Praxis Precision Medicines, Inc. (PRAX) Earnings Call Transcript & Summary

Good morning, everyone. It's a real pleasure to be here with all of you, the government [indiscernible], so don't have to worry about that. So we can focus on our update for the R&D Day. Praxis is incredibly humbling at to be here with some of the updates that we are going to be showing today. Before I get started, I just want to make sure, we're going to be making forward-looking statements. Refer to our SEC website for some of them. And together with myself, we're going to be joined by some of our same colleagues at Praxis, but also by Dr. S.P and experts and Movement Disorder by Dr. French, that requires no introduction, an expert on the epilepsy field as well. The format of the meeting is going to be focused on some of the key topics that are relevant for us right now as a company, and shortly thereafter for each one of the sections, we're going to have a Q&A. I'm more than encourage, I ask you to participate during the Q&A session. I think we can have a very robust discussion with our experts here during all of that. Just a reminder, and I know most of you, either here in presence in Burford, New York City, or on the webcast are quite familiar with Praxis. But we do have 2 platforms: one is Small Molecule Platform; and one, Oligonucleotide platform. We're very excited about both of them. Going to be giving updates today on both sides of this equation. But one point that I wanted to make upfront is that all of that is enabled by our understanding of genetics in the brain. Right? So how genetics manifest, and how the lab creates, unfortunately, certain conditions that affect patients leading to CNS disorders. Specifically for the time we have today allocated and for the time of the year, we're going to be focusing on 3 major programs. Alex is going to discuss Ulixacaltamide, our late-stage program in Phase III for essential tremor. The main areas we're going to be covering there is the confidence we got from Essential1 after the initial analysis and beyond that to enable our Phase III program. And then the second is, how is that Phase III program? I know many of the questions we get throughout the last several months from all of you is how we are going to operationalize, what is the power of that study, like how the recruitment and so on. I think we have some quite exciting news there as well. Karl is going to be reviewing the 628 program as well, something we are incredibly excited about, like, which, in our view, it is really the ultimate way to disrupt positively Focal Epilepsy and Generalize Epilepsy in the markets, which is very much needed as we're going to continue to discuss on the next few hours. And lastly, I'm going to discuss a little bit Praxis [indiscernible] and what we've been doing about it and what we have been seeing with these patients, and I believe it is going to be quite exciting. I hope you are as excited as I am at the end of that conversation. Just going back to the principles here, and Steve is going to go in a lot more detail about this, but I want to remind us all, right, on how we look into drug discovery, through developments, derisking as a framework for Praxis. So look into genetics as like a foundation, you might be aware of that, but drugs with an understanding of the underpinnings from a genetic perspective are twice as successful at the end, when you look into all the analogs for the ones that are not. So we see this not only as an engine, but it's a derisking factor for us as well. The use of translational tools are going to be quite obvious throughout the presentation. Obviously, every single company doing drug development use translational tools, but we're looking here into very specific ways to enable the program, understanding the biology and imagine what matter and using that measure to answer the question that you are primarily asking. And efficiency and rigor, or speeds and quality are not trade-offs. You can do both when you're very deliberate about doing both. And that's for it's something we're incredibly committed about doing, and that's going to be incredibly clear, when Alex describe the Essential3 program that that's how we're calling our Phase III program for Ulixacaltamide on how we are bringing that to life as we speak. It goes without saying, and it's oftentimes more rhetorical than II, when people say they are patient -- center patient guided. But for us, it's very real. From the very beginning, when you look into genetics or population genetics or specific for what kind of translation does that matter for patients, is the way we are delivering the clinical drug, the clinical trial, are we meeting the patients where they are, is something incredibly important. Do we actually understand what are the needs? And that's going to become quite obvious in some of the areas, both in essential term or in epilepsy. They're going to go there. For, fundamentally, this audience, right? This is a value conversation. And we need to make sure, we understand, as a company, and we give you the confidence as our shareholders and investors and others that we understand the value on both sides of this equation, both on movement disorders, and on epilepsy. It's going to be quite obvious at the end that it is obvious for us, please criticize as if that's not the case, that the value is tremendous on both sides of that. I just want to illustrate, by going through a very high-level idea value for first essential tremor and then the epilepsies that we are going after. When you look into essential tremor in the United States alone, arguably someone in this room has it. Seven million individuals outside of the door are now coping with it. It is not a benign condition. As been described before, it affects every aspect of their life and it progress as the patients age in most cases, not in all cases, but in most cases. About 2 million of those patients are seeking treatment. To some extent, in despair, as Alex is going to go for the funnel here understanding like what happens when you get treatment, what happens on the next month, what happens on the next year. And unfortunately, it's not a beautiful picture here. So from an unmanned perspective, it's undeniable that it needs to be disrupted, and it will be disrupted with Ulixacaltamide. From a value perspective, it's a wide open market. When you compare to even less common drugs like, it's abysmal. The difference between alternatives patients have and every disease, in my view, is important, right? So I'm not making here a relative importance on where drugs should be developed for A or for B indications. That's not -- by no means or the chart is meant to show, but it's really the inability to address this disease with what we have right now. So one has to ask why in a situation like this. Then why is it that endogenous disease endpoints that have not been defined, understandings of the biology and fundamentally mechanisms that address fundamentally the dysfunction in the brain, the oscillatory networks that are not behaving the way one would like them to do. And the collection of all of that is what we are trying to address today, with Ulixacaltamide. And by the end of the conversation, I trust that all of us are going to be on the same page, how that's going to happen. I also hope that I was here today, and I know hope is not a strategy, and I always use that, but I do hope that we were here today saying, oh, [indiscernible] epilepsy is completely different, right? We know how to treat epilepsy for decades and decades. So therefore, the picture is different. But the picture is not that different. Most of the discussion in the field right now is about the middle of this chart. It's about the patients with refractory seizures. And yes, if you look into that alone, and there are a million patients in the United States that start the treatment, stop, don't control their seizures, cannot drive, cannot care for their families, cannot be in a hotel room alone. Those are implications of having one seizure, not many, one. They cannot control with everything because -- and the because here, I am going to be