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

Good day. Thank you for standing by. Welcome to the Praxis Precision Medicines Essential3 Topline Results Conference Call. [Operator Instructions] Please note that today's conference may be recorded. I will now hand the conference over to your speaker host, Dan Ferry. Please go ahead.

Good morning, and welcome to the Praxis Precision Medicines Essential3 Topline Results Conference Call. This call is being webcast live and can be accessed on the Investors section of Praxis' website at www.praxismedicines.com. Please note that remarks made during this call may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These may include statements about the company's future expectations and plans, clinical development time lines and financial projections. While these forward-looking statements represent Praxis' views as of today, they should not be relied upon as representing the company's views in the future. Praxis may update these statements in the future, but is not taking on an obligation to do so. Please refer to Praxis' most recent filings with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with the company's business. Joining the call today are Marcio De'Souza, President and Chief Executive Officer of Praxis; Tim Kelly, Chief Financial Officer; and Steve Petrou, Chief Scientific Officer. After our prepared remarks, there will be a brief question-and-answer session. With that, it's my pleasure to turn the call over to Marcio. Marcio?

Good morning, and thank you for joining us today to discuss the exciting results from the studies under the Essential3 program and our path forward. I'm going to be making forward-looking statements on today's call, so please refer to our updated disclosures on the SEC website. The Essential3 program for ulixacaltamide hydrochloride, as you all now know, was the first Phase III program ever to be positive in essential tremor for a drug. Both studies under the Essential3 program met their respective primary endpoints. Ulixacaltamide was generally safe and well tolerated with no drug-related severe adverse events. The result of all of that is that Praxis has submitted a pre-NDA meeting request to the FDA, and we look forward to hearing back from the agents to move this program forward. Essential tremor affects an estimated seven million people in the United States alone. It's puzzling that there is no specific drug approved for essential tremor that was developed for the condition, and we're here to change that. But before I dive deeper into the trial and its results, I need to express my gratitude to all the people living with essential tremor who participated in our clinical studies, to their families who supported them, to the advocates who guided our work throughout, and to everyone at Praxis, at the central site, the PIs and sub-Is that carry through such an ambition program to fruition. The scientific hypothesis underpinning ulixacaltamide is very clear in relation to essential tremor. Modulation of this important network in the brain by inhibiting T-type calcium channel block is fundamental. Now before we move forward and talk about the results, I believe it's worth taking a moment to walk through the developments of the last few years. Just a little bit two years ago, we read out our Phase IIb Essential1, which helped us establish the endpoints that should be used in a late-stage program, aka Phase III, the dose that should be used and many other aspects of the operation of such studies. We moved from there to have several discussions with the FDA, particularly centered around an end of Phase II meeting and subsequent communications where we're seeking and gained alignment on the Phase III program as it relates to the endpoints, to dose and the overall design. We started the Essential3 program shortly thereafter. And from the get-go, we've seen very sustained and robust interest by patients and enthusiasm by physicians. It was incredibly ambitious to recruit two simultaneous studies at the same time. As we fast forward to earlier this year, Study 1 was subject to an interim analysis. And when examining the study at that point in time with that sample size, the independent data monitoring committee, which was bound by very strict rules, recommended that the study was unlikely to meet its primary endpoints based on the assumptions at the time. In other words, a futility recommendation. Due to the late stage of recruitment for this study, the fact that they were intrinsically linked to Study 1 and Study 2, and our general belief that faced with uncertainty being the first on a position to finish a Phase III program, we decided to continue these studies. Praxis was not unblinded to any of the analysis or any of the deliberations that the IDMC had leading to their recommendation. Between that point and last month, we conducted extensive simulations and analysis on the blinded data. We consulted with a number of statistical, clinical and regulatory advisers, and we decided that the most prudent thing to do was to refer back to what we knew from the Essential1 program that was the ability for ulixacaltamide to positively modify the disease when patients are exposed between baseline and day 56. So we made the decision to change the primary endpoint to day 56 from day 84. We also simplified the key secondary endpoints based on prior feedback from the FDA. All those decisions and the change that they generated on the protocol, on the statistical analysis plans and on the postings at clinicaltrials.gov, as you might have seen, were done without any knowledge of either the interim analysis specific results or any unblinding of the data. From that point on, we are here today. In the last few days, we unblinded the study and we examined the data, and we're very happy to say that all prespecified analysis for the primary on all four hypothesis that were generated in this program were met. What are those hypothesis? So the first one was the superiority of ulixacaltamide versus placebo on the parallel group study at day 56. The second one was whether or not ulixacaltamide exposed patients for eight weeks in a blinded lead-in were able to keep the response in a superior manner than patients who are switched to placebo. That was also positive. Because of the unique nature of the Essential3 program and the fact that not only blinding was happening within the trial, but also within the trials, Study 1 and Study 2, we're able to combine the arms of those studies. And that's where hypothesis 3 with an overall combination, and hypothesis 4, which is contemporaneously using the arm on placebo from Study 1 with drug from Study 2 were done. All hypothesis resulted in positive statistically significant results. So, now let me walk you through some specifics from each one of these studies and from the next