Okay, we'll kick it off. Good morning, everybody. We're in the home stretch, the final day of the conference. I appreciate everybody making it out for these morning sessions. With that, we're thrilled to have Praxis Precision Medicines with us, represented by the company's CEO, Marcio Souza. We also acknowledge Tim Kelly, the company's CFO, is in the audience. Marcio, it's been a really eventful couple of years for the company, although actually, some would say that your entire 10 years of public company has been pretty eventful. Recently you presented data from one of your lead assets, vormatrigene, for the treatment of FOS, the RADIANT study, which really sort of began to show us the potential of the molecule. In particular, the reductions in seizures as well as sort of the tolerability profile.
In addition to the sort of presentation top line that you gave to us, I think you presented some additional data at the International Epilepsy Congress. Maybe if you could just provide some perspective on the feedback that you got from clinicians when they sort of first saw the data.
Yeah, absolutely. Thanks. Thanks for inviting us. Being here, always a pleasure. You were in Lisbon last week, very eventful as well. I would say it was incredibly interesting to be with hundreds of physicians. It was about over 4,000 treating epilepsy physicians there. Across the board, I think what we hear, right, if you look into this kind of this classical way to describe treatments in epilepsy, where a lot was going on to new drugs coming in, nothing was going on to the outcome of the patients in terms of improvement for like 25, 30 years, almost stalling there, not getting a lot, a lot better. I think we're in a moment now where there's a number of drugs, like including, or vormatrigene, we're really changing that quite significantly.
When we go back and look into the markets, and maybe that is a new understanding that needs to come to bear with particularly the investment community. I think it's very clear with the physicians, the patients being failing, drugs all along, right? The lowest number is 30%. I think the more accurate number is like double of that, that fail their current medications every year, which in the U.S. alone, we're talking about 1-2 million patients switching therapy or looking for better therapies. That is the context virtually all clinicians have in terms of what they are thinking when they are looking for new treatments. For the treatments these patients had the best results with, and this is published right on the Human Epilepsy Project 1 and many others, it's very clear that like sodium channel modulation or sodium channel blockage is that.
They know that if you can get something significantly better there, the patients at large, not subset of patients, but patients at large with epilepsy are going to do really well. When you take this, that was the first feedback, like just people incredibly excited about really having a good drug that can do much more than what they have right now from all aspects, right? Seizure reduction, seizure freedom, tolerability, you name it. I think the second aspect here that is often ignored as well is how we end up having Keppra being prescribed to so many patients in the United States and elsewhere. The answer we got, and again, these are all these three trained physicians, not me, saying it's easy, right? They just go and they give it, they send the patient home, but it was never really that effective of a treatment.
They know most of the patients are failing. If you look into our own data or the HEP1 data, it's about 70%, like 65%, 70% of the patients that failed on the first few months of treatment. Put those things together, it's very easy to understand their excitement. It's also easy to understand their excitement when they know we're actually moving, right? Like we read out, like the first cohort, as you said, of RADIANT, we wrote a number of generalized patients, a few more focal onset seizures you're having, like this last, the next readouts during AES in December in Atlanta. POWER1 , it's like really going well. POWER2 , like starting out right now. They see this movement. It's not only like, oh, maybe something's happening, but in the near future, in the next few years, we're going to have something to treat this patient.
Across the board, and we did, myself, like I think my one-on-one ones were like 70, and I think the entire team was significantly more than that. We always asked, like, what, how do you see this? Critically, no, it's no good for us to just, someone says, oh, I like it and move on. Like, give us the criticism about the data as well. We're very pleased with how well received it was. That reflects on the enrollment in the trials, on the engagement in general that we had, and so on. Good, great place to be in, with such a large market, starting with that and having really an alternative for these patients.
I'm curious, you know, when people sort of talked about the data, what in particular got them excited? You know, was it the efficacy? Was it tolerability? On the flip side, where did they have questions? Right? You know, anytime somebody interrogates a data set, they might want to sort of come back and say, hey, this caught my eye, we'd like to know a little bit more.
