We're thrilled to have with us Praxis Precision Medicines up next, represented by the company's CEO, Marcio Souza. And also, I'll point out the CFO, Tim Kelly, is in the audience as well. So, it's been an eventful few years actually now for the company that we're sort of rapidly approaching another key readout for the company with ulixacaltamide in essential tremor. I guess one of the questions I've gotten from investors recently is, you know, how you've been able to enroll so much faster than others have in the space.
And if it was, you know, just a matter of sort of unmet need, why has it taken Sage two plus years to do their study? And, you know, I can't remember exactly the timeline for Jazz, but it's not been dissimilar. You're going to have enrolled, I think, two Phase IIs plus a phase III study in that same time period. Is there risk that by enrolling so quickly, you perhaps have lost some control in terms of the quality of patients that you're bringing into the study?
Yeah. No, that. Thanks, thanks, though, for having us here. I always appreciate it, and I think it's an understatement to say how much happened actually in the company, in the last few years. I agree with you. So if looking to the different components of our clinical study, as large as Essential3 is, right? We talk about, like, the quality and the type of the patients, that's non-negotiable. That's on the, I'll say, on the right side of the curve. Not ever gonna compromise that. But we start breaking down, the areas that we can influence.
And I think anyone who is, at this point in time, conducting studies in neurology or in many other areas, is dealing with similar issues, right? There is not enough staff in the sites. There is not enough neurologists in the country seeing these patients, and the patient demand cannot be fulfilled that way. So what are you really solving here in a not so unique way? It's actually surprising that it's so much better than everyone else out there. It's really trying to understand how can we help those investigators to get patients through the door, so they can get the best possible patients enrolled on those studies.
We do that by putting a lot of emphasis and a fair bit of resource into making sure the proper patients are pre-screened, they are available to be put on the clinical study or consented to the clinical study, and that we are matching patients to investigators. It's not any different than what's done before. I think it's the scale by which we've been doing this that is quite different. So we can reach a lot more people, we can engage with a lot more sites or directly to investigators and have a more throughput.
Now, from that point on, it is still a fairly, I'm gonna call an efficient process, how we run most things in terms of clinical studies in general. It's very slow, and that's the part that we really can't change as much right now. So we accelerate the upfront and can't fix the second part. I don't think it's anything different than what all the industry is gonna be doing in a number of years, is that analytically define where those patients are and making sure they are available for these studies.
You know, I think last time we talked, you noted in terms of a question, in terms of the magnitude of benefit, in terms of how the studies were designed, you know, for the randomized withdrawal, that you were looking for a two-point gain. And then, you know, on the flip side, you would when you went to the withdrawal section, obviously a two-point loss. You maybe help people understand the sort of the relevance, if you will, or the clinical relevance of two-point gain on the ADL for patients, and what do you think that ultimately means in terms of the commercial potential for the product?
Yeah. So when we went back to Essential1, right, so the previous study that we ran on this condition, the one key thing we didn't know there is how a relatively large number of patients behave in a clinical study, number of responders, type of response. So it was rather challenging, actually, to power that study. I think we're past that point now, where we understand fairly well the distribution of those patients and what is meaningful for them. The beauty of the ADL scale and the modifications that was proposed by the FDA, is that we can relate very directly, right?
So if you think about, for example, drinking coffee from a cup, I, as you can just see here, do this, quite, I would say, quote-unquote, "normally," but a patient with essential tremor cannot do it. So when they can do it or we can reduce the difficulty, I think it's very hard for someone or not one of us that are actually don't have the difficulty to say that was not a meaningful gain. So every point on this scale was designed in a way that is intrinsically meaningful, and that, that is super interesting and super important because most scales are not like that.
They're mostly abstract scales. Here we're talking about direct translation to how patients function. The second beauty of that is that how patient function is one of the statutory ways to gain regulatory approval in the United States. So they're all connected there. When we mention about the number of movements or points, that would be undisputable. I think it's very clear that anywhere would be important, but 2-3x number of points for a given proportion of patients. And that's how Study 2 in our Essential3 program helps inform that, right?
Study 1 is a parallel group like 12 weeks, your classical 1-to-1 randomized placebo-controlled study, and that's gonna allow us to really estimate more statistically how is it different, these groups, over time, over three periods, three months period of time. But study two is telling us a slightly different or maybe, a very different story. What happens to patients in the real world? Because all of us, at one point in time, while I hope not, I'm pretty certain that was the case, we were patients, and we took drugs, and they either worked or they didn't work, and when they worked, we stayed with that.
So it's very important to understand the proportion of patients that responds, and when they respond, what is the magnitudes? So that is gonna help us, a lot in terms of potential label discussions, potential, like, payer discussions, and so on. So the combination of those two studies is incredibly powerful for all of that.