steps. So Study 1 was 12 weeks in duration. and patients were exposed for ulixacaltamide for all 12 weeks or placebo for all 12 weeks. They were randomized simultaneously between Study 1 and Study 2 from the same pool of patients. We made Study 2 blinded for patients, personnel in the study or investigators in a very unique way during the totality of the study. Patients at the end of week eight that met the criteria for response of 3 points on the average of day 49 and day 56 were then randomized to stay on ulixacaltamide or to switch to placebo. So, let's talk about Study 1 results. The primary prespecified endpoint was the change from baseline to day 56 on the mADL11, analyzed using an MMRM model. Afterwards, if that was positive, the prespecified sequential key secondary endpoints was the rate of disease improvement throughout the study, the PGI-C and the CGI-S at day 56. The baseline characteristics and demographics for those patients were well balanced between ulixacaltamide and placebo and represents a very severe affected and representative of the United States population with essential tremor. Patients randomized to the ulixacaltamide arm on Study 1 observed an average of 4-point gain after 12 weeks. This is a very large and very robust change. When compared to placebo, as you can see on this slide, those results were highly significant. All key secondary endpoints were also significant, both clinically and statistically. The rate of improvement throughout all 12 weeks the patient global impression of change and the clinician global impression of severity. Importantly, we have conducted a prespecified tipping-point analysis to test the robustness of the primary endpoints achieving such remarkable statistical significance. That sensitivity was also positive, resulting into a very small p-value, which confirms the robustness and statistical stability of the results we are seeing here. It was also impressive to see that not only ulixacaltamide acts very fast, as we can see here in the chart, as early as two weeks when the first assessment was done, but throughout the study. That includes day 77 and 84, as we discussed, being the time point by which the prior primary endpoint was assessed. If no change have been made to the time point of assessment, the study would still be highly positive. Study 1 was also robust in terms of all the other subgroups. When you look into age, sex, concomitant use of ET meds or the three stratification factors being propranolol at baseline, presence of intention tremor or family history of essential tremor, all of them did not influence statistically the robustness of the results being all very clearly in favor of ulixacaltamide. With those good news, let me move to Study 2. As we mentioned, Study 2 was measuring the ability of patients who responded to ulixacaltamide to stay responding. So the rate and the proportion of patients who maintain the response as compared to placebo was the primary endpoint. Those were supported by some key sequential secondary endpoints as the rate of disease improvement as in Study 1, the PGI-C and the CGI-S on the same period. In terms of baseline demographics, the randomization worked really well between not only the arms on Study 1, Study 2 and continue to represent the population. So how did the results come out? Study 2 was positive in the primary endpoints and on the first key secondary showing a very robust maintenance of response on patients with stays on ulixacaltamide compared to placebo. That's incredible and makes us incredibly happy to have now two studies that are likely to constitute substantial evidence of effectiveness to submit an NDA. It's also exciting that hypothesis 3 and 4 resulted into positive results. Those hypothesis supports and strength the data we've seen already. When we look into hypothesis 3, which compare the sum of the arms on drug between Study 1 and Study 2 versus placebo, the results were highly significant and highly meaningful. When we look into hypothesis 3, could only be possible in a study that is done like the one we did here under the Essential3 program, which kept all the arms and a finance 2 study blinded. We could test whether or not patients on Study 2 on the first eight weeks receiving ulixacaltamide when compared to the placebo on Study 1 had a significant difference. That is de facto a replication of Study 1 on the same time. And what we see once again is a very robust replication of what we've seen on Study 1. So let's talk about safety in this patient population. No change in the overall safety profile and no new signals were identified. The most common treatment-emerging AEs, patients in ulixacaltamide were constipation, dizziness, euphoric moods, brain fog, headache, paraesthesia, insomnia and fatigue. And we're going to talk about the discontinuations and the specifics on these rates in a minute. The majority of the treatment-emerging AEs were mild to moderate in severe. No severe adverse event was related to ulixacaltamide, and no patients die during the study. When you look into the disposition of this study, which is. Relevant for the safety analysis, patients who received at least one dose of the drug or placebo are considered in the safety analysis. For all the other analysis we discussed today, patients had not only to receive one dose, but to have a post-baseline assessment, which is very common practice and has been prespecified and reviewed in all the documents that we had and formalized with the FDA. Now speaking about safety. The vast majority of the patients had a treatment-emerging AEs. Majority of them were mild or moderate in nature across the board in the different arms or studies. A small proportion of patients had severe adverse events on either ulixacaltamide or placebo. No serious AEs were related to drug in any patient in this study. Approximately 30% of patients receiving ulixacaltamide and approximately 2% on placebo discontinued due to treatment-emerging AEs. And the overall discontinuation in the study due to different cause were around 35% for ulixacaltamide treated patients. In terms of the adverse events themselves, as you can see here in the table, the top four were constipation, dizziness, euphoric mood and brain fog. Those were all expected for such an active and potent drug as ulixa is. Those are very common across CNS active drugs, and we believe that physicians are going to be able to manage in the real world for this population. With that in mind, I want to conclude those remarks by thanking everyone involved on this study. It's not many moments in life that we are the first to develop a drug specifically for a condition with such a high unmet need affecting millions of Americans and to have a package that we believe could lead to an NDA approval in the near future. Now I'm going to open the call for Q&A. Operator?

