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

Good morning, everyone, and welcome here to the Apella at New York City and in the webcast for our very first and inaugural by definition, Movement Disorders day and Analyst Day. It's seen somewhat of a bitter sweet matter that we have this year, in person, well, the sweet part is to be here in New York. The bitter is the fact that not everyone could come rightly so and totally understandable. We put all the precautions in place to make sure we could be here safely. But we do understand that the world we live right now is quite complicated, quite complex, volatile. And we thank you, everyone, that cannot be here today, but is watching through the webcast. Very excited to share a number of things about Praxis, about movement disorders in general, but really about advancing science. That's very much what the world needs. We'll be saved by scientists throughout the last 2 years and for many years and many decades to go. And we're hoping here, and I always say hope is not a strategy, but in this case, it is, that we're going to be able to quite meaningfully impact the life of lots of patients coming in. I will be making forward-looking statements during today's presentations, and so from our colleagues from Praxis. So I refer you to our SEC filings at the EDGAR system and any other filings we might be making during the course of the day today. For me, I'll walk you through the agenda we have here. It's structured in a way that we're attempting to communicate what Praxis is about, what the patient experience needs and how many of them are out there for movement disorders and many other of the conditions we are helping, and we're attempting to treat. Looking to some data right after that. And are we delivering on the promise that we've set up to do, and end up with talking a little bit about financially, where are we as a company, where we expect to be in the next few years or so? So other than myself here today, talking to all of you, and most of you know me, but just in case, I'm Marcio Souza, I'm the Praxis CEO and President, real pleasure to meet the ones I haven't had before. I'm going to be joined by Nicole Sweeny, our Chief Commercial Officer, Nicole is going to review the second topic of the agenda today, in terms of the market size, patient dynamics, all the insights we have. Then Bernard, and I always say when I talk to him seriously joking I call him Dr. Ravina. So Dr. Ravina, not only a Praxon but a dear colleague, is going to come on stage and talk to us about what it is to treat patients with movement disorders. Most of you know Bernard through his extensive experience on treating patients, on doing research at the NIH, at University of Rochester. Maybe some of you don't know that he's actually a movement disorder expert. So he see these patients, treated these patients, helps develop and advance the agenda. So it's a real privilege to have someone like Bernard coming here and helping us and guiding what we are doing as a company. And to close the prepared part of today's presentation, Tim Kelly, our CFO, who's going to come to stage and want to talk about what are the catalysts next year? How are we seeing this capitalizing part of the company? What are the capital needs that we believe and how well positioned we are to deliver on all of them, and really wrap it up before a Q&A. We're going to break in between before we get too anxious about being here for a couple of hours. So we're going to break in between for the ones here in New York and obviously on the webcast, and then you're going to recap and do the Q&A and between course presentation, Bernard, we're going to do a little a short break as well. What is Praxis all about? It was quite important we start there because why we are focusing on movement disorders. The company is much more than that, right? And it centers on a principle that is being used a lot, but being deployed too little. There is the needs of the patients in the middle of. So I would invite you to read our mission statements here, not because there is anything extraordinary about that as mission statements go, but because what is within the mission statements is extraordinary. The needs of patients with CNS disorders are devastatingly urgent. We take that urgency to hearts. We're not developing drugs many, many years in the future. Hopefully, we will develop more drugs there, but we take seriously developing them today and bringing them to patients today because that's where they need. And our mission is to help patients by delivering life-altering treatments. Not small increments, life-altering treatments, faster, and therefore, the principles we operate the company and more effectively than has ever been done before. That already would be fairly bold, if you ask me. But we intend to do that again and again. How can we bring to life a mission so bold? We have a set of principles for drug developments and for development in general in the company that are rather simple, but when used together incredibly powerful. So the first of that is the identification of the targets, identifying every single target, current and future through genetics. Why is that meaningful? Because when there is a mutation in a gene, when there is a model of genetics, what tells us, it's not only the mutations that that pathway matters, is that altering that balance or that imbalance matters from a pathological perspective. So we are intrinsically derisking the process by using that as a filter. We can only bring drugs efficiently if we can derisk every step of the way. When you move to the translational tools at face value, that is nothing unique about that. The way we like to use this at Praxis is what we call forward-looking, fully integrated translational tools. What does that mean? We're not hopeful. We're not in a fishing expedition on translational. It's not because something moved, they're like, oh, look at that something that moves. But we rather determine what we expect to move based on those markers, based on the biology, based on our understanding of the pathophysiology and then ask, did we move them? Did we move them meaningfully? Does it make sense for the mechanism we are? And this has been quite important for us to derisk the programs as well. As Bernard is going to show you, we extensively use electrophysiology to answer the question, is the drug in the brain? Is this the kind of margins we are satisfied with to move the programs forward? And that allow us, once again, to de-risk to move to the right-hand side of the charts, the rigorous and efficient clinical programs. Right now, every single trial that Praxis is running, and there are many, as we're going to see, have a maximum duration of exposure of 3 months. We believe that is quite important to ask a question and quickly get an answer for the patient perspective, from the robustness of the question. And the answer -- and from a capital deployment, looking into putting that all together to bring more drugs to patients. It's not a fishing expedition. Now it's not really a strategy, so really moving things forward. And while patient-guided is at the bottom here and is our last pillar, it should be obvious based on our mission, that is a cost of entry for everything we do. It's on the center of everything we do. Not written in a wall, but really every single day. How do they live? Who are they? What are their needs? How do they take this drug as because [indiscernible] going to explore a future day. We're looking into this -- the market for essential tremor, not only from others x patients out there and you multiply for another number, and we are good with the size. We ask them. We look into their records. We ask, why are they feeling this way? We conduct in-depth interviews with each one of those patients. And then we can understand -- already start to understand since you're never going to be able to welcome their shoes or their proxies here on how to bring meaningful drugs to that. By using all of those principles, we end up with 3 distinct franchise. Not because one drug end up in each one of them, but really by following the biology, by following the need of patients, by maximizing the value as you're going to see in a second. So currently, we're restructuring psychiatry, movement disorders and rare disease. There are 2 key principles that we use to move programs forward. It goes without saying that science is one of them. It has to pass the bar, which is fairly high, and it has to create a very meaningful impact to patients. But the second is the value, monetary value. We believe the best drugs are the ones that make it and that the ones can finance the next drug. So we not only have to deliver those drugs to patients. They have to help us bring one more. Remember at the end of our mission statement that says to do it again and again. So we're not hopeful if market size either. Because it would not be in service of patients if you cannot sustain that drug in the market. And that should become clear at the end of today's presentation, how we are doing that. But before I move there, I just wanted to go a little bit from memory lane and a lot in terms of what's in-store for next year. The way we break down the last 12 months and the next 12 months is basically in simple phrases. So last year was the year of exploration, where we're using all those principles and asking the question, does this one program merits moving to the next phase, more investments, more structure. Was also the year that we IPO, we brought some capital for the company, some very incredible talents, structure, systems, everything that is necessary. There's a behind the scene that we not always talk about, but it's incredibly important for drug development and commercialization eventually. So it created that initial structure. This year, we solidified that structure, not overgrowing, but creating each one of the necessary systems positions in a very flat way. We are a flat based organization. So very lean in terms of how we move these programs to advance significantly. And as you can see here, that's exactly what happened. There are no ghost projects at Praxis. So they are merited, moving and continue to move forward. We're going through this filter constantly, is the value there, is a science there, are the patients' needs there? But it was quite meaningful what happened. We went through no placebo-controlled trials the year before to a very significant number. We're ending the year with about 6 controlled studies in Phase 2 or Phase 2/3. We started our very first registrationally driven study. We're incredibly excited about, and it created a foundation for a sustainable company. When you look into next year, is the growth year. Now there are going to be many more growth years, right? This is the first growth year for Praxis. And I just wanted to go one by one here on the key things we expect to have from a drug development perspective, a catalyst perspective as well. Most of you heard at this point in time, how excited we are on developing 114 for major depressive disorders. The excitement stems from the science, the operation, the interest we got and really all the controls we put in place in these studies, showing us now with data because we've been monitoring the controls that they are working. So it creates an excitement internally that you're really going to realize the value. We're going to be reading that study in the first half of the year next year for both MDD monotherapy with Aria or PRAX-114, 213 for the ones familiar with -- with the number. That's really well enrolled right now despite all the difficulties despite that the pandemic did not make it easier to enroll trials. But you have an incredible group of investigators, an incredible group of Praxons, as we refer to ourselves, working together to make sure that trial finalized. But standing here today, I can guarantee we're going to read that out in the first half of the year because we know the trajectory, we are the ones that are in prescreening and when you're going to get to the end of enrollment. I'm not going to tell you today when that is. At the moment, we get to the last patient, last visit, you're going to hear about it, and you're going to get an estimate for us on when the data is going to be out. But stay tuned for that. Together with that package, there's a dose-ranging finding study Acapella, it's our 114, 214 study, and they should come about the same time line. Very excited to have that package. Being successful on that program means that by the end of next year, we will be in Phase 3 with the second registrational study, which would allow us to complete the efficacy part of the program for a submission of an NDA. There's tons of things to work on the background, the safety database, many other things. We're diligently working on that, but we're being solid ground. So hopefully soon, we're going to be sharing exciting news with you. Because the biology is so strong and the needs of patients really suffering with PTSD are equally strong, we decided to start to study PTSD as well. That study is up and running and expect to read out next year as well. So fairly meaningful from a psychiatry perspective. The real meats of today is movement disorders. So I'm not going to spend a lot of time here. But what I want to say is we're going to finish the randomized withdraw phase for the current Phase 2a and going to be announcing that soon, early next year. Going to finish since we have started our Phase 2b with a parallel group, as Bernard is going to discuss today during the year, and that's going to allow us to be ready for a Phase 3. That's the key objective for PRAX-944 in essential tremor, to be ready for a Phase 3 at the end of next year. But it does not stop there. Once again, following the biology, following the understanding of the pharmacology, we decided to start a study with PRAX-114 in essential tremor as well. And Bernard, once again, is going to be discussing today. We're incredibly excited about that. All the cards really converge into a very strong hypothesis, and we are testing that in a very fast but quite meaningful way. In the last piece of the puzzle here for movement disorders, 944, 114, combinations of then other molecules we're having development would all be used to address many other movement disorder disease, and we are actively looking to that and going to be updating all of you fairly actively as well on where we move there. The last point I want to cover is rare disease. And we do understand it's somewhat controversial to have these 3 completely different approaches. The 2 on the top for very large common disease in the rare disease here in the chart. So I wanted to address that today. The way we look into rare disease is two-folds. One is what I call a gateway, but I was told that is not clear when I say what that means. So I'm going to try to clarify here today. All the programs on the top came through screening through rare disease assays and targets. So that's what the gateway is. It becomes a filter for us to look into -- to examine the meaningfulness of the biology and then ask what else can we do? There are many programs that we are screening for this right now, and we believe they will become either rare disease programs or common disease programs. So it's incredibly exciting to be able to get an engine that continuously screen it. But then the ones we decide to keep in the rare disease, they have to pass another test because the unmet needs is very clear in rare disease. Are they valuable? Because once again, the best programs are the ones that make and can sustain the rest of the pipeline. And each one of them here passed the tests. We have a very high peak revenue thresholds for each one of our programs, and we've been using them to actively filter. All those assumptions are based on current addressable markets, not future, not the patient that we don't know where they are, but the patients that are here today that request these because we believe that, that's the best way to filter and to look into rare disease. But outside of how we get there, let me talk about the 2 programs that we got there. So 562, we're developing for a number of indications. Two of them are here: one, a rare cephalgia, I will start with trigeminal neuralgia and SUNCT/SUNA. And just to give you an idea, between trigeminal neuralgia, primary trigeminal neuralgia and SUNCT/SUNA, there are more than 100,000 patients right now in the United States in need of treatment. So it's not only quite important in terms of the unmet need, but it's quite important from our business. We are starting that trial right now. No trial was run in that disease successfully before. You're going to hear pretty some innovative ways to engage patients and to get them to these trials and really should do something different here. We're excited about that. So we can get to the results very quickly as well. We have finished our juvenile program -- juvenile tox program for the molecule, which would allow us to the beginning of next year to start treating patients younger than 12. That was our current tox program limits. And then we can start to treat development encephalopathies with 562, [indiscernible] recently 2 weeks ago and the level of excitement on this program was off the charts by people that have patients that want to treat them as soon as 562 is available. The last part I want to cover on this chart is PRAX-222, it's our first ASO. We're obviously incredibly excited about being able to modulate the sodium channel in that 1.2 in the brain. It's quite meaningful that implications for understanding that for many other diseases, that is an incredible unmet need here. These are day 1 of life seizures, they never go away on these patients. And there is absolutely nothing for them. So we drove the program quite aggressively in terms of the preclinical package. We met with the FDA recently, and that's the part I would like to share with you before we move to the next phase of the presentation. Thing for all of us that knows Praxis, we cannot be called unambitious, right? We drive things fast, we are decisive. We want to make sure we get to these patients. But I got to say that for once, the FDA was more ambitious than we were. We proposed a multiple ascending dose study to the agency to start the programming patients with [ accentuating ] of function, and they push back. And they told us, why not a seamless Phase 1, 2/3 study that would serve as the main registrational study for this program. We like when we are made wrong because we learned, and in this case, it's wonderful to be made wrong because we can advance the program much faster. We don't know yet what the design is going to be. We literally just got this a little bit over a week ago as a feedback. We're working very diligently to get to that program. But what we know is we can and will start the program and finish and if meaningful for patients, if we reach those endpoints, if you get to your point of getting a registrational study, we're going to be able to get this drug to market in an unimaginable time line. So we're incredibly excited, potentially that being our first commercial drug. So very excited to be there, as you can see, throughout the pipeline. But if I move to what matters here to some extent, there is no way to break the model. And what I mean by that is, can put as many haircuts as we want. Each one of those franchise deliver well in excess of $1 billion in peak revenue. Nicole is going to explore the size of the movement disorders. I think the size of the psychiatry is a little bit more obvious, and we just heard how we filter from a value in terms of rare disease. So really building not only a sustainable company, but one that's going to be incredibly successful. So having said that, I'd like to move a little bit to what we have in-store for the next 12 months for the Movement Disorder Day. And you're going to see this again and again. So I'm going to go very quickly. One of the philosophies we use in the trials is, which one is the key question? We can pile hundreds of questions in clinical trials others do and then becomes very confusing. But what is the one key question? Who wants to answer in each one of those that's going to allow for the program to move. And as you can see here, PRAX-944, the next major study is what we call Essential1, reading out next year. And only once out of the trial is a dose for the Phase 3. Why don't you ask don't you want to see the efficacy, the safe, tolerability? Of course. We're pretty confident we're going to get there. So we need to get that dose to move to Phase 3. With 114, GABAA PAMs work for tremor. That question has been answered. As you're going to hear from both Nicole and Bernard, there are multiple examples of GABAA PAMs, they have addressed the needs for tremor and essential tremor, none of them in a safe and tolerable way. So the question here is, can we, as we will find a concentration, a dose, and there's something very special about 114, Bernard is going to talk about that allow us to do that at daytime. They don't have any tremor when they're sleeping, essential tremor patients. They need to be treated at daytime that allow us to move this toward registration. We're going to get a yes or no, and we're going to move on or not move on with that level of discipline, and that's happening next year. And the last one is Parkinson's and really has not been an effective non-dopaminergic treatments developed, two lesser the tremor and other manifestations of the Parkinson's disease in many decades. We want to be part of that, ones to help these patients. And we think 944 can really do that. So we're starting the study right now, and we're not giving quite a guidance on exactly when we're going to read out, but it's going to be as fast as we possibly can to help these patients. So enough of me here. I'm going to ask Nicole to come and join us and to explore the essential tremor markets, the unmet need of these patients and what we are doing to address that. Thank you. Nicole.