explained later, right? It's not only the efficacy, that is the tolerability that plays a huge role here. That alone would be a massive market. But I'm going to invite you to think about what's happening with the other 2.5 million patients today as well. Because they are by no mean like enjoying what's happening. And just like leaving their lives, as most of us here are without the constant fear that they're going to have a breakthrough seizure. Or with the constant fear or that the side effects are too much for their life and they might need to trade off like having a seizure for continue having a side effect. So that's quite important. But to also know, we do have a smaller indication and small is always relative. In terms of the [ DEEs ] that we are aiming to resolve. When you look into their markets and while there are fantastic advance there, like looking to the left-hand side, and I'm very thankful for the scientists, for the companies, for people in the fields actually driving like great solutions for SCN1A. Patients for Dravet syndrome or patients for [ Lennox-Gastaut ] or patients -- there are still residual needs there, absolutely. And I'm glad there's many, many companies working on that, and it's wonderful for the fields. But when you look into the right-hand side there, like if you start walking from that first bar, the needs for patients with other [indiscernible], and we created subset here on things that we are actively working to address are incredible. The difference is that there is nothing for them right now. So when a patient with SCN2A, gain of function or loss of function, but let's focus for a second on gain a function here, exhaust all the interstitial medications as they happen very quickly. They are at the mercy of the next seizure. And that's quite important, right? Because think about your own life and loved ones and having that next seizure, how important it is. So I'm going to take that opportunity and to some extent, the hope there to talk a little bit about the 222 program because we haven't really explored to its depth, how much excited we are about it. So as you know, PRAX-222, now we have the proposed INN there. So we can give them a name and hopefully, some last name. The aim is to revolutionize the way ASOs are developed for epilepsies. That was the aim from the beginning when Dr. Petrou and Alex, Kelly started working on this as a very small group of people trying to solve this problem, right? But it is still the aim today, that we are really working very hard to these routes. Maybe just to ground everyone on 2A. When you look into the condition, patients with mutations on the gene that encodes to Nav1.2, this sudden channel in the brain or SGN2A. They have a very predictable to some extent, life. They seize at birth or no later than 3 months at life, and I know many people in this audience here and the webcast have kids. So just imagine that for a second, right, a newborn and [indiscernible] at the day, they don't go away. There are many other conditions that kids have seizures at birth. And I don't wish any of them to actually ever happen, but that you can control and control pretty well, but you cannot. They're refractory and they continue throughout the life of those patients. The one concept that might have been lost is that, that is a direct correlation between sudden and unexpected [indiscernible] with the number, frequency and severity of seizures a patient have. So when you're talking about reducing that, we are talking about survival, right? We're directly linking not only quality of life as many talk, not only the reduction in an end point, but really keeping these kids alive for better medical advance, better treatment, better understanding of how to give those treatments or simply to enjoy more time with their families. So our mission is really to change the trajectory, like 1 patient at time. And we always said that, right? A lot of you have been interacting with us in a very long time. But this came to life several months ago, like about 7 months ago, in a way that was unexpected for us, and that's how I would like to start this conversation. We got a call from a team saying, "We have a patient here with us, and this patient was born in convulsive status epilepticus. We try to do everything we could to rescue, where a lot of you know, like other companies are working on that space as well, they couldn't do anything. So we know the trajectory, right? They're going to continuously seize, have both our seizures and unfortunately, perish -- the most part. And the question at that point in time is, would you be willing to provide PRAX-222 in an emergency base. No. Put ourselves in our shoes at that point in time, right? This would be the first patient ever to receive the drugs, an emergency case. And as you can see here, was not only that, it was a preterm newborn. So we go back to the framework. Are we here to help or are we here to just like play into the development the way we normally have plans. And I think the decision at the end of the day was we're here to help. Obviously, we had multiple meetings with the team there. A fantastic team of physicians and parents that we're engaged on this. And the expectation at that point in time is, well, maybe you can help them get a little bit more rescue medications going on and a few other things, to keep this kid stable. But what we're actually seeing was fairly dramatic. So what we see in this patient is after 1 dose, the very first dose within the very first month, it went from continuous convulsive seizure. We're talking about an EEG that does not change patterns here. So I want to be clear, right? This is not like you are 5 minutes and then it goes away and then 5 minutes and go away as sometimes Status Epilepticus is. This is a very, very severe kid on the ICU without really any other. And what we see in this periods that was not happening. So encouraging, but not necessarily the end of it. Now you fast forward to 7 dose of the drug. And remember, 7 dose is not like 7 days. 7 dose are 7 months or more, here, right? We were talking about twice as long of a period of observation for every antiseizure medication that has been approved in the United States to date on their pivotal trial. I want to put that in context, right? The way to approve drugs is 12 weeks observation, versus the 28 days before at baseline. Just to create the framework that it goes beyond that normal period of observation for the first [indiscernible] studies that are looking. And as you can see here and read all of this or -- it's dramatic, the change. No status, basically no seizures. And what for me was quite phenomenal, one was shared by the clinical team is like being able to breast feed, right? That is a very high function, requires a lot of coordination, requires a lot of like other things going on in the environment for a patient like that. That patient is clinically stable. This actual 7th dose was just delivered days or so. So really doing great. Now if I show you data from 1 patient or say, no, Marcio, this is great. And I think we're all excited about it and I'm glad you're helping 1 patient. So our next question is, what is happening with our [indiscernible] trial in the United States, rather being running a study in the United States, as you are all aware, which we call EMBRAVE. And just to bring it back to what we aim to do EMBRAVE in the current study here in the U.S. So we're looking for primarily, safety, right? That was the objective. So got to the end of EMBRAVE, gave them 4 dose. The patients were safe like no major issues, no major like side effects, would say success that was a success. No. Because we care a lot, our bar was, we expect to see something going on as well on their seizures, and overall. Patients were dosed every month and then they're collected daily seizure information and then the following month and so on. So at this point in time, as we stand here with you today, we have 3 of those completed -- 3 months observation. So 3 dose plus 2 weeks after for the observations completed for all those patients. The fourth period is forthcoming in the next few weeks as