[Operator Instructions] We have a question coming from the line of Athena Chin with TD Cowen.

Sorry, this is Ritu.

Hey, Ritu. Sorry.

Okay. It's my fault and our registration fault. Congratulations on the data this morning. Guys, it sounds like the variability and the low end from the dropouts contributed to the -- for lack of a better word, bad luck on the interim. Can you talk a little bit -- first of all, correct me if I'm wrong and if it wasn't variability and low end on that interim. But given the dropout profile that we've seen, can you speak to anything that was done or could be done in the real world to manage some of these brain fog and these dizziness symptoms and the transients and sort of other clinically relevant aspects of these side effect profiles in the real world that could be improved?

Yes, absolutely. And thank you so much, Ritu. Like we're ecstatic and excited about being able to help these patients with quite definitive results here. I think we're there in terms of like bad luck, I would say, it does strike from time to time. But today, I think what we talk about is not luck, it's certainty and the certainty is with the final results that we have for both studies showing very clearly what we're doing with for these patients. When you look into such an active drug, right, like incredible, arguably larger-than-expected effect, that is an expectation that some patients might be overshot in terms of the group exposure dose, whatever it is here. Not uncommon to think and we talk to hundreds of neurologists and very, very, very common in neurology for them to, after a drug is approved, take matters on their own hands as they should as treating physicians and look into the patient versus the cohorts. As we look into a trial, we're looking into the cohorts, what is the best thing for the cohorts. And that's what we've done here. And I think it's undisputable that, that call was correct. When you move to the real world, there's better counseling can be done because now we know the drug is effective. So, counseling a patient on an effective drug is very different than on a likelihood of being on a drug that might or might not work or placebo and multiple things that can be done to minimize or even eliminate that. One of them is time. And we know that the more time you spend on the drug, the more accustomed, I would say, to some of the side effects, but there's other ways to manage as well, definitely better hydration on this older population. If we take the very worst-case scenario here would be helping five million patients in the U.S. I'll take helping one person every day of my life. I certainly would take five million. But we do want to help as many as possible with this drug being the only game in town. So we're going to work very diligently with physicians to help them guide the way if you are so lucky on getting the NDA approved upon submission to the FDA.