Thank you, Marcio. Thank you, Marcio, and good morning. It's great here to be with you all today. I wanted to just echo a point that Marcio shared and just that we have great enthusiasm for our movement disorders franchise. And today, I'm pleased to share with you our review of the current ET market and really specifically to talk about the true unmet needs that these individuals face. A quick headline. This is a community, the essential tremor community that's long been underserved. And what I mean by that is that 0 medications have been approved specifically -- excuse me, designed specifically with the needs of essential tremor patients in mind. The one product that has been approved by the FDA, that product was approved over 50 years ago, and it was based on one very brief study and a population of 9 individuals. Yet, we know there are 7 million individuals around the United States that are impacted by symptoms of daily tremor each and every day. So a logical question and one that I was asked -- I've been asked quite frequently is why? With a large problem affecting 7 million individuals, why have other companies not gone into this space? What's holding this community back? And simply said, there's 2 reasons for that. One is that the disability, the impact of this condition has on those living with essential tremor is not fully appreciated. The other is that the mechanism is not well understood. So therefore, the industry has been unable to move forward and bring solutions. We see that as a time for change and an opportunity for Praxis to set forward and help the community with new and better treatment options. At Praxis, we have a call to action. And you can see it on the slide now, dare for more. And this is something that we truly challenge one another each and every day to dare for more. And behind dare for more, it's essential. It's trying to make the impossible possible for those who need our help. We dare for more, for the patients who need better options. We dare for more from our products to support their needs, and we dare for more from ourselves each and every day. So we see the essential tremor community. We know it's been long overlooked, and we're excited about the possibility, again, to bring relief and to bring options to those in need. But let's start by just taking a closer look, more on essential tremor and talk a bit about the patients as well as the condition that impacts them. I said earlier that there are 7 million individuals in the United States that are impacted by essential tremor. That's 7x greater than Parkinson's disease. And what happens with these individuals is that they have a daytime tremor. So this occurs when they're trying to conduct daily activities, the tremor will present itself, typically in the hands, but also in other parts of the body. And from the patient side of things, this can impact patients of all ages from their 20s all the way through to the 80s. But what's interesting, and I want to focus a bit on, is that we do see a family history here. We see that 50% of patients have a family history. Yet what's also interesting is that there's still a tremendous lag between the time that someone experiences symptoms to the time that they treat. And that lag is well over 20 years. So that's surprising in that if you think about it, and I know individuals who have tremor, where they go to Thanksgiving dinner every year and they see their mother shake, they see their grandmother shake. 50% of patients see that, yet they still wait a number of years to initiate treatment. That signals that there's something going on. Something is holding them back from actually managing their condition the way that they'd like to. Excuse me, can I go back? Thank you. Sorry, I pushed the button. This is also a condition that is heterogeneous. Yet it brings disability to all individuals. And what I mean by heterogeneous is that, that disability affects each and every person a bit differently. What's consistent though is that it's progressive over time. And so in engaging with patients, engaging with members of the community, we hear that consistent theme of disability. And we hear consistently that tremor is absolutely more than the impact of the tremor -- or the -- excuse me, the tremor itself. And so what I'd like to do is I'd like to have an opportunity to have you all hear from members of the community and hear from them, when I say tremor is more than the tremor itself, what that actually means. Could you roll a video. Thank you. [Presentation]