well. And what we're seeing -- I believe shocked us, to some extent, not because we're not expecting, but because we're incredibly happy with what we are seeing. As some of you research [indiscernible] leaders, wrote in your reports on the analyst community here on the ones, investors on the phone that talked with us. If you've seen 10%, 15% seizure reduction on this cohort, we should be really, really happy, right? Because all those patients are on best standard of care. Like everything was tried, they are stable on that dose. There is nothing else to be gain from the treatment area. But what we're actually seeing, is much better results than that at this point in time. So we see here after 1 dose, 2 dose, 3 dose, [indiscernible], we're seeing orders of magnitude than our expectation. And as you can see on the range on the bottom here of the slides, of course, there's variability within those patients. But every one of them benefited. So when you put this together on 4 patients here, the patient on the emergence access, it becomes very, very hard no matter how much you want to maybe add some caveats to not believe that this is the most incredible results that's been seen in this disease ever, right? It would be great to just stop here, right? But one of the things we heard again and again from key opinion leaders in this field is, did it reduce just the number of seizures? Or there is any other measure associated with that, that might be important for the patients, for their lives? As you all know, there is a big like agenda push rightly so by the FDA on understanding how does that impact patients' lives at the end. And then when you look into the number of days in demand, that they did not seize at all, right? So 0 seizures entering that day. See the baseline there, 21% on the first month. And then in general, it's almost double, right? So from 21% to 33% number of days, it's a very, very significant. So I'm going to ask you once again to ask yourself, you have a kid with this condition, 24-hour care, what happens when they are actually not seizing the day to your life to a quality of life to the interventions and everything else. Now, there are much more to come as we continue to advance this. But it's quite incredible and unprecedented. It's also timely to some extent as we're preparing for this conversation in the last few days. And I got to back on Saturday saying 1 more patient died in the United States, 10-year-olds, with this condition. That hurts because our speed is never as fast as the families expected us to be as these patients needed to be. But it creates a motivation for me at least and for all of us at Praxis to actually move this, to actually help these patients more and more. Now none of this would matter if the drug was incredibly toxic and we couldn't give this to patients, they're having all sort of weird side effects, but that's not the case. We had no treatment emerging, adverse events or they are related to drug or serious adverse events related to drug. Not showing all the lab values and things like this here, and we're going to do this in a later date. But I can tell you that it's pretty an eventful as well [indiscernible] as safety should always be for situations like this. So incredibly excited, but it does change the trajectory of the program for us, because our target profile was less than what we were seeing with this cohort right now. So they are very rare times in history of drug development that one can reach the target profile in the first cohort. So our proposal for next steps here is, obviously, you're going to wrap it up the collection. We want to make sure that we do that, compile this package on the next several weeks, have an interaction with the FDA, which we obviously expect them to be very open to the benefit risk that exists here for disease without any other treatments. There's not only any other treatment available, there is no any other treatments in development. There's absolutely nothing else in the clinic for these patients. So therefore, the urgency as well. And having now decided that this dose is efficacious to expand this cohort and to run a pivotal trial. Actually, now that I said that the dose, I was remiss to actually reflect on that dose. You're all very familiar with intrathecally delivered ASOs. And with the great benefits that are being seen with some of the setbacks that happened in the field as well. And if that is one thing we know about drug development in general is like, should always try to give the least amount of drug that's going to give you the maximum benefits, right? Not only because it's nice, but because drugs do other things when you give a lot of them, chemically or biophysically or biochemistry, they just happen. And this -- so we knew from the very beginning is incredibly potent, distributes really well on the brain and it's giving a 1 milligram dose every month. So very, very happy with what we hear, incredibly humbled by where we stand as well. They study in the U.S. by design was done with Dr. James Willis and -- in Tennessee. So I would be remissed not to actually thank him and his team were like word leaders in this kind of study, they really jumped in, brought all their patients there, did the best possible care these patients could have and -- but ultimately, the heroes here are those patients, right? When they got to the trial, despite not having other alternative, they didn't know the risk they were putting the kids in. So I just want to take this moment as well to thank them. It brings me to our like moto, tagline, philosophy for life, at Praxis, we always say, we are there for more. And we, therefore, more for each one of those patients for every execution for every study we conducted for every patient and life we touch about every conversation we follow you. I'm sure you all will relate to that. And this is a very clear example of what there for more actually means for these patients. So I sincerely hope that you are excited as I am as everyone else, at Praxis and obviously, the community at large out there is for this drug to move forward. So before I move to Alex to give us an update on Ulixacaltamide, I just want to review very quickly and go back to the calendar for the milestones for us here. As you can see, I'm going to focus on the right part. So the -- we're going to be discussing the Ulixa Phase III program, 2 studies as Alex is going to review, Initiation [indiscernible] we're in Q4. Hard to believe we are here already, but we're starting there. We're going to be fast and furious about driving that study to completion as going to be clear by the end of this conversation. Karl is going to discuss the readout -- expected readout by the end of the year for our PPR study with 628 and why we are doing, it is why we believe that's an important additional piece of information. We just talked about EMBRAVE in general, there are many other things. The one change that I wanted to highlight here is why we have very good interest and patients for the 562 study. We underestimated the fragility of these patients during the enrollment periods. And really the ability to get to these patients on the time that we had. So we're extending the time to complete the enrollment for that study a little longer. Mostly to allow for this entire screening process and the stabilization process actually for the accounting of the seizures and make sure these patients are there. We also pivot to a hybrid study design for 562, where one of the biggest issues that we are facing is that patients want to participate in the trial. They are willing, but they can't go to the sites. Because there's really a lot when they moved. So we created a hybrid network, where the health care team goes to their house and do the assessment versus the other way around, which is to our knowledge being discussed for a lot in epilepsy, but has not been implemented. We're very happy with the implementation with the quality of it and using their learnings for future studies as well. So before further ado, I'm going to ask Alex La Croix, our Head of Movement Disorders to talk a little bit about the Ulixa Program.