And our next question coming from the line of Yasmeen Rahimi with Piper Sandler.

Congrats to the outstanding data and honestly, for not giving up on the program and really plowing through really remarkable and a great decision made for patients and for the company. My question is, team, given that you have requested your pre-NDA meeting with the agency with a very data-rich package, what additional analyses are you planning to complete as you head into the meeting? And then how do you plan on sort of communicating sort of the next steps with the Street? And maybe one other. If you file your NDA in early 2026, how do you envision sort of getting commercially ready? So I would love to learn sort of what's on the to-do list between now and the next few months?

Thanks, Yas, and thanks for all the ongoing discussions throughout the years about this program. I sincerely appreciate that. Very happy to now talk about what is next, how do we get this drug to the market, right? I think the first important step here is that there is a lot of change happening in the United States, and we're very happy to know because these statements of facts of opinion that the staff of the FDA have been working with us from the end of Phase II is there from like pretty much all levels. Like they understand the conversations we had. They've been guiding us along the way and to be very responsive about our interactions. So we do expect to get the meeting pretty soon. We -- there's always a number of other like sensitivities and things like that, that can and should be done throughout. But the bulk of that, I think we were 15 out of 10 on our slide deck this morning. I hope you all agree. We put a lot of that out already, right? Like the classical like is there a subgroup here that is Q and the answer is no. I think that's a very classic like this works across the board for all those patients. Is there anything that will change the original guidance for safety? And the answer is no. Then the things you don't know because we haven't communicated, we have concluded all special population studies, renal and hepatic. We have completed all the preclinical package. As a matter of fact, we have already finished 80% of all the documents. that are related to the NDA. We never stopped because we always understood very clearly the need. So in very advanced stage of preparation for the NDA. We have a specific CMC meeting with the FDA, which is always very important, particularly at this day and age, to understand what else we could do. So, I can give you the assurance that, number one, I may actually have to say that it's an outstanding team, right, that we have here because we hear companies that are not even close to where we are in terms of submission of an NDA, and they already like way beyond the point. So the team was very diligent with very little resource since we are, until this point, a limited company, completing 80% or so of the documents for an NDA is no small feat. So, we're very confident that everything the agents guided us so far, we have done. We are in a very good, I'm going to say, relationship with the agents in terms of like being very transparent with them, being a very direct dialogue. It's good. The neurology is kind of our house in a sense there. We have several programs. They know how serious we are scientifically. So we can't state for the agents, but I'm grateful on how much guidance they gave us. I'm grateful on how much time they gave us throughout the years, and we're going to tell you all soon. Once we get there, then we're going to talk about how to maximize the value. I think there is -- no one would doubt and certainly, I believe your model would support us the lowest end of the expected sales here is at least on the mid- to high single-digit billion. And the very reasonable estimate is on the mid-teens for billions for -- if you use just regular like pricing and penetration assumptions. So we always took that in mind when you are planning manufacturing, when we are planning other things, and I look forward to discuss all of that with you and everyone else very soon.

And our next question coming from the line of Joon Lee with Truist Securities.

Congrats on the really impressive results. You have indeed put out a lot of details even for this top line data disclosure. On Slide 14, specifically, the efficacy peaks at around day 49, 56 and starts to decline a bit thereafter. Any reasons for that? And would the study have hit stats at day 84 without any changes? And then are there any flexibility in the dose titration to help mitigate some of the AEs that led to the discontinuations?

