All right, we're going to get started with our next session. I'm Andrew Tsai, Senior Biotech Analyst at Jefferies, and it's my pleasure to have Marzso Souza joining me today, CEO of Praxis. Welcome, Marzio.
Thank you. Thanks, Andrew. Appreciate it.
Maybe really briefly, because we do want to—I do want to tackle a lot of things. Maybe walk through what you're working on in the pipeline and milestones we can expect over the next 6- 12 months. That would be helpful to start.
Absolutely. It's always a pleasure to be here. That is always a lot. I feel every time we talk that there's a lot going on with the company, and we're very pleased and happy with that, but still remain quite humble on the heels of a very successful essential tremor readout on both studies. We have that filing coming up, hopefully early in the year. By early in the year, a number of epilepsy assets progressing, including our GE program with relutrigine. First, for a rare indication or two rare indications for SCN2A and SCN8A, those are coming up. The interim analysis, we're doing that study kind of right now, and by right now, I mean Q4. We're continuing to recruit quite nicely, may I say, on the larger study, what you call Emerald, which should read out next year.
In between, assuming that the interim is going to be positive here, of course, I would be filing an NDA for that indication. The next—if I restrict to the next six months, two potential NDAs and two potential readouts.
You also have the focal epilepsy.
Yeah, yeah. And then another readout for focal epilepsy. Thanks for reminding me of that. As you can see, there's a fair bit.
Okay, very good. I did want to tackle essential tremor to start, top of mind of many people so far. I'm sure you get this question a lot, but to begin, you did have this original interim look, and by the way, congratulations on a successful readout.
Thank you.
This interim readout was determined by the DMC by futile. How do you reconcile the turn of events between the two incidences?
Yeah, it's pretty—and maybe just to recap, right? Early February last of this year, there was an analysis done by an independent Data Monitoring Committee assessing what was expected to be 50% of the patients on this study. The idea of conducting that analysis to begin with was there was no successful phase three study ever in essential tremor for a drug. Faced with a situation like this, we try to learn as much as possible as one goes as we went through. Based on that analysis, the committee came back to us and said it's unlikely to be successful, which we call futile. I think the first misconception is that when someone says it's unlikely to, they don't mean it's likely will not, right? It's not a certainty. It's actually an expression of a probability on that point in time. We know what happened.
It didn't, right? It was very successful at final. How do you reconcile that? I think what your question is, is by going back and actually asking the question, why? The why here, and in most circumstances like this, would be pretty simple if people actually continue as we did. It was too early. I think that that's the simplest and, to be honest, the most accurate situation that happened was planned at 50. When you look into the final end, it was actually around 40, a little bit over 40%. When you consider 40% pretty early on a study that was fully powered at the end and with the variabilities at that point in time, with the understanding that they had of the data, they could make no other choice but to recommend as not to. Why haven't we stopped, right? That's the other question.
If I can hijack your question for a second here. Oftentimes we're asked, why haven't we stopped? That is an even simpler answer. We were basically fooling roads at that point in time for this study. It becomes more of an opportunity cost type of situation where the risk of not continuing was pretty easy to determine, right? The opportunity of continuing was actually pretty easy to determine as well. Considering the investment was so small, but the actual asymmetric upsides were so large, we chose to continue. The last thing I would add there, the previous study was at eight weeks, was pretty clear at eight weeks, and we knew there was some variability in general with these patients. We wanted to get to that answer very clearly. Yeah, here we are.
Great. You made the right decision. One more maybe question around that front. If DMC determined as futile, can I infer that the placebo-adjusted change on modified ADL was maybe, let's just say, zero or worse in the first batch of 40% of patients, meaning that the next 60% or so of patients, maybe their Placebo-adjusted delta was closer to five for you to show around a 2.6? Is that kind of the right concept?
It is not, actually. The placebo adjusted difference there, number one, maybe to clarify that, and particularly with this being a webcasted call, there was no point in time that placebo was better than drug on this study at interim or at final, at any time points. I think that's super important to understand. There are two concepts, right, that determine, well, there's one concept, but two components that determine the actual p-value in this case or the probability there is one is how placebo and drug do, also how the variability does at that point in time. You can get in a very early look, the standard error can actually play a bigger role or it always plays the same role, but in relative terms, a bigger role for that smaller sample size.