First, I just wanted to come back from the video and thank the International Essential Tremor Foundation, the patient organization as well as the patients in the video for sharing their stories with us today. Certainly, they're sharing vulnerable moments of their life, and I want to sincerely thank them for that. Well, there's a lot in the video to unpack. There's really 2 key points that I wanted to discuss. One key point is, and I think you hear this very clearly, there's a message of hope and that these patients, while their needs have been underserved for over 50 years, they're hopeful that more options will come forward, and they want more options to come forward. They want to treat their condition. In addition to that, I mentioned earlier that tremor impacts them well beyond the tremor itself. And that, that disability is certainly very real. And that's something that I'd like to continue. Thank you. Moving forward to talk more about in terms of the impact that tremor has on the individuals and the disability that they face. I think you heard in the video, when you saw instances where they're impacted on an individual level in terms of how they're interacting with others, social impact. And a good example of this, it's not in the video, but certainly a story of a patient that we've interacted with is a gentleman who for his career and his profession, he's an ad agency creative. And so he has to present his work to clients on a regular basis. And that involves actually holding lightweight foam core boards to share his ideas and to share his work. What he has shared with us that on several occasions, these boards were shaking so much that the embarrassment was tremendous. And it left him having to explain. It's not that he lacks confidence in his work. And it's not that he's nervous. It's that he has essential tremor. Now I shared this story in the present tense. The ending of the story though is that this gentleman suffered with this embarrassment. It impacted his career. He left the workforce midway through his lifespan. So 20 years before anticipated retirement. So when I share embarrassment, I want to make sure the impact of that really rings true. In addition to that, you also saw in the video, and you heard from Karen, the impact on self and that the patient sharing with us, she really feels as though she's not able to contribute, right, to her society and those around her. And that's very real in terms of the negativity that this condition can bring individuals. And the third piece is really relating to just this condition more broadly. We've talked about the social impact, the impact on self. These individuals are also facing other comorbidities in terms of a high rate of depression, a high rate of anxiety. And when I say high rate, I mean numbers in about 50%. So if you take a step back and consider this is far from a benign condition. The burden of the disease on these individuals is tremendous, but it's really only half of the equation or half of the struggle that those living with essential tremor face. The other half is treatment. And at the beginning, I shared that no options have been designed specifically for the needs of the essential tremor community. And I want to bring that back up here and that today, patients basically reach a point where they've coped long enough. And while they've been interacting with physicians for any number of years, there's really a delay with the physician initiating an essential tremor treatment until the condition progresses so much until that disability progresses that the patient can't cope. But you have to go back to the treatments. They can't intervene earlier because they don't have good options to help the patients. So they're holding out. They're holding out until those patients progress. And today, the approach that the physician takes is highly subjective. They evaluate the clinical characteristics of the patient as well as the patient need. As an example, do they have a career? And again, truly trying to understand the magnitude of disability that's impacting the patients. But going back to the treatment with no targeted treatments, there's no set protocol here in essential tremor. It's truly a matter of trial and error, taking products that have been designed for the needs of other patient communities and trying to apply them here in tremor so that these individuals can get some level of relief. And there's 2 options, if you will. One are the as needed options, and this is really when the magnitude of tremor and the impact is considerable, but the time period is shorter. So think about it in terms of someone who may have a business meeting or a life event, where, again, that magnitude of the tremor could be considerable, but it's really for a shorter duration, if you will, in the course of a given day or their week. The other option is chronic and chronic therapies are typically considered when that magnitude of tremor certainly is there, that magnitude of impact, but the high-frequency also exists. So think about someone who, on a daily basis, they're waking up, they cannot brush their teeth, they cannot dress themselves to button their shirt. And you'll see when Bernard talk later, a patient trying to do this. It's not a simple task as well as even an inability to feed themselves breakfast. Just to picture -- just to highlight a few examples of a typical morning for someone. So that patient's really candidate for chronic therapy to help them truly get through all the moments of their life. So I want to talk on this slide and the next slide about the current treatments. And the headline for both of these slides is there's a few options. Patients are realizing little relief and the side effects, the tolerability concerns really weigh on the patients. Well, let's start with the as needed options. The first is alcohol. And this is something that is currently utilized to provide transient relief. So relief over a 2- to 3-hour time period. What's interesting is that alcohol is actually GABAA PAM. So it does prove that GABAA PAMs can be effective to manage essential tremor. I would say the cons are here that certainly the patient and the physician, they must be very careful with their use of this approach given abuse concerns with alcohol. And I'll also just share that personally, I was a bit stunned in reading peer-reviewed journals in 2021 that alcohol is a commonly utilized treatment for essential tremor. The other option they have is propranolol. And propranolol actually goes back to, I mentioned one treatment has an indication for essential tremor. This is a beta blocker. So this is a product that was designed for a very different need in mind. And that's really an important point because it also has a number of contraindications. And those contraindications are actually very common comorbidities for those living with essential tremor. And when I say contraindications, I want to help quantify that. And that 50% of essential tremor patients are not candidates for propranolol because of these contraindications. In addition, those that do go on propranolol, we hear quite commonly they cannot tolerate it and that more than half of the patients cannot tolerate propranolol. So I just want to take a step back and do the math here. And that if you think about all of the essential tremor patients, half of them right off the bat may be a candidate for propranolol, yet then those that go on propranolol, half or less can actually stay on that treatment. So if you're thinking about all of the ET patients out there, less than 25% of them are truly candidates to utilize and stay on propranolol, a small fraction of the market. I mentioned chronic options as well and certainly this is where patients do have a few more options, but these options all do come with related side effects, and the side effect list continues to grow. And the concept of treatments that were designed to support other patient communities rings true here as well. So these are the chronic therapies that are typically initiated. I also recognize that benzos, BOTOX, deep brain stimulation, there are certainly other options that are available for patients that typically come into play as the patients progress and more specifically, as they really cycle through different treatments. Because what we find is many patients don't respond to a treatment or they get a limited response. So therefore, they spend quite a bit of time trying other products to see if they can get the level of efficacy they're seeking. So just in summary, I want to pause and consider what we've discussed so far. We have a patient population with a considerable burden of disease, again a condition that's far from benign. And now if we think about the treatment options, these are treatment options that leave them wanting more, wanting more in terms of seeking relief from their condition with both efficacy considerations as well as tolerability considerations. And this is really where Praxis comes in. And taking a look at this community, very clearly, we saw an opportunity, an opportunity to help. And as Marcio shared earlier, we have 4 pillars to drug development. One of those pillars is to be patient-guided. And what this means is that we really dive deep. We dive deep to truly understand a community to understand their current situation and the challenges they face, but more importantly, their future needs, so that we can really guide our team to make sure we're developing products that truly meet their needs. And essential tremor, we did just that. And we spent quite a bit of effort to really understand the needs of the community. Our efforts included market research, engaging with the International Essential Tremor Foundation as well as local patient support groups. And in addition to that, we also conducted a thorough claims analysis to understand the marketplace. While there's a lot of insight to share, I really wanted to, in the next few slides, share more about the insights that we took away to gain a better understanding of the marketplace. We evaluated claims data over a 5-year time period from the Compile database. So it was 2015 to 2019. We specifically went deeper on 2019, and that it allowed us to take a look more specifically at diagnosis, at comorbidities as well as treatment. But with the 5 years, we had an opportunity to look longitudinally and do a look back, if you will, to see and understand, is this market, our treatment -- is the treatment currently today steady? Or is it shifting around? I want to also share the magnitude of the data from 2019, and that this included claims for over 100,000 patients and over 1 million claims, all relating to essential tremor. We believe that this analysis is the largest of its kind conducted in essential tremor, and I'm excited to share with you some of the key results. First is that very clearly, the claims data tells us that the addressable market is 2 million in size. And when I say addressable market, I mean, those patients that are [ both ] treated and those patients that are diagnosed and not treated. And if we go deeper and talk more about the patients that are treated, we did some follow-up research to truly understand their behaviors and what their wants were in future treatment. What we hear very, very clearly from them is that there's a portion of these patients that do respond to treatment today. However, 30% to 50% of the treated patients are in the cycle that I referred to earlier. So they're on treatment, but they're actively trying to find something new. So this tells us that they do want to be treated, but there's a high degree of dissatisfaction with current treatments. In addition, the vast majority of these individuals that are treated were very clear and that regardless of the treatment that they were on, the tolerability issues were very real and interrupting and affecting their every day, similar to you hearing Ken in the video discussing how basically the medication put him to sleep, and he didn't want to spend 4 hours of his day sleeping. That comes through loud and clear in the patient research. Now if we go to the right-hand side of the slide, and we talk about those that are diagnosed but untreated. The key takeaway here, and it's very simple, they don't see the burden of treatment as being worth it. And there's actually 2 groups representing this 1 million patient population. The first are those patients that have discontinued. So these are patients that have been treated and then decided, treatment is no longer something that I want -- that I think is worth it. These patients have cycled through all of the different options, literally all of the available essential treatment options and said, I'd rather cope with the disease than continue to try and stay on therapy. So they shared with us that they've never been able to realize the level of efficacy and find relief in the condition that they were seeking. Now there's another group that's sitting in this 1 million on the untreated side of the slide. And those are patients that are naive to treatment. Now their reason for lack of treatment is a little bit of a different angle. And what I mean by that is they are aware of the treatment options that are available, but they are very dissatisfied with the potential tolerability concerns. And so for them, they'd rather continue coping and managing with the symptoms of essential tremor instead of signing on for the tolerability issues that they see others confront. So in taking a step back, for me, looking on the left-hand side of the slide as well as the right-hand side of the slide, there's really a theme, and it goes back to the treatment options that are available today. I shared with you earlier that none have been designed specifically with their needs in mind, right. They've essentially been repurposed for other uses. This plays out in the feedback that you hear and experience from the patients and that there's a high degree of dissatisfaction. They continue to seek more efficacy, and they continue to struggle with tolerability of side effects, if you will. And so from the patient side of things, the need is very, very clear. Now I've shared a bit with you about the current marketplace and current treatment. In our analysis, we also identified 2 areas that we see as potential growth within this current addressable market. So within the current addressable market of 2 million patients in size, there's 2 areas in particular, where we think there is potential for growth. But growth in the future when new treatment options and more treatment options are available. So I'll start and then share a bit about those patients that discontinue. I mentioned those on the previous slide. This equates to 200,000 patients discontinuing treatment on an annual basis. But what's interesting is that, that 1 million number in the blue bubble, the treated population, that 1 million number stays consistent across the multiple years of this claims data that we analyzed. And so that tells us that while 200,000 patients are discontinuing treatment every year, 200,000 patients have to be initiating treatment every year. There's an equilibrium in play, if you will, keeping that treated market study at 1 million. But we ask ourselves, look ahead, look ahead to a market where you can have new and multiple treatment options available. Those 200,000 patients would need to discontinue therapy. There's the potential with new and better treatment options for those patients who are currently part of that treated market to stay on therapy, to realize better outcomes and to increase treatment utilization of that 1 million group. So that's the first pocket of untapped potential that I wanted to share with you. Again, this is looking ahead when new treatment options are available. And the second relates to diagnosed patients and that the claims analysis also told us very clearly that 200 patients are newly diagnosed each year. Now earlier, I shared that many of those patients were staying away from treatment because they were seeking options that were more effective. So imagine in a future time with more treatment options available that those 200,000 patients that are newly diagnosed each year can more quickly initiate treatment for essential tremor to better manage their condition. And over a 5- year time period, that would equate to 1 million patients. So I want to go back. And that when I started the current view today is that the addressable market is 2 million strong. But again, if we see these 2 dynamics or 2 potential areas of untapped growth, you could see that growing 3 million plus at a time when new and better treatment options are available. And that's really the area or the market, if you will, where Praxis is focused. And I'll zero in on the green bubble on the slide, the 3 million total addressable market. As I shared today, this is 2 million, and it's really capped at 2 million because they don't have better options. But with -- by bringing new treatment options forward from Praxis as well as from other companies, we believe there's an opportunity for the community to increase their treatment. Now if you add that up and consider the 3 million addressable population and a 50% treatment rate, that creates a $4 billion-plus market opportunity, an opportunity which we think is very attractive. Now I want to also be very candid and that we've taken a bit of a conservative approach. And what I mean by that is that, as you can see, the treated bubble on the slide is 50%. That's based on the claims analysis of current treatment. So the current treatment rate is 50%. So we think that it's certainly safe to consider in the future that with new treatment options, there's a potential for that treatment rate to even go up higher. So we see a market with tremendous opportunity and that we're excited about bringing not one, but 2 treatment options forward to serve the community and certainly advance on the opportunity of $4 billion in size. And those two treatments, we believe, in speaking with patients as well as speaking with healthcare professionals are greatly needed. They're needed to finally empower physicians to have treatments that are tailored for the needs of essential tremor patients so that they can truly utilize treatments to meet the needs of each individual patient. And that starts by having treatments that truly allow for an as-needed approach to be taken. So that patients can treat for a particular moment that they can thrive in that moment or that single point in time for a few hours of duration. They can also have as needed options so that they can initiate treatment sooner in their journey with essential tremor and that more chronic options are needed so that patients can face their day from beginning to end without tremor interrupting. And we're excited to bring forward 2 options: PRAX-114, a GABAA PAM that we're currently evaluating for both chronic use and as needed use as well as PRAX-944, at T-type calcium channel blocker that we're evaluating for chronic use. Bernard will share more about these in just a few moments. But I'd be remiss if I didn't also take a step back and consider the long term. I was very clear earlier in that Praxis is focused on what we believe is that growing addressable market that's 2 million strong today, but with new treatment options could grow to be 3 million plus. And that new treatment options will help patients realize better outcomes and that, that's really the starting point to truly evolve and advance the treatment of essential tremor today. But we also recognize that this is a far larger opportunity and that there are many more patients that need our help and that there are 4 million other individuals who are suffering from symptoms today yet have not yet been diagnosed. And so we fully recognize that the lift that will be required includes investment to drive awareness, investment to drive diagnosis as well as efforts to bring our treatments to them and make sure those treatments are accessible. We see that as the long-term opportunity for Praxis. I want to be very clear on that. So as I wrap up, I just wanted to first thank you for your time, but also just go back to the beginning, and that we've very clearly reviewed essential tremor an extreme level of disability that this impacts individuals on a daily basis. There's tremendous unmet need as they've really been making do with treatments that weren't designed for use in essential tremor. They continue to seek efficacy to get relief from their condition, while also trying to limit any potential side effects so they can truly thrive. And we at Praxis, are very excited to bring about change, to bring new and better treatment options to this community because we believe it's time that they've gone on too long in terms of their needs being underserved. So before Bernard steps up and provides an overview of our current development efforts and how we're -- our teams are truly daring for more to bring new options forward, it's my pleasure to also let you know that we have about a 10-minute break. Thank you.