Yeah, no, I think it was very clear the onset of effects was very exciting because we just don't see it, in general. The depth of the response when you look into, we show some of the data at IEC with the results across the board, right, with not only 50%, 75%, 90%, 100%. You look into the curve and it's quite impressive and, like comparatively, quite meaningful for these patients. The fact that this is the most difficult patient population to treat, right? There was no sub-selection of patients. This is really the patient, the worst patients they had in a sense, the ones they put on this drug. That was seen as very positive. I would say the side effect profile was seen quite positively as well. We sometimes were not seeing these patients every day. We look into these numbers and, like, oh, there's CNS side effects.
We forgot to ask the questions like in proportion, right? This is significantly lower than anything else that we're seeing so far in the market. That was quite positive. I think what we were disappointed, maybe since you asked there, was that we could, and one could argue should have done an even stronger work with the sites on the discontinuation management, and so on. We know that across the board, particularly when multi-sites are involved, like when it's not one or two sites that are conducting the study, that some have better counseling than others and so on. We think that's where we were seeing POWER1 already. It's a much, much different picture in terms of that.
As one always must criticize themselves as well, that's the area that I would say not that anyone is concerned about that from a physician perspective or the markets, but it is something we wanted to do better and we're doing better.
With those sort of operational things, right, because you haven't made any sort of protocol changes or stat plan changes to POWER1 , correct, have there been operational changes based on some of the things you learned from RADIANT?
Yeah, I think all along, as we were seeing some of the things happen on RADIANT, and remember that's why we did RADIANT as well, right? There was a number of questions we wanted to answer, and one of them is, are there any operational things we can learn as we're executing POWER1 and as we're planning for POWER2 ? One of them is really this, tighter counseling of patients in general to participate on this study. I think we checked that box big time because there was overlap on the recruitments at one point. I can tell you right now, I mentioned this in another conference in the last several weeks.
When you look from a blinded perspective on POWER1 , you can see that the rate of discontinuation is significantly lower, even if we assumed that everyone was on drug and no one, no one on placebo on the discontinuation. We're in a very good place there, in terms of being effective without really changing, to your point, anything fundamental that could change the results of this study.
I did want to touch on POWER3 , right? The monotherapy study. It sounds like this is going to be a single arm study. Do you plan to use a historical control or what's going to be the comparator there? Obviously, you can't run a placebo monotherapy study, right? In this day and age, you wouldn't, you'd get zero enrollment.
No.
It would be deemed unethical and you probably couldn't get any U.S. sites to participate. How are you looking to do that, and what are the goals of the study and how should people be evaluating that?
I'll take a step back there because I didn't give this feedback. It was a little bit surprising. We've been asking people, like what we mentioned in our disclosure, we're talking to a lot of investigators, experts on what is the best way to design that study, to finalize the design. A lot of the conversations, like when people would come to the room in Portugal to talk to us, one of the things I heard the most was how excited people were on POWER3 , which was a little bit surprising. I think the excitement came from, yes, we know how to interpret studies like POWER1 , we know how to interpret studies like POWER2 , but they are always somewhat confounded by the fact that these patients are treated very differently across every study, right?
Like two medications, three different doses, different concentrations, they are of different ethnicities, and you name it, things that can influence studies. The actual need is to reduce the drugs and to remove the drugs, and that has not been for many, many years, any drug that we're confident enough, and that's what we heard from them, on the efficacy to do that, that the drug stands alone, not in combination in terms of efficacy. The idea here is to, like we could use the escape rates that were done historically. I think they're very mediocre. The majority of the patients actually escape on that. I don't think reducing from 60% of failure to 40%, which would be significant, is what we're looking at here.
Really, the overall thought in our minds at this point in time and what physicians are advising us to do, and by no means that is the final, is really to gradually remove the background, probably like 25% at day one and then the other 25% at week two and so on, with the aim of going to zero and establishing a monotherapy. I'll bring back to the conversation at the very beginning of this talk. What is incredibly surprising, I'm sure not only for us but for others developing drugs in epilepsy, is just how hard it is to appreciate from the external perspective how big this market is, right? The refractory market is massive, right? We're talking about millions, as we said at the beginning.