Thank you, Marcio. So as Marcio mentioned, my name is Alex La Croix, I'm the program lead for ulixacaltamide at Praxis. So two things, so there are two topics on the slide. But first, I just want to emphasize this is not a clinical update on ulixacaltamide, but really, how are we leveraging the insights from the Essential1 program into our Phase III program. And as Marcio mentioned, the Phase III program is Essential3. Before I get started, I just want to point out, I work with an exceptional group of people at Praxis, whether it's the study teams that are supporting the program or the broader network of staff that are supporting those teams, and even our leadership team which is highly engaged in the program and, as Marcio said, is daring the team to do more as well. So I just want to recognize that all of the data you're going to see is really reflective of that team's efforts over the past 7 months since we released top line data. So essential tremor is underappreciated disorder. And as Marcio mentioned, it's often referred to as a benign disease, a benign tremor. And I would ask the question of benign compared to what. Like, vanilla ice cream is benign, but a disease, no matter what the disease, is not benign. And if you were to ask a patient with essential tremor or the family members that support those patients, essential tremor is not benign. And it's really surprising that there's that perspective of this disease because essential tremor is the largest movement disorder in the space. That are approximately 7 million patients with the disease, and their daily activities are severely affected. And because they're affected, these patients also acquire comorbid conditions around anxiety, frustration, depression, things that not only impact them and their family members but also are triggers for the disease as well. One of the reasons why there is a misperception around essential tremor is a perception that the modalities for essential tremor are viable for these patients. There's an approved therapy, propranolol. It was approved back in 1986. But the vast majority of patients cannot take propranolol because it is contraindicated due to health conditions, health risks, other medications they're taking as well. And based on our claims data, we know that the small fraction of patients who actually take propranolol rapidly discontinue. So a small number start taking propranolol, an even smaller fraction of the patients who seek treatment end up maintaining propranolol therapy after 2 years, 20%. As Marcio has mentioned, our goal is to disrupt care in essential tremor. We intend to be not only the first in class but the best-in-class novel modality in essential tremor. And we, based on our emerging profile with Essential1, are going to be significantly differentiated in terms of efficacy, clinically meaningful benefit to patients, safety and tolerability, adherence. And it will be able to be used in a broad section of the patient population, not a subset like propranolol is. And we'll also share some early data that shows that it can be used, even in the subset of patients that are on propranolol, with or without having incremental benefit. So essential tremor -- I'm sorry, Essential1 has demonstrated clinical benefit at multiple time points in the study. And I'll share that with you. But even in the first 8 weeks of the study, the efficacy has been compelling. We'll show more data that shows that it's long-term benefit and durable and also is confirmed in patients that are switched from placebo and also has a well-tolerated safety profile as well. And one of the other things that we did in Essential1 was deliberately tested concepts and operational strategies that we intend to implement in our Phase III program as well. And an important aspect of this is that we were able to have a data-driven discussion with the FDA in our end of Phase II meeting, so where they agreed to mADL11 as our primary end point, a study duration of 12 weeks, and other design elements with the study as well. And another operational consideration here is that we're going to be taking a robust patient recruitment strategy, which I'll talk about more later in the slide presentation, and applying that to our Phase III program to rapidly enroll this Phase III study. So I'm sure everybody is aware of the Essential1 study schema, but I just want to point out three things because there are three main takeaways with the Essential1 study. So we saw in the first part, through week 8, we saw proof of concept, clinical proof of concept, with the Essential1 with ulixacaltamide. In the second portion, in the double-blind lead-in, which I just want to remind folks is, when we took all of the placebo patients and transitioned them on to drug in a blinded fashion, patients did not know if they were on active or placebo going into that study. And we saw two things in that period, one was a durable effect and the second was a confirmation of drug effect in the placebo patients transitioned to ulixa. And then the third part of the study, in our crossover design, we confirmed drug effect with a randomized withdrawal. And I'll walk through the data in subsequent slides. So again, FDA has agreed to mADL11 as our primary end point in the Phase III program. And when we look at the Essential1 data, through that lens, in 116 patients, which was the study population in Essential1, we see statistically significant results and separation between placebo and ulixacaltamide patients. And when we look at two clinical outcome measures, one is a patient-reported outcome and the other is a clinician outcome measure, so PGI-C is a patient-reported outcome that is the patient's perception of whether their condition is improving or worsening. And when we look at that data and compare it to placebo, again, we see a nominal value in that group. And when we look at the clinician perspective using CGI-S, which is severity scale, again, the clinician's perception of whether a patient's disease is actually becoming less severe or more severe, again, a p-value that is significant as well. So we now have three data points: mADL11 and two clinical outcome measures that all point in the same direction. So it's a reasonable question to ask, is mADL11 a clinically meaningful measure? What is clinically meaningful about a point improvement, 2-point improvement, 3-point improvement in mADL11? So shortly, after we had our top line results back in March, FDA came out with guidance about how to use these clinical outcome assessments, like PGI and CGI, and correlate them to a clinical measure like mADL11. And we applied their methodology to this analysis and found that a 2-point improvement in mADL11 was clinically meaningful. And that is our minimum clinically important difference. So when we look at our data through that lens and actually setting a slightly higher bar, not 2 points, but a 3-point improvement in mADL11, again, at 8 weeks of therapy, we see a clear separation between placebo and ulixacaltamide groups, statistically significant results. And one thing I want to point out again, this is not a mean 3-point change. It is patients, the proportion of patients who met that threshold, and almost 60% of patients on ulixacaltamide responded with that, met that minimum 3-point change. And I just want to put it in context as well that it's a minimum of 3 points. And at the upper end, it was a 17-point change in mADL11, so a pretty significant effect. And when we go out to week 14, there are two conclusions that we can draw from it. The first is that the patients who are on ulixacaltamide throughout the study continued to improve. And it was 55% at week 8, it's 64% at week 14, so a continued improvement in that group overall. And more importantly is that we see a confirmation of drug effect. So when the patients who are previously on placebo at week 8 are put on drug, we see a comparable effect a rapid-on effect in the patients who were transitioned to ulixacaltamide. And again, this was a blinded period in the study where patients didn't know if they were coming into that period on active drug or on placebo. And a slightly different way to look at this is when we take the subset of patients who were on a stable dose of propranolol, there were patients that were on placebo and propranolol in gray and you have patients on propranolol and ulixacaltamide in blue. And you see a nice separation and what seems to be a clear drug -- incremental drug effect when you layer on propranolol. And what we haven't included here is also an analysis going out to week 14 where we see those placebo patients who, again, 25% of the patients met that 3-point -- placebo patients met that 3-point threshold. At 14 weeks, they look just like the ulixacaltamide patients on this figure, so a nice confirmation of effect. So moving away from a discrete time point and looking at the continuous variable from week 8 to week 14, again, when patients who have been on ulixacaltamide throughout the study, and looking at their continued improvement beyond the primary period of the study, in the double-blind lead-in, we see almost 2 points additional improvement through week 14; and again, a confirmation of drug effect in the placebo patients who were transitioned at week 8 and have a rapid response to ulixacaltamide and again, looked very similar to the patients who are on ulixacaltamide throughout the study, almost -- over a 3-point change in that group as well. So all of the data that you've seen to this point is patients going on the ulixacaltamide. And in our randomized withdrawal study, our crossover design study where we randomized patients who are on a stable dose of ulixacaltamide to either placebo or ulixa, the patients who withdrew drug had the