Is it your sense that, you know, and obviously, you need to qualify or quantify those specific two functions that patients are potentially getting, and that importance. But do you think that those, sort of qualitatively, the benefit goes beyond those two specific and discrete functions on a daily living in terms of the overall well-being for individual patients?
Oh, I have no doubt whatsoever, right? When we consider and we hear this from patients all the time, when they no longer need help, then the disutility to the family reduce significantly, improve significantly. But that's not quantified. So if I always need help in the morning to, like, put up my clothes to go to work or to prepare, like, some food for breakfast or something like that, and I no longer need the help, yeah, the scale does not capture that secondary part.
But when we talked to the families last year, we did an event in our office that was focused on the caregiver, right? Just on the, like, spouse and other loved ones from those patients, and what they tell us about the impact on their life is heartbreaking. That is not obviously collected in the scale, but it's an indirect benefit of this treatment for the patients, for sure.
Okay. Now, I did want to maybe turn towards your epilepsy portfolio. And, I mean, I've said this a number of times, but it's always, it's easy to forget with Praxis, that you were founded as an epilepsy company, even though many of the key readouts were in arguably sort of like adjacent spaces. But one of the key catalysts for the story, in the last six months was the readout of the PPR study for PRAX-628 in focal onset seizures. You know, this is a model that historically has proven to be very good in terms of translating ultimately efficacy in larger clinical studies.
But these are small studies, and so when you talk to investors, what gives you, or what should they think about this data? Obviously, you have an active agent, but is there a risk that, you know, perhaps around dosing, that things could be overinterpreted, and how do we think about that confidence moving into Phase II and ultimately Phase III?
Yeah, so get a little go into a little trip down memory lane for SCN8A, because I think it's relevant for the answer. When we first discovered SCN8A, and we tested a number of genetic and general models of epilepsy, so we've seen first in vitro and then in vivo, quite unprecedented, like, activity. We're seeing this very different electrophysiology profile that translates into incredibly wide therapeutic margins and very, very, potent, very efficacious on the animal models.
And those models are very good, right? If you look around, at any, epilepsy company that's been successful, on this space, and you look into the models they use, it's the same ones I'm talking about, right? The maximal electroshock seizure model, the 6 Hz, to 32 and 44 amps or milliamps, and many others. So at that point in time, there was already a pretty high probability of success that moving this drug to the clinic would work. What kills drugs at that point in time, when they have very good preclinical data on efficacy models? It's tolerability, safety, like toxicity in general.
So we wanted to make sure we're getting to exposures that were not toxic. So we did a very extensive phase I program, like multiple dose on a single dosing, very high exposures on the multiple dosing. And at that point in time, we were very convinced due to the tolerability profile and the safety profile, that we had the kind of drug that everyone's been waiting for, right?
This is the most potent agent ever developed in epilepsy, and we do have all the data to back it up, what I just said, with now incredibly large clinical margin, right, in, in patients. So what was the missing link there? One could argue, and I think many investors argue with me, why not just jump straight into a large focal epilepsy study at that point in time? There were both technical and, financial reasons for us not to do that. So we took the intermediate step to further de-risk the program. The PPR study was nothing but, a de-risking of the focal epilepsy or the focal onset seizure study that we're about to start.
We never made more, out of it. I think there was a tendency, because the results were so clear and they were so good, that people wanted to make more out of it. But all it's really telling us is confirming the prior hypothesis, that the drug is active, that the concentrations by which we expose those patients are in the therapeutic range, and that we should feel even more confidence to move this to a focal onset seizure study, and that's exactly what we're doing.
We're about to start the beginning of the second half of the year. And that study, yes, this is the one we must be judged in terms of efficacy of this drug, which we do believe we're going to continue to be unprecedented when you compare everything on the development program so far.
With the PPR study, you did test two doses. The 15 and the 45. Both had showed response, 100% response, although the 45 was a little stronger, right, in terms of g etting a higher rate of complete responses. When you think about moving forward, given the tolerability that the drug, you know, has shown in the healthy volunteer study, do you anticipate needing to advance two doses, or will you sort of focus on a single dose?
Yeah. When you look into concentrations, right, that we should be exposing patients to get the maximum benefit, since I always prefer to look into that versus dose, and we look back to regulatory precedent, number one, 'cause it's quite important here, the guidance itself, what we are trying to achieve. I think it's important to remind ourselves what we're up against. There are over 25 drugs approved for focal onset seizures or the different names the condition had over time. All of them do something for these patients. That's why they were approved.