Yes, absolutely. I likely would disagree with your statement that like if you look into the confidence intervals within each one of the points, right? And I know you are good students of science and statistics that is the precision is just within for all those time points. So the effect is actually largely and very large maintained throughout. Very important to notice that the every time point is statistically significant, right, that they all favor drug. They all to the right of zero here on Slide 14, as you mentioned. So no doubt whatsoever there. On the other side of the question, as you know, we hit it out of the park in terms of how fast it starts, right? By day 14, by two weeks of treatment, this effect was established. So it's not unreasonable, and we did talk to a number of neurologists to think that for some patients, they might just slow down a little bit. It's a lifelong condition. Patients were living with essential tremor in this study for 30 years, right, for about a little bit less than half of the median life expectancy in the United States, they've been living with essential tremor. So maybe another month that's going to be up to them, and I'm sure they're going to do it. You know they're going to do it because we're practicing before, and that is likely going to help for some patients. But for the cohort, for the 70% or so that get to incredible benefits without any detriment that I'm sure they're going to go full-blown as well because what we hear from patients is that they want the effect. They'll be waiting for it. The most emotional part of this process was receiving Patrick's quotes that is in our press release. When into interacting with each one of those patients through the study to getting letters from them to the central sites to the PIs and telling us, you change my life. I can go and go back to something else and holding that excitement. I share this excitement now is going to be throughout the United States where we have plans for this drug. But not going to keep going there because I think you've got the gist and I appreciate the question and so on.

Our next question coming from the line of Yatin Suneja with Guggenheim.

Guys, let me add my congratulations as well. Truly a positive surprise, I think, for us and for many of our investors and stakeholders. So congratulations on the team. I have two questions. I think those will help some of our investors because we're definitely getting a lot of things on that. So the first question is on the NDA requirement. I know, Marcio, you touched on it, but could you maybe talk about what is the ICH guidelines for something like this? Is there a particular long-term safety requirement for a disease like essential tremor that affects many people, if you can comment there. And then one more question, if I may. And again, this is an investor-related question or driven question. What alignment was reached with the FDA when you made the protocol changes on either the stat plan, whether you can evaluate on an mITT basis, ITT basis? Anything you can provide, that would be really helpful. Again, thanks very much.

Yes. No, absolutely. And thank you. The ICH guideline for safety itself gives a range, right? So what we've done instead of taking the liberty there is actually we had a discussion with the agency and like knowing the safety profile of the drug, which is the same between the multiple Phase -- is we conducted the Phase II, what was the requirements. And what they very clearly stated to us is 100 patients for one year and for 300 patients for six months and then 1,000 total exposures. So we have zero concerns about getting that package available for the agency. That is also considered what the minimum ICH guideline, which should tell you their impression about the safety of the drug in general. So no concern there for the submission itself. There were a lot of conversations that we have both formally and informally with the agents throughout the years on this. We have a very good understanding on how they see this analysis. We have submitted and clarified the analysis plan with them. And that's obviously great from your perspective and investors. But maybe even more important here is that it is largely irrelevant because the trial would have been successful without any change. And we put that specifically on the press release that analysis, just to remind everyone that it really doesn't matter in a sense, right? The trial is positive independently of how it's analyzed on the time point of 56 or 84.

And our next question coming from the line of Jay Olson with Oppenheimer.

Congratulations on these landmark results, and thank you for your persistence in successfully completing this development plan on behalf of patients in need. Can you talk about your medical education strategy for ulixacaltamide in essential tremor, especially since you're going to be pioneers? And also, how are you thinking about the duration of therapy with ulixa? Or would it be dosed chronically?