exact opposite effect. Instead of a rapid-on when they go on ulixacaltamide, they had a rapid-off, and you can see the dramatic difference between the placebo and treated groups. So one thing I want to point out is, again, like going into the Phase III study, it is not 1 data point that we are hanging our hat on. It is multiple data points over multiple time periods across multiple treatment groups. It's an orthogonal analysis that is supporting our Phase III strategy. And again, in multiple different ways, mADL is confirmed as a viable phase primary end point in our study. And we've also demonstrated what is clinically meaningful -- what is a clinically meaningful level of response with mADL11 and also testing various elements of our Phase III strategy as well. So just want to again point out, 7 months, it's been 7 months since we released our top line results. And in that time, we requested our end of Phase II meeting, put together a briefing book, had a very successful meeting with the agency where we aligned not just on the primary end point but the duration of study and dose; and also shared preliminary concepts around the Phase III protocol. Coming out of the end of Phase II meeting, we quickly finalize those protocols, shared them with the agency and receive feedback at the end of September. And in parallel, the study team has been working on start-up activities and also doing pre-engagement with the patient community around interest in the study, which I'll talk about more in just a moment, and we are poised to expand our recruitment efforts and initiate the study later this quarter. So again, 7 months, this team has done. and again, an exceptional team of folks has supported this. So our Phase III strategy consists of two primary studies: a parallel design where we'll compare 60 milligrams of ulixa to placebo and a randomized withdrawal study as well where patients will be treated for a period of 8 weeks. Patients who meet a prespecified responder criteria will be randomized to either placebo or ulixa and evaluated over a 4-week period. And I'll talk a little bit more about that design in just a moment. Now for those paying attention, you can see an innovative Phase III program in the title. And that isn't particularly innovative in and of itself, right, I mean we've done a parallel design study with a Essential1. This will be the third time we've done a randomized withdrawal study with ulixa. So again, the structure and design of these studies is largely derisked, almost wholly derisked, I would say. But there are two studies. And in a traditional Phase III development, two studies means two protocols, two IRB reviews, two eligibility committee reviews, two of everything, two recruitment pathways. What we're proposing to do is have these under a single protocol, have single recruitment, have a single eligibility committee review, single screening. And patients that meet the eligibility after screening will be blinded, blind randomization into one of the studies. So it will be a single pathway. The benefit is, is that we are looking at the same profile of patients in both studies but evaluating them in two different ways. And one of the benefits of this approach is it reduces study bias, a randomized withdrawal study. Again, patients know they're going on active drug. With this, we're actually reducing that bias, randomizing the patients in a blinded fashion, so that nobody knows which study they're on. And all patients that complete the study will have the option to roll into our long-term safety study as well. So a little bit more detail on the study design, clicking into it one level down, we anticipate enrolling a total of 600 patients into the study across the 2 sub-studies. So the parallel design study, we will enroll 400 patients. The end point that we'll look at is mADL11 change from baseline out to week 12. And it's powered -- 90% powered to detect difference. The randomized withdrawal study, we anticipate enrolling 200 patients. And again, I mentioned it will go out to -- the patients will be treated for 8 weeks. A subset of those 200 patients will go through a responder analysis. And those patients who meet that threshold will be randomized into the randomized withdrawal study. And the end point there is a little different. It's basically taking the week 8 baseline and determining response at that 8-week baseline and looking at the patients who go into the randomized withdrawal and comparing the response rates after they go into the randomized group. And it is also powered to 90%. So one of the key learnings in Essential1 was that we need to prospectively stratify the patient population. We've talked a lot about intention tremor patients as a bit of a confounder in the Essential1 study from a placebo standpoint. We will be prospectively stratifying that patient population because we do recognize that the intention tremor population, as long as its ET plus intention tremor, is a part of this disorder, and we need to understand it clinically. So we'll be ensuring that we are balancing that patient population across the 3 arms of the study effectively and also prospectively stratifying around ET family history and propranolol use as well. And we'll be looking at, among other things, in the secondaries, TETRAS-ADL and the clinical outcome assessment, CGI, PGI-S and PGI-C. So another innovation to our study design is we'll be deploying a completely decentralized study. As Marcio mentioned, we're doing a hybrid approach on the epilepsy side. This will be completely done in the patient zone. And as he mentioned in the introduction, we want to bring the study to where the patients are, right? And the design of Essential3 is suitable to being more flexible in that regard. mADL11 can be done virtually. All aspects of the study can be done virtually, beginning with a structured video that will be a neurologic exam, that will be read by the investigator and then also confirmed by the eligibility committee review. And then all assessments will be done in the home as well. There will be a high touch of health care professional contact with these patients, either through home health visits with home health nurses or with investigators via telehealth visits as well. And one of the additional benefits of this having a decentralized platform to gather data is that the data capture will be real time. Again, in a traditional study, oftentimes, a site -- a patient goes into a site, gets their exam done, are monitored, and there's a piece of paper that just sits off to the side and it may or may not get entered in into the system right away or it might get entered and there'll be queries that will go on for weeks with a site. This will enable us to do real-time data capture and do quality checks in real time as well, which will simplify the process as well. And in order to maintain consistency across the study, we're going to have a nationwide network of investigators that will be trained on the protocol and evaluate patients in a standardized way in terms of the assessments and outcome, again, minimizing the variability across sites that we saw in Essential1. So again, we are bringing the trial to where the patients are. And what you see on the left-hand side of the slide is our social media campaign that, when launched, will be the starting point for patients to opt into the study. And again, it is a single recruitment portal where patients will regardless go into one evaluation and be randomized to 1 of the 2 studies in a blinded fashion after they are evaluated using the same inclusion-exclusion criteria as well and we'll also again stratify across the studies to maintain balance across those key variables. A really exciting aspect of this is going back to the -- when we were completing enrollment with Essential1, we had thousands of patients that were interested in Essential1, and several thousand of them opted into receiving future communications from us. We began reaching out to that patient population in September. And in less than a month, we had 600 patients put up their hand and say they were interested in participating in Essential3. And not only interested in participating in Essential3 but also we're really excited about participating in a decentralized study. So -- and when we -- just based on, again, a few thousand patients reaching out that when we actually expand this to nationwide recruitment we're very confident that we're going to hit our enrollment target in the first half of 2024. So we have all of the elements in place to execute on the Phase III. I've talked about the protocol, the design, patient-driven approach. Again, a lot of our success comes down to the way we work. A lot of companies talk about that, right? We actually do it. We take it to a new level. I've been at my fair share of companies and this -- and Praxis, definitely, is different in that regard. And the one thing that I do want to emphasize is that while we are focused on the Phase III design and execution right now, we are hyperfocused on NDA readiness as well. So once we have results, we will be ready to pivot and file. We're really confident in the program as it stands. We've derisked the endpoint. We know clinically meaningful -- what is clinically meaningful about mADL11, we've got an engaged and activated patient population, and we've got a motivated team. We have all the elements that we need to succeed on this program. I know there will probably be some questions. So what we'll do is I'll invite some folks up, Professor Espay from the University of Cincinnati, who's Director of the Movement Disorder Center and Endowed Chair at the University; Rich Able, our Head of Medical Affairs for the ulixa program, and invite Marcio backup as well.