The vast majority, vast, vast majority of patients cycle through drugs in months. There is an urban legend that it takes a significant amount of time for them to cycle through drugs. Virtually, no one's becoming seizure-free, virtually no one is getting to 50% seizure reduction. So that what we're looking for here is an exposure that is given with PRAX-628 in this study that makes an unprecedented, again, level of response in this patient population. So when you see the design, pretty soon, that's what I would ask you to keep in mind. That's what we're going for.
We're going to the best possible efficacy, ideally, the best efficacy ever seen on focal onset seizures for these patients. We design a study that's aimed to show that. So the exposures will be pretty high, and they are in the range of what you're seeing on the 20 mg and 30 mg on the multiple ascending dose before, which are anywhere between 10-20 times the MES equivalent multiples. Just a reminder, the maximum anyone ever dose a patient before was around four.
So we're really going here to test the ultimate hypothesis that if we expose these patients more to a drug that is safe, they will have, in general, higher rates of response, because that's what they need. They don't need another me-too. They don't need a drug that has a different mechanism, but does not give any better results, or the patients discontinue, or they're having, like, insanely high levels of dizziness or falls or urinary retention or anything like that. They need a better drug.
And one of your other epilepsy assets is PRAX-562, and we're waiting for the readout there, and I think you've now said that it'll come in the third quarter.
Correct.
You know, in the past, you've sort of characterized this as a disease-modifying therapy. You know, how do you think about disease-modifying therapy? Most drugs in the epilepsy space are focused purely on seizure reduction. You know, ultimately, you know, how do you characterize or fully characterize that in clinical development, or is that something that will happen down the road?
Yeah. So if you look into SCN2A and SCN8A gain of function, there are two populations who are doing this proof of concept for PRAX-562, that's reading out next quarter. There are mutations in sodium channels, right? Exactly where this drug primarily acts.
What was never done before is to get a drug that is clean enough, meaning no off-targets, very potent, very clear, targeting those channels that could remove those channels at one point in time from the available pool and get these kids, because this is an exclusive pediatric population to gain function back, should not be sedated all the time, should not be completely not necessarily, like, fully with us as I would call when they're being on treatment while delivering very good seizure reduction.
So when you're looking to modify the disease, there are multiple ways to modify a disease. I would argue that when you reduce seizure in a condition like this, and you extend life, because the more seizure, the more SUDEP, the more other complications, and patients actually die, that is already a modification, a ultimate modification of the disease. But there are other things: alertness, patients that can actually now look into their parents, that regain some motor skill, that can remove other medications.
And you're going to start to see this not only on this proof of concept study, that's our expectation, but primarily as the program continues to develop. So, stay tuned. We're incredibly excited to share. It was not designed as a powered efficacy study, right? I want to be incredibly clear on that. It was designed so we can actually power the next phase of this program, but we are incredibly optimistic that the data is going to be clear enough that's going to allow us to do that.
How do you see PRAX-562 fitting alongside PRAX-222, right? Which also targets SCN2A dysfunction in patients in that program. I mean, is it going to be one or the other, or are they targeting different subsets of that group?
Yeah, I think it's going to be not going to be one or the other. I think the, if I think five years from now, these drugs are likely going to be used together. I don't think that's unusual. Like, you are addressing slightly different ways. There's only so much can reduce the expression of a gene or increase an expression of a gene. But quite importantly, it's not a constant, right? Once you, once you are using the process through an ASO, a gene therapy, or so on. I think it would be absurd if I tell you: Oh, we're going to give this gene therapy for disease A, but we're going to remove steroids.
You know what disease A is. No one is making that proposal, right? We're talking about the same, the same thing here. We're giving a disease-modifying with PRAX-222, and we want to get to the point that it's optimal. So it might require, in certain case, something like PRAX-562, but PRAX-562 does not stop at 2A and 8A. There are many other exclusively pediatric disease that will play a role. So while we're starting here, we're not ending here, at all.
You know, for elsunersen, PRAX-222, or otherwise known as PRAX-222, what progress have you made in terms of working with regulators on designing a phase III? And I guess also going back to PRAX-562, how quickly could that be starting a pivotal study?
Yeah, well, maybe I'll go to the easier one here. So we want to flip very quickly 562 to a pivotal phase, so we're going to give that update as well in the coming months. For 222, we continue to dose a number of patients globally, so we're still learning a lot from them. We had quite positive engagement with different regulatory agencies, but one determination as a company we made is that we do want to get a general agreement among the major regulators here on a single pivotal study for the elsunersen.
And in order to do that, there is some conversation that is always required, some back and forth, and we're in the process right now moving as quickly as we can. I think the regulator has been great. There's a very clear understanding of the unmet needs. There's a very clear understanding of the activity of the molecule, but since it's a pivotal study that it requires, sometimes more than one interaction. So that's the process we're in.
Okay, well, I think we are unfortunately out of time. So with that, we will thank you, Marcio, and.