as the essential tremor component, but they are, from a clinical development perspective, not a good source of patients because they add a significant amount of variability.
To your question about the prevalence of the that feature with essential tremor patients, I think that the question's up in the air. I don't think it's unreasonable to estimate between, like, 15%-30% at this point in time based on the data we're seeing. But that is not something that is clear in the fields at this point in time.
Okay. To clarify, Marcio, you do think that they derive a clinical benefit. It is just largely from a clinical trial execution standpoint that they are bad candidates for ulixacaltamide.
That's correct. That's correct. Let me give you a little bit more color, right? We look into that analysis, excluding them as you've seen on this study because we just cannot control for the variable. That's the most proper way to do. When we compare them, just a group of patients who had intention tremor and essential tremor, there is no harm towards using ulixacaltamide. It's actually small benefits that we're seeing there. It's just so imbalanced because they change, like, in a lot more erratic way, I would call, than the patients we expect, that they're not proper to be analyzed. Had we known this before the trial, there was no literature for us to base, there was no other trials for us to base, we obviously would have excluded them.
Maybe a note here or a color is in the II to I dataset, which was basically what we used to define this trial, as you recall the previous phase II-A study, there were two patients with this feature. It went back to the dataset. We collected data there as well. Those two individuals, they stayed online for four after the randomized withdrawal. One had been a good responder, another one not, so they kind of cancel out. All the calculations we made based on the randomized withdrawals are still pretty much valid, and they were all driven by the patients who are the pure essential tremor patients, the ones we're showing without the analysis here.
That was what drove usSo de facto, and I know a posteriori it's easy, and I'm not trying to make an excuse whatsoever. I know you know me well. We're looking into this. It was the intended population that we wanted to treat, when we removed those patients.
Okay, great. Thank you. I'll hop back into the queue.
Thank you, Doug.
Thank you. Our next question comes from Tazeen Ahmad with Bank of America. Your line is open.
Hi, guys. Good morning. I have a few questions. Maybe can we just start off with your decision to propose to move straight to phase III? Just based on the data that you've presented today, it does seem that you may still have some questions that need to be sorted. I guess why not just do another phase II to answer these questions rather than, you know, in a sense, risking it on moving to, you know, a phase III, which could be, you know, costly for the company? Then I have a couple of follow-ups.
Hey, Tazeen. First and foremost, right, I actually don't believe there is such a thing as questions left here to move to phase III. The results of a phase II are to inform basically three things, right? 1, exposure response. We checked the box. Is there a minimal dose that drives the effect? 60 mg clearly does. The second is there a new safe signal or additional incidents of a safe signal that we should be looking for the size or moving forward or the safe database, and we checked that box. The last one is, can we define, one, a clear population and, two, a clear endpoint that to power that phase III and to move forward? We have both of those as well.
That is, actually would be maybe disingenuous not to move, forward. How to power that trial, what is the exact duration and the design? I think those are open questions for us to discuss with the FDA, that's why we're saying the proper path here is an end of phase II meeting, not, like another, phase II. I'm actually curious on what another phase II would answer, that we haven't answered at this point in time.
Yeah, I asked that just because maybe do you wanna have a better sense of what the titration schedule should look like? I guess related to the population, you just said it was the intended population. I think in the past you had said that older patients might skew the results a bit. Did you have a good distribution around age in this particular study?
Yeah. Thank you so much for clarifying that, Tazeen. The titration, we did not explore much, so I understand why you would ask the question. The titration actually is very clear that after 20 mg, the patients start responding. They can go there to individual response up to 60, but not beyond that. There's no additional response. We're pretty clear on that titration, and, like, we chose not to show all the data today since we're already being quite comprehensive. You are correct in relation to the age as it relates to severity, and the proper way to control for that moving forward is really using stratification factors, and we're gonna continue to do that.
Okay. Thanks for clarifying. Just on the total enrollment of patients was 132, right?
Correct.
You included 116. Just wanted to see what that delta was?
Yeah. From the very beginning of the analysis, the full analysis set or what we call mITT here, were the patients who were enrolled under version four of the protocol. What that version four means is after we amended the protocol for efficacy as the endpoint, they had to have a minimal severity in terms of the ADL and the global severity as moderate to severe and had to be randomized to either placebo, 60 mg regimen, or a 100 mg regimen. That analysis set was defined prospectively and allowed for patients who were previously enrolled to be included as well. The trial was blinded, so we didn't know how many was previously enrolled, so we made an estimation.