That's why we tend to power to a given effect size at a given size of this study. That's why the concept just was too early. We see a more stochastic than actually increasing here. It's all to say or to translate that it does vary a little bit every several patients that you add to the study, which is not uncommon. It's actually pretty common in several studies, which the precision of the final gets improved as you go. It was not negative and then became positive, it was positive and became more clearly positive at the end with more power.
Interesting. Okay, thank you for clearing that up. Two weeks prior to unblinding the data, you did make a couple of tweaks, adding two hypotheses, changes to that SAP plan just slightly. Did you already notify the FDA back then before you toplined the data? Did you hear feedback from them that it was okay? Is that kind of the purpose of this, one of the purposes of this upcoming meeting that you have in Q4?
Yeah. Two, I think what Andrew is referring to, right, a few weeks before the disclosure, we updated clinicaltrials.gov with the full hypothesis for these studies. It meant to serve several reasons or several masters, one could say. One wanted to make exquisitely clear that all these changes were done before any knowledge of the data, before database lock, before everything. That is one of the reasons why even the clinicaltrials.gov in itself posting has a period that we submit and then gets published. It was not exactly what you are seeing.
What we chose to do as well after we finished all the simulations, after we finished the updates to the statistical analysis plan and the protocol and implement the protocol and get the IRB approved and get PI signatures and so on and so forth was to inform the FDA of all the changes through filings to the IND as is required in the United States, but also through formal communication to the agency about the changes in which we actually notified them on when we're planning to lock the database, which gave, of course, an opportunity for interactions that they chose not to exercise, but it was all done several weeks before, as you would imagine then, when the posting at clinicaltrials.gov became up or available. All of that was done.
Okay, thank you. Bottom line, as it stands today, the degree of FDA alignment you have around the regulatory pathway is both studies needing to succeed is how I understand it, using the modified ADL 11, FDA is on board with that. Is there anything else you would add that you have alignment as we think about the regulatory review of this?
Yeah, yeah. There are a couple more things there that might be important. June 2023 was our end of phase 2 meeting with the agency based on the Essential1 program that was the prior that served as the hypothesis to be confirmed as it was in the Essential3 program. During that meeting, we agreed on a number of things with the agency: the two studies, the design of those studies, the safety database, and that's something we have not mentioned yet, and what would be necessary for an NDA filing. They quite explicitly asked us to very specifically calculate the mADL 11. That calculation, where you actually use 11 items instead of the 12 and you calculate your three, was actually a very strong recommendation. One could argue a mandate by the FDA.
That was an alignment very clearly back then and two prospective studies versus one prospective study. That is why we have done those two different studies. Also agree on the design of those, meaning they were very supportive on one study being a parallel group and the other one being a stable responder randomized withdrawal study. That is why we ran that way.
Okay. One clarifying question, do you have buy-in necessarily at this juncture to do a week eight primary analysis versus week 12, which was the original, and then to do the analysis on an MITT basis relative to ITT?
Yeah, so it separates those two, right? The MITT basis for years being on the protocol and the analysis plan and everything from the beginning, it really doesn't matter. I mean, it doesn't matter because the way the model is specified, I'm more than happy to take that offline because it's highly technical. They would result on the exact same number in this case. Yes, the answer to that question is yes. The choice of the time of the assessment is always a sponsor's, right? We know that it's acceptable to do eight weeks or 12 weeks. We did change, and being incredibly clear about that, from 12 weeks as assessed at the average of day 77 and day 84 to day 56.
Pretty minor change, but maybe even more important than that is the study was successful at every time point, including the one that it was changed from. So maybe.
You did not need to change it.
We did not need to change it. Yes, that is another way to think about it.
Okay. Did the study succeed on an ITT basis across every time point as well?
Yeah. As I mentioned before, and I know this is not the easiest concept to understand, mixed model repeated measure requires the term two chains in order to use the term, meaning there is no term, there's no data between zero and 14, and therefore the estimate for the estimation for the ITT and the MITT are identical mathematically.
Oh, okay. Great.
The numbers are the same.