When we actually go down to the potential of even a fraction of the markets to switch to zero, to switch to one treatment like with vormatrigene, then we're talking a completely different game. If you're looking to the three or four potential players in epilepsy right now, the sum of the market caps times two is still a fraction of what this market should be actually looking for. That is such a major overall market discount, and that's why today I'm speaking a lot more about the commercial potential because for ourselves and let's say for Xenon, because they were the ones that were closer, we're like at the goal line, like it's pretty close. In a few years, we're hopefully going to be treating all those patients commercially. It's time to change the discussion towards commercialization now that I think there is no disagreement these drugs help patients.
Now we have to talk about how they help patients in a commercial setting.
I guess that sort of follows up on that, right? You clearly don't necessarily think that epilepsy is a zero-sum game. Also, to your last point, I think a lot of people sort of define the market like there are +3 million epilepsy patients, but then you sort of use a certain number, a third are "refractory patients." Even within those who are not necessarily "truly medically resistant," there's probably significant unmet need because those patients are "controlled" or managing through it. Maybe their seizures are relatively low, but they are dealing with side effects, especially, like levetiracetam, right? We all know it's the most broadly prescribed and causes a lot of agitation.
Yeah, there's no catheter adhesions.
Yeah. Spending any time on Reddit, for Keppra, you really sort of learn about if they're not necessarily happy, even if their seizures are under control. I guess what's your perspective on thinking about that market, right? You know, in the refractory, and then should we only think about, you know, the million patients or million plus patients that people sort of often define as the market opportunity for you, which is certainly big enough for.
Maybe that's what I would start, right? You could justify times three, four, five, the sum of overall opportunities people see by only looking to the 1 million patients on the refractory markets. For us particularly, we don't need to, right? We can look into the markets and you can attribute whatever market share you want at that point in time, and then start asking what happens when you replace these other treatments as well. To your points, and this is well documented in the literature, that's why it's confusing sometimes. It's the patients on monotherapy right now, a lot of them are completely unhappy with the side effects that they're, and it's not only side effects that we obsess about, right?
We talk about headaches, and which I have one right now, so, and I'm not on any medication, so clearly not the issue there, or dizziness to the extent that it's mild. Talking about psychiatric manifestations that are really life-limiting for these patients as side effects, not as primary condition. There is a lot to be done there, and the efficacy is not that great. You might have seen one of the posters we had at, and one of the conversations actually we had at the IEC was the second cuts for the POWER1 study. About half of the patients, 40% or so, they call themselves controlled, which most physicians would put them on this 60% of controlled patients, but they're actually having seizures on the previous week.
I don't think there's a lot of other conditions that people are like, oh, I'm controlled, but I just had a seizure, which is like the definition of the condition. This idea that a small part of the patients are not controlled is quite erroneous from the patient perspective.
I guess, you know, maybe just help people understand where you are and the timelines for both getting the POWER1 data, which is, you know, coming up really soon.
Really soon.
As well as POWER2 .
Yeah. The strategy we had was, finish POWER1 in terms of recruitment and then get POWER2 kind of back to back. We wouldn't compete with ourselves, but we could accelerate both of them. We haven't announced anything yet, so you should wait for that announcement. What we did say, like POWER1 finalizing this year, POWER2 is starting like in Q3. I think we are in the last month of Q3, if I counted correctly. You should read between the lines, like what's going on here, from the interest that we have from the sites. We actually increased a lot last week. We cannot possibly accommodate everyone that came to us and said they wanted to participate on this study, logistically speaking, but they were more than willing to refer their patients to sites from their colleagues in the same country and things like that.
We believe that POWER2 is going to grow pretty quickly as well, just like POWER1 , just like RADIANT. With finishing that enrollment next year, we might or might not be able to accelerate a little bit and then maybe even have the readouts next year as well. When you put that all together, we're talking about an NDA submission shortly thereafter. That's what we're really talking about, right? The next year in this conversation, we might be talking about the date filing the NDA and getting to the market and so on. That's pretty quick.