So we'll get started again. Thanks for rejoining us. I'm Bernard Ravina. As Marcio mentioned, in his intro, I'm a neurologist and I specialize in movement disorders. So it really is a pleasure to be talking to you about these programs. And it's really a privilege for me and my colleagues to be able to work on these programs and advance them. Nicole articulated how there haven't been targeted treatments designed for essential tremors, and the reason for that is that the mechanisms were not well understood. But that's changed over the last several years. So when you put together really many years of human imaging studies, electrophysiology studies, and animal model studies, it's clear there is an underlying tremor network in the brain. And that stems from the Brainstem, the inferior olive up through the cerebellum, then into the thalamus, the vin nucleus of the thalamus, and up through the cortex. Now, this connected network wasn't put there. It wasn't designed to generate tremor, it's designed for the integration and control of movement. But when it doesn't work well and it's oscillating, it causes tremors. What we're excited about at Praxis is that we have two mechanisms. And really, I would say, the two leading mechanisms to modulate this network, dampen tremor and improve the disability associated with tremor. So we'll start with our 944 program. So PRAX-944, Nicole alluded to it, is a selective T-type calcium channel blocker. There are three isoforms or different flavors of T-type calcium channels. These are expressed throughout that tremor network. And 944 is similarly potent across all three isoforms. Consistent with our principles of drug development that Marcio talked about, these channels are genetically linked to ET, particularly familial ET, also different forms of generalized epilepsy. There are unique characteristics to these channels and that they kind of act like first responders. So they activate at very low voltages, and then they trigger other kinds of channels like sodium channels, and so they can entrain a whole network. They go into this burst firing mode, which you see here on the left is very characteristic for these kinds of channels for T-type calcium channels to be able to drive it. And that causes oscillations, which can occur in a nucleus, like the interior olive or in the thalamus or it can drive oscillations across the whole network, which is when you get tremor. What's really unusual in this program is that we have human physiology data recorded directly in the brain, in the thalamus from patients with essential tremor as well as Parkinson's disease. That was done because those patients actually undergo deep brain stimulation, only the most severe people choose to have deep brain stimulation, and you can record as part of that procedure. So what you see here is actually intraoperative data. And you see the burst firing pattern driven by these T-type calcium channels. It correlates with the presence of tremor and then the probe delivers an electrical pulse, silences that burst firing, and you can see the tremor goes away. So you need to have human physiology data in both populations, ET as well as Parkinson's disease. So really compelling linkage rationale for this channel and this target to ET. Our second principle of drug development is to use electrophysiologic biomarkers. So obviously, it works really well when you're modulating ion channels, there is a particular EEG frequency associated with T-type calcium channels. It's called Sigma frequency. It's about the 10 to 14 Hertz range. It occurs specifically during non-REM sleep. You can see there it's not present during REM sleep. We know that this EEG frequency is generated by T-type calcium channels because when you knock them out, any of the particular isoforms, you markedly attenuate this sigma frequency. So it's a great biomarker for us to use to help guide dose selection. And it's a translational tool because you can do it in animals as shown here, and you can do it in patients just with quantitative EEG. So that's exactly what we did. What I show you here on the left is our Harmelin model data of tremor. This Harmelin model is a well-validated model of tremor. It has good predictive validity for drugs that work in patients. And you see here a nice dose-dependent and large magnitude change with treatment with 944 in this Harmelin model, down to about 75% reduction in tremor. Coming back to this translational biomarker, we're able to use it and show that the concentrations, the exposures of 944 that reduced tremor in that model totally overlapped with the exposures that reduce that Sigma frequency. So that further informed this idea that we could use Sigma frequency as a translational tool and help us guide dose selection for studies in ET and Parkinson's disease. So I'll turn from the preclinical work to our clinical data, a little bit more background about PRAX-944. I mentioned that it's potent at all three isoforms, which we think is important because those are expressed in different degrees throughout that tremor network. It's highly selective, not just for relative to other ion channels, but particularly other types of calcium channels like L-type and N-type, and those are important for cardiac rate control, blood pressure. So we have about 100-fold or greater margin relative to those types of calcium channels. And it's got no active metabolites, so we can get uniform exposures and not worry about differences in the metabolic profile. We have extensive clinical experience with 944 for many different healthy volunteer studies. This program started off with different forms of 944 initially and immediate release. What we found with the immediate-release formulations is that it tended to be limited by C-Max-related side effects. So that led to the development of a modified-release formulation, which blunted that C-Max. The NTD, the highest tolerated dose with the immediate-release and other early formulations was in the 20 to 40-milligram range with the modified release formulation, we've been able to titrate up to 120 milligrams initially over the course of a month, but in as little as about 10 days, we haven't had any severe adverse events and have not hit a maximum tolerated dose. So the most common AEs we saw there were dizziness, headache, mild to moderate AES. To give you a little bit better feel for what this formulation looks like, here's a PK curve from 20 milligrams. You can see relative to what the IR would be, this has a very blunted C-Max. It's got a low peak to trough ratio, which is what we are after. And importantly, it's got a nice, smooth profile throughout the day so that patients with ET or Parkinson's disease could take this once and get good control of tremor throughout the day. And that's the key. Remember, a tremor is an action tremor. It occurs during the day. There are no manifestations at night times, you want to be able to dose once and get tremor controlled throughout the day. To come back to this translational biomarker, we've shown this PK/PD curve before. But here, we've overlaid the doses of PRAX-944. So point out a couple of key things. So one is we have a nice dose-dependent effect. We reduced Sigma band in a nice dose-proportional way. But the effect kicks in, we reduce Sigma, which tells us we're getting drugs in the brain or blocking T-type calcium channels. And we're doing so in the right territory in that thalamic cerebellar network -- the thalamo-cortical network where we know these are generated. That kicks in, in the range of about 5 to 10 milligrams proceeds dose proportionately, and then hits a plateau at about 80 to 100 milligrams. This gives us a very wide dose range to work with of about 20 fold. That's great because, as Nicole talked about, it's a large heterogeneous population, one dose will not fit all. This is also a chronic condition. And so people are going to be -- want to be able to titrate over years. So really important to have a wide dose range that we can explore and that people can stay on for many years. So with that, we'll turn from our healthy volunteer data and how we think about defining our dose range into our initial studies in patients with essential tremor. What did we want to learn from this PRAX-221 study, which is our first ET study was really what does the tolerability look like in patients? I heard earlier that this is really the challenge for the existing standard of care therapies. They're poorly tolerated, and so patients discontinue at high rates. So that's our first question. And is that whole dose range well tolerated. We also wanted to understand what the overall effect on tremor looks like. And the key for us, this is a learning study. That's how we refer to them internally. What can we learn about the clinical measures, how do they perform and how can we conduct future trials more efficiently? With that, I'll turn to the design to remind you here, we've talked about the part A data before. Part A was conducted before we had completed the titration in healthy volunteers up to 120 milligrams. So we went up to 40 milligrams here over a 2- week period and then patients had a safety follow-up. We've previously reviewed those data. We thought they were very compelling. The drug was well tolerated. The impact at 40 milligrams was consistent across the patients. We saw nice consistency across different ways of mentoring tremor, including accelerometry and central ratings. In Part B, the real question was about this titration, the tolerability at higher doses. We titrated people up over the course of about a month. They could down titrate if needed. And then we kept them stable for a couple of weeks. The data that we'll talk about today is from this open-label titration period. And then in the first half of next year, we'll have completed the randomized withdrawal. We'll go over the aggregate data and those randomized withdrawal data. Before we go any further, I just want to remind everybody, Part B is an ongoing study. We're actually recruiting through the rest of the year. So we anticipate a couple of more participants. So these data are preliminary and truly subject to change. A little bit of background about the clinical measures that we used here to assess tremor. It was primarily a tolerability study, but we're also exploring these measures and how they performed. These measures from the TETRAS really come out of the kind of clinical tradition of how we assess tremor in the office and get a gestalt really of how people are doing. So the TETRAS scale is divided into two parts. One part is the performance scale, and that's just a visual assessment of tremor in all the different body parts, ahead, the hands, and the legs. We have focused on tremor in the hands because everybody has that, and it's really the main source of disability. So a couple of things about the scale. One, it is a visual rating of tremor, which is not optimal. It's just kind of an eyeball instead of directly measuring it, that came up in conversations with the FDA that it's subjective and prone, -- just to error. The other element about this scale is that it's not linear. So if you get a 1, a one here is a 1 centimeter or less tremor. But a 4 isn't 4x worse. It's a 20 centimeter or greater tremor. So it's a nonlinear scale. So you have to convert it back to an amplitude, which is how we look at the scale, we think it's the most informative way is really telling you about the true amplitude of tremor. And the last thing I'll mention about the scale, it really has problematic floor effects. So most people with ET who come into a trial, they come in with tremor in the 2 to 2.5 range, which is up to 3 to 5 centimeters. It's still a large-amplitude tremor. However, the best you can do on this is one, the barely visible tremor, you never get below that. So you have a very limited dynamic range. And it's not uncommon for people to come in with scores in the 1.5 range or so. That's the case. The only room to go is noise with no change or up. So those are the limitations of the TETRAS performance scale. The activities of daily living are a pretty straightforward part of the scale. This test assesses across 12 very concrete day-to-day items, how people are doing. Can they pour water, can they feed themselves, can they dress? 0 is normal here. A 1 is that you have tremor but doesn't cause disability and then varying degrees of disability above that. So this part of the scale is very clinically intuitive, meaningful. It requires no interpretation about how important a change on it is. For that reason, in our discussions with the FDA, they really gravitated towards ADLs as being the key in the primary outcome. They did have very specific modifications that they suggested for how this should be scored and we'll refer to that as modified ADLs or FDA modified ADLS. They suggested just pooling the 0 on the 1. So 1, which has no disability would be a 0 and adding a couple of items that they thought were relevant from the performance scale, handwriting, and drawing spiral. So that's the modified ADL, and we'll show you data on that. So the overall patient disposition for 221, again, ongoing studies, so these numbers might change for Part B. In Part A, we enrolled seven participants, six completed. Per protocol, went up to 40 milligrams. There was one participant who discontinued, and that person had an AE of mild anxiety, but they changed their propranolol. They could have stayed in the study. They changed their propranolol dose. So, therefore, they were no longer evaluable, because they didn't have a stable baseline. In Part B, we've enrolled 12 participants, eight completed per protocol, five on 120 milligrams, and three down titrated with a range of 20 to 100 milligrams there. There were four participants who discontinued. One made it to day 21 and discontinued after being on 40 milligrams. And there was one site that had three participants who discontinue basically immediately after starting 20 milligrams. Those participants had pretty typical AEs mild-to-moderate. They did not come in for visits and had no evaluable data. The conduct was very unusual, and we hadn't seen that in any of our previous studies or in any of the other sites. So we investigated and talked with the site. Unfortunately, we found two major protocol violations there related to eligibility, and the other, the third participant was questionably appropriate. So we've suspended the site. We're investigating the drug product appears to be fine. We include all of the data from anybody who took a dose of PRAX-944 in the safety, but those participants don't have efficacy data. To go over the demographics here, pulling the two cohorts, this population is very representative of the population that Nicole described. So it's a broad age range from 40s to 70s. About half of these people have a family history of ET, a first-degree relative with ET, which is pretty typical, long-standing, so it's chronic 30 to 40 years of tremor, most of these people have discontinued their tremor medication. So basically it means that they've given up on treatment. Some are still on propranolol, but overall, a pretty typical population. The two cohorts were conducted sequentially at different sites, and they are, I think, different in meaningful ways. Part B cohort was about 10 years younger, and they were much less likely to be taking their medications. So only two of the participants were on propranolol. Otherwise, they had discontinued everything. This suggests to us that this is just a group that, for whatever reason, didn't tolerate their medications or didn't benefit from ET medications as well. To go over the safety data, and this is for Part A and Part B. What we show here are the AEs that occurred in more than one participant. These are pretty typical AEs that we had seen earlier in the program. The thing I'd emphasize here is that we're all mild to moderate. We didn't have any SAEs, again, even pushing the dose here up to 120 milligrams. We had no severe AEs. AEs here are pretty typical for the class and cognitive disorder just described a little bit further. That was difficulty with attention or difficulty focusing. And paresthesias are just numbness or sensory disturbances. So nothing new in the safety profile, and we're pleased to see that the AEs remain mild despite going up to higher doses in titrating. The AEs associated with down titration or discontinuation, really look like the overall AE profile. There were four participants who down titrated. That was only allowed in Part B. And then the discontinuations, there were a total of five, one in Part A, four in Part B. So pause here in terms of what these data are telling us. The discontinuations actually occurred at the lower doses. So four of the five discontinuations were at 20 milligrams didn't tend to happen at the higher doses. I mentioned there were some less than optimal conduct at the site in terms of how they coach the participants through this, how much they discuss these AEs with them. And so as well as those protocol deviations, typically, we would go and monitor a site after their first participant is enrolled. But this was conducted during the pandemic with lockdowns in Australia. And so I wouldn't expect these kinds of issues to come up without those extenuating circumstances. Nevertheless, we take the safety data at face value, and they're consistent with what we've seen overall. And so the easiest way to address this is to make it easier for patients to start on PRAX-944. The way to do that is by starting at a lower dose. We have previously shown you that we have pharmacodynamic effects in the 5 to 10 milligrams range. What we'll do for the essential one is start titration at that range. And in healthy volunteers, we saw little or no AEs there. So that's, I think, a very straightforward way to address AEs that may occur at the outset before patients have had an opportunity to benefit and see that they have control of their tremor. With that, I'll turn to our efficacy data. And we'll start off with the modified ADLs. Again, these are the FDA-recommended way to approach ADLs. And we're very pleased to see these data. I will explain what we have here on the