Okay. So now you have a meeting scheduled in Q4. When do you think you'll come back to the street with a response? And what exactly are you going to then ask the FDA?
Yeah, I think the question, so we have the meeting confirmed as a pre-NDA meeting face-to-face with the agents this quarter. I know the quarter is getting shorter by the minute, so there's only so many days left.
Is it fair it's December or?
I think it's fair to say it's this quarter, which doesn't have a lot more weeks left, right? Effectively. I don't think we're going to have Thanksgiving together at the agents, although I would welcome sharing with them. The key question is always about the evidence. If you go back, and I know you know this, but maybe for the audience, every pre-NDA meeting on an approved drug is available publicly. Just go back and check which questions are asked. Of course we're asking about the package itself. There's normally a bunch of, I'm going to call it administrative questions about the structure of the filing and so on. We're asking some of those as well. I think it's proper at this day and age that we just wait for the minutes.
Obviously, a thousand different scenarios here that can play out, but you should assume that the base case is that we wait for the minutes. Thirty days later, we make a communication. We expect that communication to be when we're filing the NDA based on the discussion with the agency.
Great. Thank you. Do you envision the FDA? Investors like to ask me what kind of degree of analysis will the FDA do in this pre-NDA meeting? Is it pretty deep or is that something, is it more of a review issue once this is accepted in your view?
I personally never seen the FDA run an analysis on a pre-NDA meeting, right? I am not saying it is not possible. Normally what happens is the sponsors, our case, submits the briefing package. In the case of a pre-NDA, 30 days before the meeting happens, it is a very comprehensive package. I think we call meeting materials now, but we used to call briefing book. Very, very comprehensive. It allows the agents to really explore the question, right? It is our position on the question that we are asking. We think, again, it is pretty straightforward. Could they and would they ask questions for us to better inform their review of the NDA? Possibly. I think that is quite reasonable.
We try to ask ourselves which questions could they ask, which sensitivities could they be interested in understanding, and we included those already on the briefing package to make the discussion more effective.
Thanks. We'll be patient about that. You'll submit it in early 2026. Let's just say it did get approved. I'm hopeful it gets approved. How many sales reps do you think you'll need to launch this drug ultimately?
Yeah. The essential tremor, there's one drug approved, right? Propranolol, as we know, is a beta blocker being approved many, many years ago on a number of cases that were submitted to the agency. If you go and look into the file, you're going to find that it reflects what happens when you take propranolol for this disease. It's very ineffective. Tolerability is a major issue, and it's really used, unfortunately, by a very small number of patients. There are 7 million Americans living with essential tremor. About 2 million-3 million of them are actively seeking treatments because it is to a degree that impacts significantly their activities of daily living, which is why the agency asked us to measure that as previous. When you look back to those numbers, it's obviously an incredibly large market.
The beauty of this market, one is that we understand this incredibly well. During our recruitment campaign for the Essential3 program, we built a database with over 200,000 patients. And it's not wrong. It's 200,000. That was a relatively small company that we are and we were back then, which gave us great insight on how to reach these patients, how to understand, how to get there. When you project to what can be done between now and the launch, and let's argue in about 12 months or so, I believe we can get to a much, much larger number there. What allowed us to do as well is to understand where those patients are being seen, how are they being treated. The vast majority of them are neurologists, non-movement disorder physicians. Actually, one could argue fortunately, another one could argue unfortunately.
I'm going to pick the fortunately because there's not enough movement disorder physicians to see patients even if they want it. And the neurologists are more than capable of caring for those. To cover the 13,000- 14,000 neurologists in the United States with the ramp up, we expect to be with a very robust DTC campaign. We need about 300 or so people on the ground to reach our midpoint of the estimate for the launch is around $8 billion-$10 billion in peak sales. To get to that point with this drug, that's what we believe we have to start. Obviously, that's not where you end, but it's where it starts.
Maybe one more question. We have five minutes left. I've spoken to doctors, neurologists, and the feedback for some of them has been the week eight efficacy looks stronger than week 12. There's a slight waning of effect. That leads me to think this open label data set or study that you're enrolling could be meaningful. Do you plan to share data cuts in 2026 to show us the durability effect?