If you look back to the posters that we presented at the MDS conference last year, gonna see that that analysis was pretty clearly defined there. We did not change that. The difference was some patients were randomized to 20 mg since at one point in time there was a 20 mg arm, and a few patients who did not meet the severity criteria for the analysis sets.
Okay. Thanks for answering all the questions. Appreciate it.
Of course.
One moment. Our next question comes from Ritu Baral with Cowen. Your line is open.
Good morning, guys. Thanks for taking the question. A couple on my part. One, looking at slide 15, I guess I'm trying to figure out the scales here. I'm looking at sort of the different bars on slide 15. Are we looking at effect size on improvement? Because even relative to each other, say dressing and using keys, it looks like the bars are of different proportion. The items of benefit between the two analyses. As a follow-up to that, in the meeting minutes, FDA clearly says, you know, social impact, not important.
Conversely, are there other portions of the meeting minutes that are more important to them that there's some minimal threshold because, you know, using keys sounds terrifically important, but so does something like working or feeding with a spoon, which shows less impact on this.
Yeah.
Thanks.
Thank you so much, Ritu, for that. When you look into the bar, what you're trying to show here, right. The impact at baseline for each one of those items is different, as you can imagine, and that's why we are looking to the difference, the adjusted difference between placebo and a drug to give an idea if that is what kind of magnitude it is. We're gonna continue to present this data at AAN and other scientific conference. We're gonna see a little bit more. Your second question is, yes, it's very clear on the social impact. It was not clear. It was not called out by the FDA on any other item. I'll give you color on things that are important to discuss and by the fields.
The average age of those patients is 70, as you saw at the demographics. Working is different as we age in society, so we don't consider necessarily that should be negative or less impact, but just the amplitude of the impact versus continue to dress as we all dress in the morning and sometimes more times in the day, independent of our age or using keys and other small objects, or, the general disability impacted by this disease, and so on and so forth. They all meet, as you know, the criteria of function under 21 CFR.
Got it. Do you think some of this, as you think about the reliability, do you think this is a function of sites? Do you have to think about which sites and maybe, do more site evaluations, for lack of a better term, for the phase III?
Yeah. The patients reported part, right? The ADL was very, very reliable. I'm not answering your question because we're asking about the site. Our patients with essential tremor who comes to a site and assess the last seven days and talk about they were very, very reliable. We see that between screening and baseline throughout the visits. They're incredible subjects to participate in this trial. The sites did very good quality work here as well. I do believe when you look into data that is not here, but I'm gonna talk to you about screening to baseline, it is just very difficult for these physicians. I'm not saying the quality of the site was low because was not. They did a very good job.
Rather how difficult it is to turn a neurological exam into a score. I think that's what a little bit of the FDA was trying to warn us as well on the communications. You probably read that. Could other measures fix this? I think both ourselves and others attempted to do video. We did on this study. We observed the video. We lose one dimension, that is placements and things like that. There are central raters. We use a central QC for the screening, and I can go on and on. We're trying to fix a broken endpoint.
I think the best way for all in the fields to move on is to really no look back on the, on the performance scale and abandon once and for all something that is not added validity to the, to the fields or to those patients.
Got it. Very last question, I promise. Any falls seen in this study?
Would you say it again, please?
Any falls, patient falls as a side effect?
Falls? No. Yes.
Falls.
Incredibly relevant. Incredibly relevant, right? This is an elder patient population. We had a little bit of dizziness. No, we did not have falls. We did not have fractures. We did not have anything that would be problematic here, I would say thankfully, and I'm very happy for their safety as well.
Great. Thanks.
Thank you.
Thank you. We have a question from Laura Chico from Wedbush. Your line is open.
Hey, good morning, guys. Thank you very much for taking the question. I'm gonna ask probably a naive one, but can you remind us when the FDA feedback that you aced was provided?
It was about one and a half years ago, Laura. We requested the feedback in Q1 2021, took a little while, I think, to get the response. Obviously when we got the response was about, when we were running the II-A. I would say just back then for context, right, as the field was always influenced a little bit by the literature in the fields, everyone was looking to upper limb and measures on upper limb. So our question or briefing book was really based on that. I think they came and gave us the response that you're seeing that they don't really like the upper limb. We shut that one out, and I think we talked before.
We're looking and we're working with them, I would say on the, on the rest of the scale on things that could be relevant. As we know right now, I think we can just put the nail in the coffin of the PS and maybe invalidate that scale.
Okay. That's helpful, Marcio. Then I guess, you know, kind of following up on the other question, just with respect to trying to get certainty around what constitutes an approvable endpoint or a regulatory path here. Would you seek an SPA from the agency?