y-axis, we show reduction in ADLs or reduction in disability. And we've got this organized from left to right, the participants who had the least severe tremor to the right participants with the most severe tremor. We're pleased to see that about seven of the nine participants here had nice improvements in their ADLs. It's good to see open-label data that not everybody improves, which suggests you have some objectivity in the data and reassures you about placebo effects. The magnitude of the effect here, I think, is really important. So as you saw with that ADL scale, every point on there is really functionally relevant. We know from recent studies that placebo effect on activities of daily living is very modest. So it's about 10% or less. Most of the participants here have a 20%. The range is about 20% to up to over 80% improvement in ADLs. That gives you a feel that's really taking people from disability associated with their tremor, the little or no disability in the 50% or greater range of improvement. So really marked clinically meaningful and very readily interpretable in terms of the impact here. On the next slide, what we've done is ADLs on the bottom here. This is the original recipe ADLs. And then on the top, we have the combined upper limb tremor. So reduction in tremor. Combined upper limb here just means that we took all the items that measure tremor in the hands from the TETRAS performance scale. And the clear take-home here is the consistency of the reduction in tremor and the correlation with ADLs. So for participants who had improvement in their ADLs, they had marked improvement in their upper limb tremor as well. The other thing I would point out on this slide is that we really see the impact of the floor effect of the scale. So we took a broader pool of patients in this study, enrolled a broader pool of patients here because it was a safety and tolerability study. For essential one, we'll have more rigid eligibility criteria in terms of baseline severity of tremor. But as you can see on both the tremor scale as well as the ADLs, if people come in at the floor and you're not able to measure improvement, the only thing you can do is either vary around the baseline or go up slightly. So that's readily addressed in the essential one eligibility criteria. Then the last slide I'll show on these data is to bring back Part A, which we've previously shown. You see the same general pattern sorted by severity, that you just get more variability for -- people have more mild severity. But the overall direction of change and the magnitude of change is very reassuring across both. So in Part A, by the end of treatment, six of the six participants showed improvement in Part B, five to six of the participants, and that's of an evaluable population overall of 15 here. I think it's important to pause, these are people with long-standing ET who had failed most of their medications and stopped taking medications and about six of them, they continued for propranolol. So if we were talking about a depression trial, you'd call this treatment-refractory population. But here, the study is a mix of monotherapy and people have discontinued therapy as well as on top of propranolol on five or six of the participants. So this data gives us a very nice consistent signal, large magnitude, and a very good responder rate overall, especially for this population. The data themselves here can be a little bit abstract, but I just wanted to share a video with you. This was sent to us by the family of one of the participants in Part A, and they were so excited about the response they saw in their dad, they just unsolicited sent this video to us. If you listen carefully, you'll hear them in the background saying, look at that. He's enjoying a meal that's not easy to eat. He's eating peas with a fork. So let's show you. You did see -- he's doing that very easily. Those are the kinds of ADLs that are hard for people with tremor feeding themselves, especially something like peas. So it's nice, and this person is one who had been on propranolol and stopped taking it, but has initially had a benefit. So they have a frame of reference. They said this was just like that response to propranolol. So really encouraging in terms of the impact on patients. So that's where we are with Part A and B and lessons learned. Safety and tolerability, which is what we set out to understand. Overall, the safety profile is very consistent with what we've seen, again, mild to moderate AEs throughout the dose range. Tolerability was good relative to the other options that participants with ET have -- patients with ET have. I think a very clear, lower the starting dose and give an easier ramp for essential one. The efficacy was compelling. The consistency across the measures, the magnitude overall in the proportion of responders. We have clear lessons learned for patient selection, which is if you don't have room to change on these measures, they should not be enrolled in a study like essential one. There is work to do about endpoint evolution, given that those measures haven't really been optimized for use in clinical trials. So I'll talk about that a little bit more. I mentioned that TETRAS upper limb has these floor effects, and it's a visual inspection. We're working towards more objective measures of tremor as well as more objective ways of assessing ADLS. We have a number of different approaches going on with sensor technologies and ways of objectively looking at tremor to avoid floor effects. There's one study with BioStamp, which is a wearable sensor. It can be used while doing the TETRAS, so you can get the standardized exam without floor effects. But you can also wear for longer periods of time, so we can get a better sense of how patients function at home, what their tremor looks like at home. So we're doing a validation study actually with colleagues at Columbia University now, and that's going very well. And then the next approach we're taking is to more objectively assess activities of daily living. So the scale works pretty well. That's why the agency likes it so much, but it is based on participant recall. So what we've done is take items from that ADL scale and just bring them into the clinic so that you can rate the disability associated with that activity. I'll show you a video from what we call the performance scale. And just a couple of examples here. You can see at rest, she doesn't have any tremor, would guess there's anything wrong. As soon as she starts moving, tremor kicks in. You see she has difficulty pouring, spills, goes back to rest, no tremor. This is really dramatic. She's unable to button a shirt. You can see the impact this would have at home, and it's interesting that a lot of the tremor is very task-specific. You can do different activities with different kind of manifestation in severity of tremor, which is why just an exam itself isn't sufficient. The other thing that I would point out from that video is, people ask about placebo effect a lot. Tremor is not under voluntary control. So quite the opposite. When people move with voluntary action, the tremor actually gets worse. That's when it kicks in. So that's why placebo effects tend to be very low, you can't control it. It's not influentiable in that way. So that's 221 Study. Again, we're going to finish enrolling Part B by the end of this year, then we'll have the randomized withdrawal. We'll present those data in aggregate in the first half of next year. Essential1 has started. We talked about some of the lessons learned that we'll apply to Essential1. The goal of Essential1, as Marcio articulated, it's a dose-ranging study. We'll have three target dose levels, 20, 60 and 100 relative to placebo. That will allow us to select a dose or doses based on overall safety, tolerability and efficacy. We'll select a dose for Phase 3 registrational studies. With that, I'm going to turn to our second ET program, PRAX-114. So we're equally excited about 114. It's a little bit earlier in the thinking, but the rationale is really sound here. So we come back to the same tremor circuit. 114 we think will work in a different part of this circuit, primarily in the connections from the brain stim to the cerebellum. There's a reduction in GABAergic activity there. And we think that 114 would increase that GABAergic activity and silence some of the tremor output coming from the cerebellum. More importantly, though, and both Marcio and Nicole mentioned this, we already know that GABAergic drugs work in ET. So alcohol works, benzos work. They're just not used clinically because they're limiting due to somnolence to sedation. And so the question we really had is, can PRAX-114 as a GABAA-PAM control tremor without somnolence or sedation? We've discussed in the context of our depression studies this extra synaptic hypothesis. PRAX-114 modulates and enhances extrasynaptic GABAergic receptors much more than synaptic, about 10-fold. So that raises a question for us is, is there an extra synaptic hypothesis in ET? We're really pleased to see these data, which were conducted by one of our collaborators, in which they used extra synaptic GABA agonist in wild-type animals as the delta sub-unit containing ones on the left. They have normal extrasynaptic receptors. And then they knocked out those extrasynaptic receptors to delta sub-unit. And what they showed was in the far right bar in each one, in the wild-type animals with extrasynaptic receptors, you get a marked attenuation of tremor. When you knock out those extrasynaptic receptors, you lose that treatment effect. So it told us that extrasynaptic receptors mediate this treatment effect and could have a very important role in the treatment of ET and that 114 would be very well suited given its profile and preference for extrasynaptic receptors. So that led us to do like we did with 944, a harmaline model study of tremor. We got nice reductions. I don't show that here, but a harmaline study of tremor with 114. Nice improvement in tremor, and we had a similar translational biomarker that we've talked about in depression, which is beta power or beta frequency on EEG, which is just an EEG frequency that moves with GABAergic pharmacology. And what we saw was we got tremor control at doses that corresponded to beta power of about 1.3-fold increase from baseline. We already have human data showing that we can get that kind of increase in beta power and that we achieved that in doses in the 10 to 20 milligram range, which we've dosed during the day, it didn't cause any somnolence or sedation. So that helped us zero in on that question. Can we give 114 at doses at controlled tremor, the harmaline model suggests, yes, that aren't sedating typical limitations of existing GABAergic drugs? And these data suggest that we could do that with about 10 to 20 milligrams. So that led us to design a study that Marcio referred to in the intro that we think will be very efficient. It's a three way crossover design. We give 10, 20 milligrams or placebo, single dose in each of the three periods. There's a washout in between. We'll do after each dose multiple tremor assessments, multiple PK draws, we'll have a very good understanding of just that question. Do we control tremor at doses and exposures that don't cause sedation or somnolence? This study is just getting underway, and we expect it will read out in the second half of next year. Then come back to the big picture that Nicole talked about, which was options for this really underserved patient population. So we have two very well grounded mechanisms for modulating the tremor network, controlling tremor and reducing disability. 114 would be well suited we think based on what I just presented as a as-needed treatment or potentially as a chronic treatment. And I will -- reflecting on my own clinical experience, a lot of people with tremor start off with as-needed therapy, need tremor control for work for a presentation just having a meal or getting together with family. And then there's years' of progression, and those needs become more continuous and they need a chronic therapy. 944, which we'll use with titration, will be well suited to that. And I will come back to the point that people will titrate and use 944 over a period of years. In clinical trials, we titrate out quickly to conduct the study. But in clinical practice, people will start, reach a dose that works for them and then titrate up over a period of months to years. So we're excited to have both of these, explore them further in ET. And now I'll move to our Parkinson's program beyond ET and talk a little bit about the background of PD and just ground you in that. So Parkinson's is the second most common movement disorder after Essential Tremor. It's also the second most common adult neurodegenerative disorder preceded only by Alzheimer's disease. So there's about 1 million people in the U.S. with Parkinson's disease. It is an age-related disorder. So peak on says 60s to 70s, but incidents goes way up with age, and there's a 60-40 male predominance. So most people are familiar with the key motor symptoms of Parkinson's disease, slowed movement, difficulty initiating movement or bradykinesia, rigidity, stiffness in rest tremor, different tremor then occurs in ET. It occurs at rest and sometimes spills over to action. There are also very profound psychiatric and cognitive aspects of Parkinson's disease, which are often worsened by existing therapies. So Parkinson's progressive and debilitating. There are many treatments for it, which I'll touch on in a minute, but a lot of those worsen aspects of disease. The main state of treatment is dopamine replacement. So people of Parkinson's lose dopamine-producing neurons. The main state of treatment is supplementing dopamine various different ways, orally, subcutaneously and other routes or preventing its breakdown of metabolism so it hangs out longer. You need dopamine for movement, but there's a real yinyang relationship in that. Dopamine can worsen certain movements. It causes hyperkinetic or excess movements called dyskinesias. And those psychiatric manifestations that I mentioned like impulse control disorders, psychosis are all worsened by dopamine. And so those tend to predominate in the later stages of disease. There's a really marked need despite all these dopamine-based treatments. There's a really marked need for a non-dopamine-based therapy for Parkinson's disease, which we envision could be used early on to prevent some of these complications as well as later on in combination with dopamine treatments. I just want to dive into the rationale for 944 in PD a little bit more. We come back to the same network. It's the cerebello-thalamo-cortical network. We're just going to ignore the cerebellum for a little bit, though it does play its key role here and focus in on that thalamic and cortical pathway. And on the right, I showed to you in more detail in the healthy state and in the Parkinsonian state. In the healthy state, there's normal dopamine. And the two paths, the indirect and the direct pathway that modulate the thalamus are well balanced. In Parkinson's, you will lose that dopamine and then you end up having abnormal input in the thalamus. What happens is the sub-thalamic nucleus becomes hyperactive. That's associated with burst firing driven by T-type calcium channels, just like we talked about in the thalamus for tremor. That hyperactivity leads to a net silencing of the thalamus, reduced stimulation to the motor cortex and an overall reduction in movement. So one of the most important treatments for Parkinson's disease is deep brain stimulation of that sub-thalamic nucleus where you silence that bursting and quiet the STN and get normal outflow from the thalamus to the motor cortex. You get marked improvements in motor function. We think we can do that with PRAX-944 pharmacologically instead of requiring a brain surgical approach. We know the drug going back to some of our EEG data. We know it gets into thalamus and related nuclei, and we know we can reduce T-type calcium channel activity. So I'll show you some of our preclinical datas conducted by one of our collaborators where we work with a very well-validated Parkinson's rodent model. It's called 6-hydroxydopamine model. It will lesion or knock out the dopamine production in this model. He recorded in the subthalamic nucleus showed with the lesion, whilst the dopamine that could get the burst firing pattern and then infused a T-type calcium channel blocker into the STN. What he showed on the right panel of the slide was that he quieted that burst firing. And as a result, this 6-hydroxydopamine model, the rodents usually don't move, and you see those limited red tracings there. When you block those T-type calcium channels by infusing in the thalamus, you return movement to a normal active movement distance as measured by distance and velocity. So given the nature of the model and the overall clinical data we have so far is very compelling approach to use 944 in PD. So we designed our first Parkinson's trial based on that as well as our overall experience in healthy volunteers, EEG in Essential Tremor will titrate up. There's a randomized study from 5 to 100 milligrams, and then maintain patients at steady state for close to a month. Some of the features of Parkinson's disease respond more slowly and require kind of a plastic return and more time than in Essential Tremor. So it's a bit of a longer study. The key outcome here is to look overall at their motor function and associated disability. The main scale that we'll look at is called the Unified Parkinson's Disease Rating Scale. This measures both motor function and disability. We will look at it in a couple of different ways. In the morning prior to patients having taken their standard dopamine medications. So we'll get a sense of the impact of motor function alone. And then they'll take their dopaminergic medications, and we'll see it in combination with their standard of care therapy. That's our Parkinson's program. I'll wrap up there, both ET programs and Parkinson's and turn to Tim, who will talk about milestones for next year, not just for movement disorders, but across the company.