No, I appreciate it, Jay. And I guess I'm going to give you a call for headlines next time because I missed the landmark on ours here. So we've been super fortunate to be guided by a number of experts, number one, and you saw three of them, our three co-leads principal investigators quoted in our press release, and I think you can feel their enthusiasm there. All the members of the eligibility review committee, the help of the study and many others, right? And last AM, and I'm sure a big expansion of the following one, we had the opportunity to talk to a lot of people about this and how it's going to be used. And I think the answer we get, and I'm sure the answer is going to get when you go out there and ask those physicians as well is right now, it's incredibly frustrating because there's nothing they can do. They know it's getting worse. You might have seen that on our slides on the demographics. Over 90%, about 95% of the patients got worse in the last three years. We've been out there. We've been limited in terms of how much effort we put on this, just as our previous disclosures in terms of limiting the investment. We're going to increase that moving forward. But we are seeing a very responsive, positively responsive like community already expecting. I'm going to switch to a slightly different topic here. 200,000, over 200,000 patients currently in our database. People who raised their hands and said, I want to be part of any effort to advance treatments for essential tremor. That was with the limited resource a company like Praxis had to this point and with the discipline to really just put so much resource to this one program, right? You can imagine what can happen here with the expansion that we should have with this positive. So we're very, very happy. And lastly, on the durability of effect, we do have several patients, many, many patients way beyond one year and so on. So I think the chronicity of the treatment here is pretty clear, right? This is a drug that very strongly inhibits a quite important oscillatory like modulator of the brain that leads to tremor and other tremors as well. And it has to be present, right? That inhibition needs to be present for. So it is a chronic treatment, the daily treatment right now. It's likely to continue as a daily treatment for the time being. And I think patients like the idea that it is like once a day, it's not like multiple times and things like that. A pro anecdote before moving to the next question. We asked patients at the beginning of this study like what is one of the issues that we deal with. And what they said is the fields are too small for these other drugs. So we made all the -- our fantastic CMC team made all the field is larger for this study, like already thinking on compliance, already thinking on making their life easier in the future for commercialization. So super happy with everything, but really been thinking about commercializing this drug all along.

Our next question coming from the line of Brian Skorney with Baird.

Congrats on the great data. Just a couple for me. Maybe I missed this, but can you walk through how discontinuations were accounted for in the mITT analysis? And have you run a tipping point analysis on the results yet? And then my second question is, I know there are nonscheduled drugs that can show euphoria and there's precedent with type calcium channels for not being scheduled. But given the delta that you see on euphoria, can you discuss any regulatory discussion around evaluation of abuse potential?

Absolutely, Brian. So the -- as you know, right, by the very follow-up of your question, the [ MMRM in MDD ] assumes as a condition of the model that the data is missing at random or a MAR assumption. We prespecified and agreed with the agents that we would conduct a tipping point analysis. And I know the press release is very large, but if you look into the bottom of the table on the Study 1, we're already showing you the results of that tipping point analysis, right? Tipping points are, as you know, gradual because you keep like going up around to what has been defined as the maximum you should do, that is about half a standard deviation or so in our case, it was around 2.5 points. you normally break or you tip. In our case, when you get there, the p-value was 0.0026. So we did not tip. In other words, as you know, but for the others, not so worse in the call, means it doesn't matter, right? You can really attempt to break by reproducing MAR data pattern here and the data is still incredibly strong. So very, very happy with that. I think you had a second part of the question that I might have forgotten. Oh, human abuse potential. So the -- we did have that. As you mentioned, we've been discussing all along with the agency. We have conducted a human abuse potential. We are in active discussions about that. At this point in time, knowing what we know about the results of such study, we do not believe that there is here a scheduling requirements. That is not up to us to decide. The agency is going to make that determination at the end. But we believe that have completed all the requirements under the "ICH guideline", we shouldn't be or should be a minimal scheduling there. So everything has been completed in regard to human abuse potential and habitual users study.

We have a question coming from the line of Doug from H.C. Wainwright.

Congrats on the data. I guess maybe, Marcio, as a starting point, I know when you conducted the interim analysis, the Data Monitoring Board had said that there was sort of the potential or sort of ask you to look at the sort of statistical model that was done. Can you sort of talk a little bit against what changes might have been made? And then just as a follow-up question, I'm curious in terms of the MDD, ADL, the mADL improvements that you saw. Were there any particular domains or sort of areas of the ADL that we saw patients see most improvement on?