[Operator Instructions] We have Dr. Espay here, who can provide clinical experience also, so we'll like to ask him a few questions directly about the experience and specifically the unmet need in this space. And we have about 25 minutes to conduct this session. As Marcio asked earlier, please engage and please feel free to ask questions.

Is the microphone on? Now it's on. No, it's not on?

Sorry, that was me. I turned it off. Pretty -- not computer savvy. Yasmeen Rahimi, Piper Sandler. Thank you again for doing this great day and your perspective. Alex, I have quite a bit of questions for you. I'm really intrigued by this virtual processing. So walk me through what measurements are done through this? Is every assessment on endpoint, recorded? And let's say you noticed that something is not done correctly, right? So investigator A, is screwing up, it's okay, what does your team do immediately? Like what will be in place, and they may be reflected back what happened in Essential1 that obviously didn't have that methodology in place. I guess what we're trying to figure out like what will we be this impact on the efficacy and the variability in the standard...

Yes. So it's a great question. So I would say that this actually gives us a lot more control over that. It sounds like it might be less control because it's decentralized and virtual. But being able to access the data faster, let's us query it, if there is something, and we also will have a system in place that we can monitor if there's any irregularities in the end points. We'll be collecting everything virtually. mADL11 is just a questionnaire, administered by the investigator. Same thing with PGI and CGI and all the other endpoints as well. So -- I think the -- one of the challenges we had in Essential1 in a brick-and-mortar type trial design was there was a significant degree of variability between sites, even multiple reviewers at sites. So sites could have inherent variability as well. So -- and investigators could have variability. So we're really trying to control and maintain for that.

Yes, and maybe I'll add something there Alex, for you guys as well. So one is, it's a smaller group of investigators with larger number of patients. So they're going to repeat a lot more the observations. So that's one important point. We're not compromising whatsoever on the screening, making sure those are proper patients. That's normally where the majority of the variability comes for a trial. But maybe what we're not clear is during the randomized withdrawal we did, we actually tested that hypothesis. We wanted to make sure that virtual visits versus on-site visits were no different. And so we checked the box as well. I think everything we've done for this study was deliberate. I think it would shock a lot of people to know that about 60% of all observations in any clinical trials right now are hybrids. I think people don't talk about it but they are just happening consistently across the industry. We're taking a step forward here because we're controlling the network, right? We're not only controlling the actual assessment but the network of patients being...

And then the last question is on the 600 patients that have shown interest and engagement, are you able to comment on how many of them would be eligible for the Essential3 study?

Yes, yes, we would. So the way we did that was a very significant interest, as Alex mentioned before we even started planning because we're so close like to start actually dosing patients in the Phase III. We went through an IRB approval process for a study. So this is actually a protocol that we go for the patients and understand where they are, are they in other medications or common inclusion criteria. We're not prescreening for Essential3 because we're prescreening for any Praxis Phase III study, which I think is interesting as well because it shows the commitment to continue to work with us. All of them being -- every single major inclusion criteria has been tested there. What I would say is, as we continue and by the way, today, there are more, right? There's a cut a few days ago, and this keeps adding every single day. It's a very significant proportion of the patients that would be off the gate eligible and a few of them that might after examination by the experts and the [ ERC ] cuts as well. So it gives us an incredible amount of confidence because we restrict the geography for this. We're not going to restrict the geography for the next phase. So like very, very encouraging.

Joon Lee from Truist Securities. Congrats on the 222 data, that looks really promising. So looking forward to the updates there. On the ulixacaltamide, how does that compare with, I think it's called suvecaltamide. I think the structures of both are known. So have you tried any side-by-side comparison for some of your functional outcomes? And I have a follow-up.

Yes, we obviously did, right? Like, as you can imagine, I think it's proper due diligence to look across. Those drugs are all -- both of the drugs you mentioned, ourselves and the drug from Jazz looking to all 3 isoforms of the channel that are different on the potency, there are significant differences in our favor on the metabolic profile, and on the number of active metabolites, which we don't have one, and they do have multiple there. The formulation from the get-go for us is very specific to actually cover the [ day ] and they're waiting to interact with the channel, and I'm going to say, if you hold for a second, and Steve is going to talk about how drugs interact with channels and the importance so maybe Steve we'll ask you to comment on T-Type calcium channel inhibitors there as well. But that difference matters. We explore the dose to the maximum here, right? We those patients twice the actual concentration that we're expected to be therapeutic right now. I know that is hypothesis out there that those limitations will limit effect. It is not. And the only ones that actually run their experiment and have the data out is Praxis so...