When would we anticipate data from POWER3 , which is not obviously on the critical path? How are you thinking, is that data that you would have at launch that you could share with the community?
We haven't started doing the full feasibility for POWER3 , so take everything I say with a grain of salt. If the interest on something like POWER3 , which is a slightly different type of patients, is any indication, I think that's going to be pretty quick, next year. It's absolutely not necessary for the NDA package, but you can imagine a situation where it's either present during review or actually is part of the package. Now we're talking about a label that no one ever had at launch for a drug like this. We're talking about a much, much bigger likelihood.
The aim would be to potentially have this included on the label, just given the power that would have from a commercial standpoint.
One of our faults as a company is always to deliver a lot. We're going to keep that. It was a little bit of a joke there. It didn't land really well, so we're going to push to deliver that to be part of the label as well.
Okay, so we're almost out of time, but I always go into stoppage time, as I call it. I did want to touch on Relutrigine, right? Because I think it is, you know, an asset that could probably justify a lot of significant value. Just where are we right now in terms of enrollment of the registration cohort? And maybe just for those who are not familiar, because I think vormatrigene has sort of really sucked a lot of the air out of the room, so to speak. What you've seen, you saw from the first cohort, right? You know, the non-red, the initial cohort of patients from the Ebola study.
Yeah. So Relutrigine for the first cohort, like SCN2A and 8A patients, they don't get better periods, right? There is no debate about magnitude. Like anything you could do that would be important for these patients. The expectation going in was we would have 20%, 25% on the controlled phase of the study, so 46% reduction in seizures, countable motor seizures, because a little bit more severe there. On the 11-month updates, that was the last one we gave, was 90%, so 9-0. I think it's undeniable how life-changing, disease-modifying that drug is. We talked to the FDA, we were granted breakthrough designation. With that comes an opportunity to actually have a conversation with the agency about acceleration of the program, right?
One of the parameters in conversations like that, and I'm going to be hypothetical for a second, here is how far along you are really with the substantial, with the data that's going to serve as substantial evidence of effectiveness. What I can say, which is a little surprising for the market at large, but not for us, rare disease studies take a long time, right? We're talking about like these patients are super fragile and so on. We started this about 10 months ago. We haven't announced completion or something like that, but what you should assume is that we are substantially complete with this study, which gives us a real opportunity to really accelerate that. I'll play a scenario here where these conversations with the FDA would allow us to actually accelerate much further than anyone is imagining for this patient population.
That is the strike one, I would call, maybe an NDA in the near future. The second one is EMERALD, right? When you look into the market for EMBOLD, that is the study, this new cohort of EMBOLD, it's about $1 billion or so in value. That alone, to your point, you justify five, six times the current market cap for the company. Then EMERALD, which is enrolling really well in the U.S. right now as well, we're talking about potentially about 190,000 - 200,000 patients, so that multiplies that. Yeah, you're right to say that Relutrigine probably didn't take as much of the spotlight, but it should because it is quite advanced and there's really, it's a white space. There is no one doing anything there. These patients need it and the drug has shown quite phenomenal efficacy so far.
When you make a comment that the, you know, an NDA in the near future, I do know that you have a pediatric disease designation for Relutrigine.
Right.
We also know that you have to get approval by September, I don't know if it's September 30th, 2026.
That's correct.
To get your voucher or to earn your voucher, because that program is as of now still expiring, do you, should we interpret that you think that that voucher is in play in terms of winning it?
It has to be in play, right? From a corporate strategy, whether or not we're going to agree on a path to get us to there is a different question. I think in the near future we're going to discuss that, but it has to be in play. It's not only because it's quite significant, like a cap tool that is non-dilutive, but because these patients need us to do whatever we can to get the drug to them, and that's what we're committed to.
Okay, with that, I guess we will wrap it up because we are, I used all the stoppage time, so to speak.
Thank you.
Thank you.
Appreciate it.