No, absolutely, Doug, and thanks for the support as well. So we looked through as I mentioned in my prepared remarks, and we decided not really to move the model, not really to change the model after very extensive simulations. They were based on a number of things, but one premise, right, that the minimum amount of change probably would be the best thing to do here under the conditions we're seeing and ended up being the best here. So there was no change on the structure on the covariates or anything there for the model. Really, the MMRM was there before, the MMRM is now, and you see the terms on the MMRM in our slides as well that did not change. So now speaking about other things, we have a lot of stuff to continue looking. What made us very clear that it was across the board is when you have four functions regained in average after 30 years of disease. Imagine something and we're no spring chicken, definitely not me or you, Doug, with all respects. And we lost certain functions throughout life, right? They are not coming back. We're not as athletic as we used to be, for example, well, maybe I should speak for myself. I am not as athletic as I used to be on my volleyball times, and regaining those functions are very difficult for neurotypical, normal-typical person for patients with essential tremor to regain function, you must have an impact across the board for those patients. So while we're going to be showing things and you can imagine that our PIs were like how many papers are out of this, and we estimated about 30 to 50 papers out of everything that was done in this study. So it's going to continue to come and it's going to continue to surprise positively you and everyone else. But as I said before, we are 15 out of 10 on the disclosure. So wait for the next several things to come that are going to support even more.

Our next question coming from the line of Francois Brisebois with LifeSci Capital.

Well, congrats on my side, too. This is quite the story here and the comeback here. So I just wanted to -- a couple of questions on the commercial potential. You've thrown out some sales numbers that are definitely impressive. I'm just wondering what -- you talked about the seven million patients, you've thrown out the five million patients. Can you help us understand a little bit what patients are currently doing, if there's anything out there that's approved and maybe what percentage of patients seek treatment? And then is there a breakdown when you speak to neurologists or to physicians about whether a patient is mild, moderate or severe? And to close it out, obviously, this is kind of a first, but any analogs on the pricing side that we can think about?

Yes. No, no, absolutely. A very, very relevant question for where we are right now, right? Well, the way we've been looking into this in our, I would say, lower case scenario is about two million patients at the TAM at launch, at the point that we are starting to gain some traction there. And that is very conservative, I can tell you. We look to historically, all the work we've done, we conducted about one million patients worth of reviews of records, use of medications, patterns of use discontinuation and so on. And unfortunately, may I say it doesn't really work like what is available right now, right? They don't stay on Etsy, it doesn't work, doesn't reduce sometimes, they try to stay on propranolol, for example, you saw that about 30% of the patients in the study were on propranolol, not doing much for them, driving a lot of side effects. And you might have seen in our Slide 15 that on top of propranolol, the effect was massive for the drug. So there is no reason to hesitate even on those, right? And the majority of them actually discontinue something else before. So we look to the TAM here, looking into the fact that this is a family disease. I think what's been happening throughout the years is that people have been hiding from essential tremor because they've seen their parents, they've seen their uncles, they're seeing like their kids sometimes, and they knew what was coming, right? And they're holding back on really jumping to do something because their neurologists, rightfully so, by the way, we're telling them there's not much I can do for you. Now we're moving to this new era where patients can have hope and should have hope, may I say, and it's going to be like a commercial success, I have no doubt. Now the numbers we threw out there, I threw out there, right, obviously, are statements of our belief in what this can happen, quite informed by all the analysis we've done. When you go for the lowest possible price, this drug should be priced at. And you can pick that number. I don't need to pick the number. It's hard to keep that in single-digit billions. I'm sure when you revise your model later today, if it's not revised yet, you're going to concur going to agree with me. I don't think there's any disagreement. There was ever any disagreement on how large this is. Take a moment to imagine another disease that affects several million Americans that don't have a single specific treatment approved. I cannot come up with one. So maybe you guys can help me out there. Now imagine what can be out of that in terms of commercial success. I don't think it's very hard to imagine the numbers we're talking about here.

Our next question coming from the line of Justin Walsh with JonesTrading.

Looking at the mean PGI-C results for ulixacaltamide, which were near 3, which I think is minimally improved on the scale versus 4 for placebo, which is no change. I mean obviously, we can see the drug is working. But I was just wondering if you could comment on how meaningful this improvement is to patients, particularly in the context of some of the dizziness and brain fog that some of these patients experienced.