Yeah. The first thing I can say, it's not a durability of effect at all, like if that's the concern here of summit, it is a variable condition. When you have the most effective, it's not even close to be the most effective treatment for essential tremor. These are folds better than anything that even being attempted here. I think it's the champagne problem to talk about point estimates that vary by half a point between one and the other. Humans love picking on the little variability versus looking to the possibilities here. It was not only that they were better on the 11 items, actually 12, because the ADL was positive as well, but they were better on the PGI, on the CGI, on the severity, and on the improvements on those.
I challenge anyone to actually show any other drug in recent history in neurology with even a close effect. When you ask patients, they are quite desperate actually to be on the drug. When you ask the majority of the physicians, they are quite desperate to start prescribing this drug as well. To answer your question more directly, yes, we are going to continue to show data. I think people are going to continue to be quite convinced on how effective this drug is.
Thank you. I would love to talk about relutrigine because recently you announced you all plan to do an interim analysis. Can you walk us through this is for SCN2A and AA, your two rare DEEs to start. Can you walk us through the scenarios of the interim? Is there a futility analysis or something like that? Is there an upsize study? Continue as planned? Walk us through the various outcomes.
Yeah. So the relutrigine program that we are developing as a precision medicine for DEEs in general, I think it's important to consider the entire program here, right? We had phenomenal preclinical work, which led us to test first on SCN2A and SCN8A, about 5,000 patients in the U.S., and I think 15,000 or so addressable in markets that have robust market access mechanisms around the world. We were granted breakthrough designation after a very successful phase two. We also had a conversation with the agency about what's next for this program. That is why we're running the Emerald study to serve as the second for another indication. It's going to become important in a second why I'm saying that. In the breakthrough discussions, we were asked how to accelerate this program.
We chose to do that by looking into about 70% of the patients on the study only. There is no futility assessment. There is no resizing or sample size re-estimation assessment here. The only choice is to progress to final or to declare successful. That would serve if successful either at final or at interim as the base of the NDA for SCN2A and 8A. Once that NDA is approved, hopefully next year, we would have a second study with Emerald that would serve as the base for sNDA for the larger indication on Z. A big part of our work has been understanding the patients, the patient needs, developing drugs that are not only highly effective, but quite convenient for those patients to take.
Instead of relying on the same old industry standard, do things is low, burn as much capital as you can, actually accelerates developments. Emerald Study is enrolled really, really well. I can tell you with high certainty that is going to actually read out next year, which means you are going to be in a position to file that sNDA very quickly and very, very likely be the first approved drug for DEEs in the U.S., which is a $3 billion-$4 billion opportunity. Just put the two and two together, and I think we are all going to realize how big of an opportunity for patients to get better, but also for shareholders to do well and for all of us.
I see. As you're talking, I just realized there is another competitor evaluating broad DEEs, but you're ahead of them, or you should be ahead of them with the Emerald reading out kind of thing.
Arguably, yeah.
Okay. Okay. Back to the interim, maybe one last question. I think you're going to do this unique analysis with the log transformation. I don't know if investors are in me, I don't know what that truly entails. I've only seen that in one epilepsy readout, but will you plan to share the traditional seizure reduction percentage drug versus placebo? If so, what is a positive, strong result to you?
Yeah. It's about half of the drugs that actually have been analyzed that way for epilepsy. It's a property of highly skewed distributions. Very common, zero controversial analysis on that regard. You can back transform to the percents. I think purists, mathematicians would say it is an approximation when you back transform, but we will show that. Most people just believe that is exactly the same numbers because zeros cannot have logs, as you know. You have to add a factor. There's always an underestimation versus an overestimation of the effects. If you want to know exactly why you can do it. Yes, it's being done. One of the most successful, if not most successful drug in DEEs actually did exactly the same analysis, got approved.
I do not think they ever got that question because there was no one with a bare thesis like trying to feed an incomplete narrative. That is a little bit of BS. I think it is important that we just say when it is.
Okay. If it's that strict, that's great. Okay.
Exactly.
All right. Thank you very much for clearing up a lot of questions for me.
Of course.
Thanks everyone for listening.
Any day. Thanks.
Yep. Thank you, Marco..