Good morning, everybody. My name is Tim Kelly. I'm the company's Chief Financial Officer. And as we're just at the cusp of wrapping up 2021, part of what we wanted to talk about is what we have in the year ahead. So we are rounding third and heading home right now. What I want to start out with though is a slide that Nicole shared earlier. And it brings together a comment she made about the total addressable market in Essential Tremor and how we see that and are targeting it. But then also, an important point that Marcio made about how focused we are on putting our resources where we see that we can create value for the company. And when we look at the Essential Tremor market, I think what Nicole laid out very well, with a series of fairly conservative assumptions that we believe have a lot of upside when we bring two very strong therapies in two different ways to treat patients that there's a tremendous opportunity for value creation for the company. And this excludes the international market and it also excludes Parkinson's disease, which is something that we'll be doing initial marketing work on as we go into the year as well. So for us, a very, very important opportunity for Praxis, and one why we feel very good about applying the resources that we are to those. Now as we go into 2022, both Marcio and Bernard have conveyed to you that we have a number of trials that we'll be conducting in the year. And just to put that together for you in a timeline, the solid bars are the trials that we're conducting, the white is when we expect to generate the data and generate the catalysts from these trials. It's an incredibly rich year for us in our movement disorders franchise, where in the first half of the year we'll read out the second half of this Part B 221 study and see the randomized withdrawal data. By the end of the year, we will read out the Essential1 study. And we also by the end of the year will read out our proof-of-concept study, investigating 114 in Essential Tremor. And so we'll be in a place where a year from now, we will have answered a number of questions about this two molecule two therapy approach in Parkinson's disease in a way that sets us up to go into Phase 3 for 944 and to go into dose-ranging studies in 114 in Essential Tremor. And in addition to that, we expect to initiate our Parkinson's trial that Bernard was just referencing in the first half of next year. But this is only part of what Praxis is doing in 2022, because we have two other franchises that are incredibly active. And you're all familiar with our psychiatry franchise, where we have two significant readouts that Marcio referred to earlier. Our Aria study and our Acapella studies we'll readout in the first half of next year, but also we'll learn about our post-traumatic stress disorder study investigating 114 by the end of next year as well. And in rare diseases, we expect in addition to the Phase 2 study we have that's begun in rare cephalgias that we will also initiate a study in developmental encephalopathies. In epilepsies, we'll also be in a position, as Marcio referenced, to begin this 222 study, really looking at what a seamless trial design looks like. It's something we're really excited and energized about. And also, we'll readout a Phase 1 study we have evaluating the ASSR correlation in 562. So it's an incredibly rich year for us as we go into 2022. When we ended Q3, we had $314 million in the bank. And when we look at our projections, we feel very confident that this is sufficient funding to get us into the middle of 2023, which means we can generate the data for all of these studies that we're showing here in the next coming year. And when we look at fundraising also, we have no intention right now to do any equity fundraising before that Aria study reads out. But it's something we continue to think about every day, how do we apply our funds efficiently? How do we think very carefully about our cost structure? How do we keep putting our resources into generating more and more out of our portfolio? Now today has been a great day for us. We've really enjoyed the opportunity to share all with you about the opportunity we see in movement disorders, both from a commercial perspective, also from a clinical and patient perspective. We have a lot more to share with you. And oftentimes, when we talk in a half hour or 45-minute meeting, it's just not enough time. So our intention is to have two similar meetings today at this location, the Apella staff here has been phenomenal to work with; one on rare diseases and one on psychiatry. And in rare diseases, we'd like to share more with you about our 562 program, our 222 program, but also looking a little bit earlier into our pipeline as well and share with you how we're looking at KCNT1 and then three ASOs as well; in SYNGAP1, in PCDH19 and in SCN2A on loss of function also. And then we also want to spend some time talking with you about our psychiatry portfolio, how we're looking at major depressive disorder but also post-traumatic stress disorder as well. So quite a lot more than we'd like to talk to you about and share more with you about our portfolio as we go into 2022. You heard from Nicole earlier how important these 3 words are to us at our company, DARE FOR MORE. And I hope what you've seen today is a company that is daring for more by looking at 2 ways to bring new therapies and options to a huge unmet medical need, by looking at a new way that's non-dopaminergic to treat movement disorders in Parkinson's disease, by looking at new ways to do trials efficiently where we can learn quickly and answer questions quickly on the opportunities with our molecules and where to investigate them for broader therapeutic use, using our funds efficiently. But it's not just in movement disorders that we dare for more, we dare for more for the patients who we aim to serve with our therapies. We dare for more from our portfolio, and we dare constantly for more from ourselves that we are constantly challenging how we can work better, do more and be better for our patients with our portfolio. This has been a great day for us. We're going to take a couple of minute break, while we shift around up here and the 4 of us will come back up for a short Q&A. Thank you. [Break]