Great. And then you mentioned the study is 90% powered. So 90% powered to show what? I mean what delta do you need to hit to be able to get that powering?

So it's beyond 90% power, as you can imagine, I'm sure [indiscernible] calculates that from the sample size, but it's slightly larger than a 0.3 effect size.

The next one is right here. He rose -- your hand was up first...

Sorry Doug.

Doug and then Laura.

Doug Tsao from H.C. Wainwright. Just on ulixa for the Phase III program. I think Marcio, you had initially indicated that you plan to exclude patients with intention tremor. And now it sounds like you're simply going to stratify them and they will be included. So I'm just curious, was that based on FDA feedback and do you have updated thoughts on how that could potentially impact the study?

So it was mostly based on the conversation with the FDA. When you look into the study, these patients were not balanced because we didn't know the prognostic factor in Essential1. Obviously, the easiest thing when that happens is just to eliminate that in [ geo ] later in the process. But in the conversation with the agency, I think we already acknowledged that we just don't know, right, what will happen. One thing that is not clear in the field right now is the proportion of patients in the population. We strongly believe that it's very small, that proportion, but there is no definitive number there. So we put a 2-tier approach and maybe Dr. Espay can comment in terms of one being absolutely certain that is intention tumor. So even an additional check. And the second is that, that wouldn't interfere with the endpoint. But the key for us here is really balance. Like if you resimulate the Essential1 data sets, balancing the data set, there is no issue whatsoever, right? Now that's small in terms of what we're looking here. It's also one of our motivations to get this study larger than we originally expected. You're probably seeing that we're aiming for 400 patients on the parallel group study. So even if there is a small difference that we are not considering, that wouldn't be detrimental. I think the ultimate benefit for that is that there would be no restriction whatsoever on the population that would be treated. So expand even further the market. But maybe, Alberto, if you could comment?

Yes. No, I would agree with what you've said. The phenotype of essential tremor is diverse. So there will be differences in individuals. And that, I think, is an additional advantage of this particular design where there is a central limitation for the 2 studies. So all these variables that we think may be relevant but don't know exactly how will be equally distributed among the studies and between the placebo and the intervention. So I'd be curious to know if there will be a biological difference according to what the clinical changes may be. We don't know the answer to that now. Be lovely to have some biospecimen data saved in this study that one could then get back to because it would be lovely to find out if there might be, in fact, something relevant at a biological level from a clinical difference. At this point, we don't know what the difference is between patients who have or don't have intention tremor in terms of their ability to respond to a calcium channel blocker like this. So I think it's a great question, but it will require more data for us to answer it definitively.

And maybe just to finish on that, the power impact was the biggest issue in Essential1, not the effects. When you remove the groups with intention tremor, the drug is actually numerically better than the ones with or without [indiscernible]. So we actually [ kind of ] win on that group as well. But because the effect is different on that group, it diluted the overall effects. So we'll take care of that as we did by just increasing the sample size.

Laura?

Laura Chico from Wedbush Securities. I guess I'd like to direct this to both Praxis and Dr. Espay. For Praxis, can you just remind me, in Essential1 were assessments made at home? And then just curious what data you have, and Dr. Espay in your experience, how does home assessment of tremor vary from -- in a clinical site?

Yes, great question. It's it is well known that there is variability in the tremor severity and amplitude. And in fact, individuals could come to us at their best of times. It's actually fascinating when they come to us and tell us, "Well, this is not how I'm typically." And so they show and they saw a little bit and say, "I'm feeling better today." It's clear that what we capture at the clinic is never as accurate a representation of what happens at the home setting. It really is not just an artifact of just essential tremor. It appears to be very common patients with Parkinson's disease in the same condition. Patients come to us and they show their best selves. So the home-based assessment will likely be more accurate reflection of what these patients' day-to-day life looks like, and particularly what that tremor might be expressing as. It is still not quite as perfect, the perfection will be if you have some kind of a quantitative measurement across a time span, but the FDA is not yet approving that idea of measurement. So we still are at the mercy of a snapshot in time. And that snapshot in time is best illustrated by the mADL11. But if we could, in the future, I would imagine that there will be more wearable technologies that allow us to then capture that in the ecologically valid environment, which is what the home is. But having anything in the home is going to be probably better anyhow than anything at the office. So I think that will likely increase the validity of the results at a population level.

And maybe the first question are there, in Essential1 and any other time, right? That the [indiscernible] was collected, the question is actually during the last 7 days. And maybe there has been a little bit of a confusion that all the physician is doing is asking during the last 7 days, how was each one of those items. So the assessment is identical. There's going to be physician in front of the patient and he is going to be delivering exactly the same questions, asking exactly the same way that is in the clinic for the primary endpoints. I think the one bias you remove from that is that as Alex mentioned, anxiety does fluctuate on those patients, and we know that it's exacerbated when they come to the clinic. So we're going to be a lot more drug effects than confounded drug effects when looking to the house. But I want to bring forth something I said before, we did this for the randomized withdrawal. We had a group of patients coming to the clinic and a group of patients not coming to the clinic. And there is no difference on the quality of the assessment, on the trajectory of the assessment on how it gets reproduced. It's just far better for the patients to have a physician in front of them but being flexible on the visits. And that's why we're going for this approach.

I'm Ami Fadia from Needham. Two questions from me. Firstly, just within the Phase III study, what percent of patients are going to have essential tremor? Are you limiting that percentage there? And also, was there any discussion with the FDA to have some sort of a prespecified subset analysis where you exclude that patient population, should you see something surprising in that study? And then I have one more.

Yes. So the answer to the second part is actually very straight forward, it's yes, and that's going to be very clear on the statistical analysis plan and how we're going to be positioning. I think there is an understanding -- a joint understanding between us that it's worth looking into that population. In case the hypothesis we have right now there was imbalance, tends to be a little bit more physiological than imbalance, does not look to be a physiological problem or a pathological problem. It's more imbalance. But if it is, would we have the ability to actually have prespecified that population without, and we will have enough patients because of the size of the trial to do so. In terms of the size or the proportion of that population, we believe it's going to be less than 25% of the patients that have concomitant intention tremor with essential tremor, right? Not -- intention tremor is more prevalent than that in other conditions, but not primarily at ET that -- that's why we are recruiting. We're not recruiting IT patients with some ET manifestations, the other way around. They have to have 3 years, very clear essential tremor and might have certain manifestations of intention tremor.