Yes. Very good contextualizing question as well, Justin. The -- like we put a lot of data out there today, right? So we decided at one point that there was like a diminishing return on adding more, but I can contextualize to you something that you should expect in the near future is talking about the improvement proportions. And you're going to be really impressed about that. Like there are two ways to look into the data from the global impression scales. One is using the continuous variable, as you've just seen here. But the other one and arguably quite meaningful is the way we look into this before by looking to proportions of patients with very significant improvement with much improved with reduced severity in general, and that is quite impressive as well. What we've seen in the study, what we hear from patients, what we've heard from the experts we discussed with is there was not even an expectation this would improve, right? Like think about, again, the patient population, the age, the overall demographics and so on. It's very hard to increase -- to decrease severity, very, very hard in a global scale, right? Not in an essential term scale. They are healthier. That's the conclusion at the end of the study, and that's quite remarkable. But more to come, good contextualization question for sure.

Our next question coming from the line of Ami Fadia with Needham & Company.

This data is truly groundbreaking and couldn't have been done without the strong execution and persistence. So I congratulate the team for that. Maybe a lot of my questions have been answered, but I was wondering if you could give some color on when the discontinuations typically occur for patients as in after how many weeks of treatment? And as you sort of look back at the data, how much of that or the timing of the discontinuations around the interim analysis may have contributed to sort of a negative result on interim analysis, but of course, positive data as we look at the full study?

Yes. I mean it does influence, right? So when you have relatively early like a median day 21 for those discontinuations at a smaller sample size with potentially higher variability, like that is just very easy to conclude that it reduce the likelihood, and we're always talking about likelihood here, right, not certainties in terms of the entrant. So, I think, yes, you are right there in terms of what could have happened. And the other part of the question, sorry for missing that.

Well, I guess maybe just what can be done maybe in the real-world setting to manage the discontinuations and anything you learned from the trial around where most of them sort of accumulate, which might tell us something about the adverse event profile.

No, no, absolutely. I think what is being done, right, throughout the study as we kept things really constant to make sure we had the best estimate for the study. But we know, for example, in the long-term safety study, what can be done is -- and thankfully, they are very simple, right? They're like hydration helps a lot for these patients. I certainly learned more about hydration in terms of like the elderly population than I would have thought in my life and how important that is. In general, I think the PIs, they were really willing and they really wanted to play with the dog a little bit. Of course, they could not. There was a very clear directive not to do. But we know that, that's going to be happening in the real world for these patients. But it's an expression of how strong the drug is as well. So we knew you might recall in other conversations, we talked about all the expectations here in terms of how potent this drug is. It just came to fruition today. We will do our best and to help to understand and to guide health care professionals, manage their patients, but it was very thrilling for all of them. I think the first calls we did with PIs, they -- I dare to say they were more excited than we were at one point, which was kind of weird and then we got as excited as they were because they are this suffering and they are touching these patients every single day, and we think about them every single day, but we are not on their shoes. So this is going to be a great partnership to help as many patients as possible.

And that's all the time we have for our Q&A session. I will now turn the call back over to Marcio De'Souza for any closing remarks.

Well, I would like to thank everyone. This is quite incredible moment in science. when we can help patients really by doing the most rigorous hard-working execution, disciplined way to look into outside that one could have. So I'm just the voice on this call. But the first thing is to say I cannot do any of this without the incredible group of people at Praxis that help every single day. And why do I push them? And they respond really positively. But the second and maybe even more important is that people who are here align on a principle. And I want to say to the patients, I see you. And that's why we are doing this for you. You know who you are, the people I really know with essential framework. This was for you, and this is for you today. Like thank you for keeping us going because like I -- every single morning, we're thinking as we criticize ourselves, as we think about what to do, the real motivation here is to help people. I started in health care 30 years ago or so to help people. This is the pinnacle of my existence in health care to help millions of people. And I'm so happy to be here, but I couldn't have done without the phenomenal group of people inside the company and with the phenomenal group of people that donated themselves to help us execute this study pristinely. So, much appreciated, much more to come. I wish you a very bright rest of the week, and I'm sure we're going to be in touch.

Ladies and gentlemen, this concludes today's conference. Thank you for your participation, and you may now disconnect.