Yeah. Yeah. I think we first, we're interpreting the feedback as one should, right? In the paragraph that they say, "Have the potential to be acceptable clinical endpoints," that is, as regulatory language goes, that's as strong as it gets. I don't think there is a margin of error here for using the ADL. Now in an end of phase II meeting, as we're ready to proceed there and to start a phase III, that is the endpoint we're proposing as well in front of them. We think there is incredibly high certainty that they would be okay with it.
Okay. Last question, just circling back to the AEs, and this has come up a few times now. This is going to be an elderly population, what stood out on some of these discontinuations, though, were due to kind of these cognitive-related adverse events such as hallucination, feeling abnormal. I guess in terms of a final target product profile, how does this influence your thoughts about positioning in the marketplace? I guess, does that ultimately impact the view on what the ultimate addressable population would be used in? Thank you.
Yeah. We're looking into that, or like before, right? Before the trial and looking through assessing. I would say the feedback we got from key opinion leaders, this is pretty much par for the course in terms of like CNS active drugs, as used in this patient population. Not really concerned. We're looking for upwards of 20% as being meeting the target profile here, we are way short of that. Those are short in duration as well, not impacting them in terms of long duration in general. From a market perspective, from a safety perspective in general, we are not concerned with what we're seeing. It's also competitively, when you look into the other drugs and developments are quite favorable.
The one point I would like to make is patients with essential tremor were moderate to severe as the ones we've seen here. When you give them drugs that really give them effect, right, to reduce significantly the disease, they tend not to tolerate and discontinue. Discontinue at rates that are much larger than the ones we're seeing here. The excitement I believe we heard from the key opinion leader is this, it's transient, it lasts a day or two. If they cannot tolerate, they cannot tolerate. Sure, they discontinue, but if they stay, it goes away, number two. Second, they respond. That is a really big deal for them because they don't have that kind of option at this point in time.
I believe that was the feedback we got, and very exciting to hear that because it's easy for us to get excited about a drug, but it's good to see the field getting excited about it as well. As I hear this morning from a patient after we release the data with the excitements on that kind of drug would be very important on that person's life. That's what really meant a lot for me. I know it's one person reaching out, but at the end of the day, that's what we are trying to do as a company, is to help people.
Thanks, Marcio.
Of course. Thanks, Laura.
Thank you. One moment. We have a follow-up from Tazeen Ahmad from Bank of America. Your line is open.
Hi, guys. Thanks for taking the follow-up. Maybe Marcio, just for clarification, when you talk about the composite primary endpoint for TETRAS, does that include the performance scale items, or is that excluded, like the spirals and the handwriting?
When we talked about the primary that we use right now, it does include the performance. When we're talking about moving forward, we're not going to be including the performance scale. I think that's the divider there. If you exclude the performance scale, as you probably saw on the slides, it becomes a lot more uniform, the groups, in a very clear separation. Not only separation, not only moving forward because it's positive for the drug. The overall behavior of the groups, the overall distribution of the groups is very clear, like placebo is not supposed to move in this patient population. That's what we see much more homogeneous versus like up and down, as we see on the other scales. I hope that makes it a little bit more clear.
Yeah.
Appreciate the follow-up.
Thank you.
Thank you. There are no other questions in the queue. I'd like to turn the call back to Marcio Souza for closing remarks.
Thank you so much, thanks everyone for asking the questions. I think I would like to close with three points here. First, everything we do is going back to whether or not we're helping patients here at Praxis. Today's a big day for that and for patients with essential tremor, and we're really moving forward to help them expeditiously and to get this drug to phase III. The second is the certainty around moving to phase III that I wanted to convey. Right? We checked the boxes, as one could say, in terms of the exposure response, the dose titration, this drug being active, the endpoints being certain, and really having the ability and the means to move to phase III enabled by the end of phase II meeting with the FDA. That is forthcoming.
The last one is, while today we are excited about Essential1 and what it enables us to do for those patients, we remain equally excited about the milestone that we have for the remainder of the year for our epilepsy programs. Helping patients at large with CNS conditions is key for us. We have three other programs in the clinic in epilepsy addressing specific populations that are gonna have updates and readouts in the next several months between now and the end of the year. We really believe that that's gonna bring significant value to the target of this call. There's our investors, but also to patients at large. That is what it really means for us. Excited rest of the year for all of us here.
Appreciate everyone's support and questions, and looking forward to continue interacting with all of you.
This concludes today's conference call. Thank you for participating. You may now disconnect. Everyone, have a great day.