All right. We are ready for Q&A, and Alex is going to read the ones from the analysts on the -- that are not here today and -- but we are ready to take any questions from the audience.

Hi, everyone. This is Chris Bialas from H.C. Wainwright on for Doug Tsao. So we have a quick question. And among the participants that down titrated from 944, [ would their ] own particular dose that patients moved down from? Was there any particular AE that led to the down titration?

Bernard?

That's a good question. Yes, there was no particular dose at which we saw like an inflection point. And I think it's consistent with what we said like it's a big population. It's a big age range. They have different needs and different levels for acceptance in terms of tolerability. So pretty representative overall. I think the main reasons for down titration, it was difficult to do with a tension, paresthesias, but they didn't stand out as different AEs than anybody else. We had seen in the overall experience with 944.

[ Sara ] from William Blair. Great presentation, guys. Just a quick question on 944 in Parkinson's disease. Will your trial enroll patients with cognitive impairment? And is there any precedent for use of T-type calcium blockers in those patients? And do you have any predictions on how they will impact the broad symptoms of Parkinson's besides movement disorders?

So, we're not going to -- the group of patients that we're going to enroll in this initial study is kind of a mid-stage group who need dopamine therapy to advance and allow us to get a really good sense of the impact on motor function overall. Typically, in Parkinson's trials, you don't -- unless you're focused on treating cognitive impairment, you don't allow that cognitive impairment. It's usually a bit of a barrier just to study conduct participation reporting. We do, however, think there could be an impact on motor function, which is the main goal of the study to assess, but also non-motor function at the very least -- the very least by not increasing dopamine and maybe reducing, allowing reduction in dopamine therapies, we expect we might see a benefit on psychiatric symptoms. We also, on our clinical experience with ET, have seen people's mood improve. We don't know if that's primary or secondary due to improvement in tremor, but there is a rationale for that, and we'll be assessing the broad non-motor impact in PD.

I have 2 questions from Laura Chico at Wedbush Securities. First, you indicated approximately 1 million patients non-treated ET in the U.S. You also mentioned that these patients' treatment burden isn't worth it. Another way to view it is that their symptoms aren't sufficiently severe. So just trying to better understand this group among the 1 million ET patients not on treatment. Can you clarify how many are naive versus previously treated?

Yes. So it is a mix of both in terms of the discontinued patients, and those are the patients that typically have the more severe burden, if you will, more disability in terms of the impact that ET has in their life because those have patients that have been receiving current treatment. And certainly, there is another portion of that market that those are individuals that are newly diagnosed, which we believe, today, they are seeking treatment. Those are patients who are earlier in the progression of their disease. So they are seeking more as needed treatment. So it is a mix in that group of patients that are seeking both. And that's something that certainly we would -- if you look ahead, you'd continue to see that trend. And I want to be clear, it's not an either/or scenario. And that's important to keep in mind that while patients who are newly treated may initiate, as Bernard shared, in terms of -- and utilizing an as needed treatment, this will progress. And there will be a time when chronic treatment will be required, but chronic treatment is not a cure. And so, I think that's something very important to keep in mind that it's not an either/or situation when you think about as needed in chronic treatment. They can be used in combination.

And Nicole, maybe to complement that, right? [ Want to expect ] that we left out of today's presentation that might be important for that question is the time that takes between presenting or being bothered by so much that are going to want to be treated and actually being called in essential tremor patients. And the current guideline is 3 years. So there is not such a thing of a patient who has a diagnose of essential tremor that is mild. The patient went through treatments with intervention for 3 years before actually gathering that. And those are the ones we're counting. So in our view, when you look at your comorbidities, use of drug, use of procedures, for our intention purpose, they are incredibly disabled. And I know we take that award incredibly seriously because putting a label of disability in the disease is not something simple. But that's one of the reasons why, and we agree with the FDA. The proper way to look into these patients is by what they cannot accomplish, and then we can bring back their ability to accomplish things.

Second question from Laura. Realizing that the claims analysis in ET was through 2019, wondering if we have any data to support how ET diagnosis rates may have changed during the pandemic. We've seen challenges in diagnosing patients in other movement disorders. As telehealth has increased during the pandemic, how do you think about how that impacts ET?

It's actually linked to some extent to what I just said as well, right? And I'll let Nicole explore a little bit more. The unfortunate reality is that 3 years is within. I can't believe we're 2 years into this pandemic, but it's with in. So there was the large pool of patients that are progressing through. Originally, neurology was now one of the key areas that had a lot of access to telehealth. But right now, it's pretty well established. So, we're seeing them more and engaging these patients is more enthusiasm, even with little developments on this community, and we see that growing. Now to stay here and say there was no impact would be just absurd. We do expect a reduction on that rates on the next year or so to come, but we're not dependent upon, as Nicole rightly said. And one of the reasons why the total addressable markets for it is a lot more down to work than other numbers have been put out there. I want to make sure those are the patients that we can address immediately, right? Once we get this drug in the market, we can go after very quickly. And meaningfully address 2 million patients or more. And then we can drive the growth of the market after that.

Yes. And I would just add to that, but certainly, that's our focus. The currently treated patients and those that are already diagnosed, knowing that, that is just considerable in size. And remember, they haven't had any new treatments in decades. So the need is substantial, both in terms of as-needed options as well as chronic. So there's a tremendous opportunity right there. Absolutely.

Okay.

Yes. This is [ Caroline Paloma ] with Berenberg Capital Markets. On PRAX-944, I was just wondering if you could talk a little more about the safety profile? And were there any difference in patients who were also taking standard of care? I think it was prenatal versus those who are not.

No, there was -- overall, the safety profile was very consistent with what we've seen previously. And we're happy to see across the dose range. It's pretty much the same AEs mild to moderate without any severe or serious. In terms of concomitant medications, we did not see any interaction. And so, it seems like it was similarly tolerated, whether they were on propranolol or not. So that suggests to us, we should be able to use it whether adjunctive or monotherapy.

I have a number of questions from Ritu Baral of Cowen. First, looking at the data from Part B, what were the moderate AEs? How transient were they? And were there any moderate treatment adverse events driving discontinuation in which ones?

So taking those AEs apart a little bit more, the difficulties and attention were associated with discontinuation of a couple of participants. So those were more moderate, but they vary from visit to visit. There's not a sharp line between those. And so, I would not discriminate too heavily between mild to moderate.

A couple of other questions on the data. Are you thinking about enriching 944 trials going forward, including Essential1? And thinking about the development plan, would you anticipate -- and this again is from retail account, would you anticipate the same floor effect with the same floor level for PRAX-114?

Just to a great extent that's already results, right? So the inclusion criteria for Essential1 already would eliminate virtually all the patients that did not respond on the cohorts we've seen here today because the baseline will have to move up. And that was by design, right? We wanted to explore how tolerable it was. So there was not a clear like obsession into their baseline during the Phase 2A, what that is a very clear obsession, including an incredibly stringent review of the eligibility for video in a central location and a training, and I'm going to say, our clinical operations team has done a phenomenal job, especially Elizabeth, making sure that we have that all sorted out there. So that is taking care off for Essential1 now. Are we going to just sit here and thinks like we understand everything? No. We're looking to that continuously and understanding what else we can do to make sure the monitoring of the trial, the correlations during the trial continue to be better. We are, and I'm going to use the word obsession again because I think that's a little bit of the trade, at least mine, but definitely for the company with measuring this objectively. The floor effect and we call floor because of how the scale is, but literally like, the scale is not adequate or the majority of the patients living with tremor right now. We just cannot measure the impact when we talk to a patient, they reduce 0.5 points on that scale, the way they tell us back how we changed their life is just not commensurate to the chain of the scale in terms of the tremor. So by using things like biosensor, like Bernard mentioned, we have 5 different initiatives right now for objectively measure tremor. We highlighted one because that's the one in validation. That's the one we fully expect to be able to deploy in the Phase 3. It's actually being deployed in Essential1. So we do not expect to have that problem moving forward. And to our knowledge, we are the only ones with a validated measure, really moving that towards Phase 3. And by using the measure of tremor objectively in the ADL, not for recall, but in front of the physician. It's exactly what the FDA comments to us that they were concerned about the current scales. It's not that they don't like the tremor scale. They don't like how unreliable it is. They like the ADL, as we talked about, and they would like to be even less based on recall, and we address both of that, and those endpoints have been used on Essential1.

I'd just add a key distinction. We think about this enrichment question in 2 ways. One is who can biologically respond to the mechanisms. We think 944 and 114 would be broadly applicable. So that tremor network is relevant. We believe in all patients and the human data, the model -- animal model data support that. The next is who could respond physiologically and who can you measure changes? And that's really what we're talking about here is the existing measures were like great for clinical exams and kind of clinical treatment, they just don't have the precision in the range for that you want for trial. So that's the limitation now. Other enrichment approaches like family history, genetics, I think are all still open to question. We don't have a big enough data set to really address that yet, but it's something we'll be looking for in our data.

The next question comes from Yasmeen Rahimi from Piper Sandler. Did you observe a dose-dependent change in oncology? I had a pop-up on my computer. Did you observe the dose-dependent change in the modified ADL and TETRAS in Part B when going from 20 milligrams to 120 milligrams, understanding that there's only a couple of patients at the lower level?

So we designed the study to really address the question of tolerability. We titrated people up in both A and B. So how long they were on drug and what dose they got are completely linked. We can't separate those. So what I would say is we can't tell yet. It does look like, over time, both in Part A and B, people's tremor improve, their ADLs improve too. But that's what Essential 1 is for. We do a parallel group dose-ranging study. It will give us a definitive answer to that question about the benefit and the safety and which dose we should take forward.

Next question is from Myles Minter at William Blair, and this is for Nicole. The 200,000 patients that are discontinuing treatment and the 200,000 coming on to treatment per year in ET patients they want episodic treatment? Or are they seeking chronic? And if both, what proportion of patients sit in either the episodic or chronic treatment preference?

Yes. So it's a good question. That those that are discontinuing, the majority of those patients will be coming from chronic. And if you take a step back and again, think about treatment today, as Marcio shared, there's a delay to diagnosis, there's a delay to initiation. So those that are receiving treatment are those that have progressed further in their condition. Therefore, the chronic therapy is used more widely. Those would be the treatment that they'd be discontinuing. If you think about the future state, though, with new options available, what we would anticipate for patients is that they have an opportunity to initiate an as-needed treatment earlier in the progression of their condition, and then add chronic, as it goes on. So I see that changing as time continues with more and better treatment options.