Okay. Great. And then just one other question. Just -- I wanted to understand, I'm getting a little bit more confused about how you're going to drive sort of consistency and evaluation in the Phase III. Can you sort of talk about the number of investigators that you're planning in Phase III as opposed to the Essential1 study? Is it going to be fewer or similar? And how will you ensure consistency relative to Essential1. Is it training? Is it some sort of a centralized oversight? If you could explain that a little bit more, that will be great.

It's all of the above. It's about the same size of the number of investigators right now, but their general availability is much bigger. And what I mean by that is if you go to any movement center here, in the city, and you ask, what is your load of patients right now. Maybe I can even ask that to Espay. Maybe you should ask like what is your relative load of essential tremor versus other patients in your practice?

It's very large. This is a very large population. Now it's interesting to note this idea of getting out -- it's slightly different to your question, but it's getting out in the community is important because some patients end up not coming to us as often because they know they don't have much that we can offer them. So in some regards, there may be some nihilism on the part of patients recognizing they can come and they get the same standard approach, but they've already often been in propranolol, they've often been on primidone, they might be on topiramate. Those are the 3 top line agents, and none of them are really that effective, unfortunately. So you end up having them on cocktail therapies that we have difficulty moving up precisely because there is toxicity that limits any potential additional benefits that they could get into. But the experience in terms of essential tremor by any movement disorder center is very high because it's one of the most common movement disorders that we see. So we all have lots of patients. As I mentioned, I think the issue with an in-clinic recruitment might be that there aren't as many people coming regularly. They might come every 2 or 3 years to see what's new. And we have forever, told them not really much of anything. So there is 0 availability of any essential tremor therapies. We don't have any. All of the essential tremor therapies we use have been designed for other disease entities, hypertension, epilepsy and found to be serendipitously good in some level in patients with essential tremor. That's sort of how we have therapies for this condition kind of by accident in many ways. This is exciting because it's, of course, the first ET-specific therapy designed by a mechanism that's recognized to drive the oscillatory behaviors of essential tremor. So this would be the first time that we will ever have something that actually has been designed for essential tremor of value. But the point that you're trying to make, though, is whether or not there would be a number of additional -- so you'll have enough -- there will be a lot of the recruitment sites coming into the fore. But the source of error that's introduced by -- for instance, in my center, I have other colleagues that would rate the scales, that will be minimized. And so that source of error will be minimized. You can have the same number of investigators, but there are going to be fewer errors that are related to the way we would be sort of scoring each of the elements of the mADL11.

Kambiz Yazdi, Jefferies. Can you remind us the nuance between diagnosing ET patients with or without the intention tremor how you'll be doing that in the current study design? And then how will your innovative Phase III study design also affect the cost of the study?

Well, so it's a good question. We are going to have a way of cap the number of people who have intention tremor. But the point you're making is an important one in terms of the overall diagnosis of essential tremor. We do not necessarily exclude or include anyone with a postural action tremor in the hands, which is the main criteria, you must have to make the diagnosis on the basis of whether the intention tremor is present or not. So we, as far as diagnosis is concerned, are agnostic as to whether intention tremor is or isn't part of essential tremor. Essential tremor is in many ways, a diagnosis that we make when we ruled out other tremor disorders. We say it is not Parkinsonian tremor, it is not cerebellar tremor, it's not cerebellar outflow tremor, it is not MS tremor, it must be essential. Imperfect by all measures. So the fact that there is a mechanism that drives the excitability of neurons that are related to oscillator activity might make that point mute, and I'm glad to know that there is an effect, in fact, not just on postural tremor without the intention component, but in fact, in postural tremor plus the intention tremor component. So I'm not sure that there is necessarily something we could today tell that distinguishes these 2 groups. But it's nice to know that there will be just by virtue of the idea of getting a therapy out there. Part of the derisking just simply means to try to make the intention tremor patients or patients with essential tremor that have an intention tremor component, a little less so that then we maximize the population where the effect size was the greatest. I think that's sort of the idea behind it. In some level, it's very hard. The community of neurologists still struggles a little bit as to what exactly qualifies as intention tremor, right? Because intention tremor is defined as a magnification of tremor as the finger gets to a target. So you're doing this and if you have a little bit of a more magnification, that's intention, well, when is that threshold where you're going from this, I didn't see it, to this. I think I saw it, right? That's kind of hard. It's in the eye of the beholder in many ways. We are not doing anything particularly quantitative that allows us to determine here it is, what you have versus here it is where you don't have intention tremor. So it's a bit of more of an art than a science in this regard.

So operationally, maybe to finish the question then to address the cost question as well, Kambiz. So we are taking a 2-tier approach to minimize exactly this variability excess in the fields. So the first assessment by the investigator and then a confirmation by a panel because then that is the discussion exactly as Dr. Espay just said, would this like level of [indiscernible] we might not clearly define, impacts the collection of the endpoints, impacts the manifestation of the disease. And that panel is completely of movement disorder like experts. So we did a 2-tier approach exactly to minimize any bias in that regard. And on the cost question, the study. We mentioned this before, right? We were aiming for the study to cost south of $30 million. They included originally the 2 Phase IIIs and a long-term safety study, as you might recall, still does. I think the beauty of how we redesigned the operation is a lot of the patients that would have to go straight into the LTSS, into the long-term safety study, participate on the blinded studies. So we're not adding any cost for the blinded studies. We're keeping them on drug and following and then switching to. So we're keeping the cost, increasing the size of the study, I think that is a benchmark to be followed out there.

We'll take a final question here.

Joon Lee from Truist Securities. I just want to clarify, given that you will be enrolling patients with intention tremor, you will be screening out Parkinson's patients right? And then that you won't have anyone on Parkinson's medication?

Correct.

No Parkinson patients, no clear dystonic patients, no other unknown CNS conditions that would potentially cause tremors and we're screening other medications as well.

We reach time. Dr. Espay, thank you. Marcio, Alex, appreciate it. And we appreciate all of your questions. We'll be moving on.