And just to add to that, too, for people who need chronic therapy, there's still a need for acute on top of that. They're not exclusive.

Myles also has a question for Bernard on the data that we showed today from the Phase 2a study. In the Phase 2a patient too went from getting worse at day 21 to slight improvement at day 42 on TETRAS ADL. Did this patient show early cognitive disorder that may have impacted ADL performance early, considering the upper limb tremor score showed slight improvement at both time points?

See individual subject, I don't believe that was any cognitive issue. I'll point out patients can vary quite a bit from visit to visit. I believe there was a high level of anxiety in that particular subject that drove the scores. And so it's always nice to have time-dependent data and see people settle in on any one visit, they can be unstable.

[indiscernible] from William Blair again. For essential tremor, do the 50% of patients with familial history show any differences in terms of onset, progression, severity, et cetera. And would they be potentially more suitable for 944, given the history of -- potential history of mutations understanding potential broad applicability potentially.

Let me just start there, and then, I guess any of us can contribute here. The duration of the disease is obviously like longer, right on those patients. They are also more tired, I would say, of having seen their families go through it, go for all these treatments that really didn't do much for them end up engaging with the system in a different way. But they are arguably the most willing to, like we actually talk to a number of them. We know a lot of people, they are actually some of our colleagues and investors, they have like family members, and we hear a lot of the stories, where they -- they want to start right away. They're the most mobilized for trials because they know what's going to happen. Even few years ago, that proportion was expected to be around 20%. When you move now to very objective data, it's incredibly high, the proportion of family history. It's not only an opportunity to engage the given patient right now, but to engage the family, right, would we show no one who have any condition. Definitely, we don't wish on any of those patients to have essential tremor. But now having it and being able to mobilize all of that is incredibly important. They probably would jump faster into a chronic treatment, but also earlier into a treatment that ameliorates just in a different way the symptom. So it's almost the ideal candidates for both 114, 944. And just one last reminder, we're talking about independent use, but it's quite obvious that we're going to be pursuing in the near future, combination use of those 2 molecules to address they need as well.

A couple of other questions from Yas at Piper. What key lessons did you learn from the claims database in regard to patient selection in the Phase 2b to minimize heterogeneity? Can you provide any commentary on what measures are in place in Essential 1 in the screening period to minimize patient heterogeneity?

Hi, Bernard.

Yes, sure. I'll let Nicole comment on the implications from the claims data. For Essential 1, we've done 2 things, which is baseline severity of tremor is required there. We also have -- as we do in all our studies, an independent eligibility review that's video-based to make sure that tremor is scored correctly. For 221 that we just reviewed, we didn't require that people have a given baseline of severity if they self-reported disability. So we'll be more stringent there. The other key thing is people with more mild or moderate tremor, they vary a lot. You saw that in the data, right? They're kind of bouncing around. They are difficult to measure range. And so the other criteria we added is that they can't change by more than a certain percentage from screening to baseline. What we've seen is if you're variable in that period, you're going to be variable later on as well, and that just introduces noise. So I feel very confident. It comes back to the other question about enrichment. You're enriching for people in whom you can measure improvement.

One more question from Yas, just to cover off here. Is there any potential to think about the combination of PRAX-114 and PRAX-944 in ET? And have you done any combo preclinical work?

Yes, we did some preclinical work. I think would -- should question our intelligence, if you haven't. So we have done work there and listen don't question that part. It's quite interesting. You're obviously going to be talking about more of that soon. As we're not showing the network is the same, but they act very differently, right, as we're modulating that. We believe that is [ say for if you ] combine these drugs that would be effective, we are not quite there yet in terms of how we're going to do it or to talk publicly how we're going to do it. I also don't believe it's the right use of capital to do this right now. Showing that each one of those drugs work would be the best way to get to a point of combining them as well, which is all going to happen very quickly next year, and then, we'll be in a position to do it. But yes, the answer is absolutely Yas, is one of the things we care about.

Hi, this is Chris and Doug from Wainwright again. So you highlighted that 144 and 944 are going to be complementary treatments and 944 is going to be best suited for chronic, whereas 144, more of an episodic as needed. So can you provide some additional thoughts on the different patient populations that you think would be appropriate for and the use cases and all that good stuff? Thanks.

Sure, absolutely. And I'll start with 944 and thinking about the marketplace today, where most of the treatment is really on the chronic side, but certainly, that's an option, where you can imagine for patients that have a higher degree of disability that's really impacting each and every day for them, that you can imagine, 944 certainly being an option that could meet their needs. And we're also looking at 114, I know you mentioned as-needed. We're looking at that for chronic use as well. So that may be another option. And I'll say in a market again that hasn't seen options in several years and also appreciating that patients, there is a certain amount of heterogeneous population in play that's certainly utilizing different mechanism of action to bring different options forward to meet the needs of a very diverse population. Certainly, we think would be suitable. But 114 also has the potential to be an as-needed treatment. And so that's something as well, thinking about patients that are newly diagnosed. And again, if they're -- if we're able in the future to get them diagnosed earlier when they're burden of disease or their disability is less that they can utilize an as-needed approach earlier on in the disease progression. But I'll also offer that no chronic treatment is a cure. So there will be moments with someone, who's on a chronic treatment, where they could also benefit from an as-needed treatment. So I'll say again that it's really not an either/or with chronic and as-needed, certainly for some individuals that can be combined use.

There's a related question from Ritu at Cowen. If GABAA, PAMs be used in combination with episodic propranolol?

Yes. There's no reason to believe they couldn't and that's something we definitely would be exploring. We don't really know how propranolol works, right? So have this debate all the time like this. As you probably know, there's a mixture there on propranolol, that is definitely not as a beta blocker that is working in the brain, but it does work for some of those patients. Some of them take as a comfort drug stopped working, but they are still there in the baseline, like in a safe net. There's no reason to believe we shouldn't. It's being done in the practice, taking propranolol and drinking. And obviously, for a lot of those patients, it's a really bad idea. And one of the reasons why they end up discontinuing, but it can be done. But the key for 114, and I'm going to go back there. If we have seen in previous trials with 114 at around 40 milligrams or so, that's what we are using on the mood disorders, [ SAEs ], patients having syncope, patients developing tremors and things like that, that are like very clearly signs of MTD as we see -- we wouldn't be moving this to a daytime use. So moving to a daytime use, it has to be pretty clean for 114. And that's what it is right now. What Bernard showed on those potentiation charts and on the beta power, and I'm not sure if it was clear, so that's why I'm going to repeat. We actually have data in our volunteers at 10 and 20 milligrams showing no somnolence. So we know that if it was similar in essential tremor, it's always a little bit more into the somnolent side, so that's why we're not making necessarily a direct projection. That would be fairly clean from a tolerability perspective and quite meaningful because those 1.3 beta power is what changed tremor in our models. One of the reasons why this trial we are going really certain on 114 [ 231 ], that is the essential trial study to get to that answer, should then explore, and that's why Nicole mentioned, either or likely both, p.r.n. and like as-needed and chronic treatment for 114. So one step at a time here, appropriate use of resource, appropriate use of capital.

Ritu has a couple of additional questions on 114, while we're on the topic. Do you have any more delivery profile tweaking in the formulation that needs to be done, is the first? And then looking at the trial, how long is the washout period, what is the treatment period? What are the assessment time points?

I'll do the formulation, let Bernard's, the other one. Like if we would Karl and his team to reformulate every drug we have, would have like 15 formulations for each one of those drugs, and he's here in the audience, he's amazing. His team is amazing as well. There's always opportunities to reformulate drugs. We do not believe that currently, we need to do anything with 114. That's why we're going for the exact formulation right now. Have a Cmax around, as you all know, around 2 hours, 3 hours out there, have a very good exposure. It's accumulated by about 1.3. When you give that continuously, it creates a very nice, steady state for potential chronic use, but it hits pretty quickly for as-needed use as well. So that formulation, it's safe that's why [ the key question is safe ], should be more than adequate. Reformulating GABAA, PAM's, in general, to just slowly release is not straightforward. We would do. I'm sure it would succeed, but that's not the priority for the company right now. It's when the patient needs treating them. So it's with the exact same formulation, tablets formulation we have right now in the other studies.

I just [ can't off of ] that for an as-needed therapy, you want an immediate release, right, that has a fairly quick Tmax. So that's what makes it an as-needed. You don't want to have to wait hours. In terms of the design of the study, like it's just -- it's single dose, and we will assess people in each of the conditions, 10, 20 or placebo over the course of about 6 hours with serial PK, serial exams. Obviously, you can't do like serial activities of daily living. It's really focused on measuring the tremor. The washout in between there is just 5 half lives, it's about 3 days. And there's no carryover from that.

Few more questions from Ritu to wrap up here. In looking at the profile of clinicians, who would you see being the primary prescriber for either treatment for essential tremor?

Yes. It's a great question. So primarily the neurologist, those that are movement specialists in particular. Although, we do know today that there is some utilization or prescribing today, excuse me, that comes from primary care physicians that typically see patients earlier in their journey. But once the disease progresses, they advance and see the specialist.

Thanks. And then just one last one from Ritu to wrap up here. What is the magnitude of benefit afforded by propranolol in tremor? And how long lasting, is it?

So propranolol, Nicole touched on this. So it's up to 50% reduction in tremor amplitude, nobody knows what the ADL impact was because that was never studied. But up to 50% tremor amplitude reduction in up to 50% of the patients. So if you average that out, maybe 25% improvement. So it's the best standard of care we got, but that's about it. And I think the second part of Ritu's question was in the duration, right? One way to look into this market is because it's stable, as Nicole showed, is there basically every 5 years, the market completely renew, sort of losing 200,000 patients every single year, and we're adding 200,000. So it could, obviously, the [ terminal there ] and remodel and so on, and it's about 2 years to 3 years that these patients have some benefit, and then it basically goes away in average. And Bernard mentioned the maximum benefits they get. The vast majority of them don't get even close to the maximum benefits with the current treatment. So it's too little, too late, like $1 short and I mean, it's late or maybe an hour late and short duration.

And it is dose to dose. So there's no durable effect after the dose washes out, so -- which is one of the questions that led us to do a randomized withdrawal. We saw in Part A, we washed people out over the course of a week, and they hadn't gone back to baseline. So I just want to understand, it could be very clinically important to know what's the real duration effect? And is there a real change in that tremor network that goes beyond the PK of the drug.

Okay.

All right. It seems to be -- it seems to be it. So it was a real pleasure to be with all of you here and in the webcast as well. Thanks for all the questions that were sent. More to come. Guys, Happy New Year, if we don't talk again. It's coming to the point and it was a real privilege as well to be able to be present with all of you. Just want to end by, we thanked already the patients, the investigators, but I want to end by thanking all the Praxons, all the people at Evreux that made this possible. It's actually pretty easy to be the ones in France here. But there is more than 100 people behind the scenes, making sure that we are capable and able to be here. So thank you all very much.