Awesome. Welcome, everyone. Today, I have the pleasure of introducing Marcio Souza, CEO of Praxis Precision Medicines. Welcome, Marcio.
Thank you so much for having us. Always fun.
Well, it's been really incredible. Last year at this conference, we had a big update on kind of regulatory plans for Ulixa and some progress you had made with the FDA. And I guess before we kinda get to the, the questions I sent you, wow! So much has happened in this one year. Can you just give us a little bit of an overview of, like, all the progress you've made over this past year?
I'll give it a try, and, and I appreciate it reminding me of that. Last year we were here, we mentioned that we had had the end of phase II meeting for ulixacaltamide hydrochloride. I think back then we would say PRAX-944, but, working very hard to say the actual INN for, for the drug now. And, we mentioned a couple key points there, right? So dose, selection, safety, design of the phase III studies.
Also mentioned that we took an extra step, that we asked the FDA, and they agree at that point in time to review the protocol, and we wanted to start the study after that was done, which we considered an important. It's not always necessary, but on that case, an important step, and that we were about to start this study in Q4 last year.
I believe, maybe more than believe, that most people, when we said we would start this study, would be well on their way at this point and with the readout by the end of the year, thought we were—we had lost our minds, in terms of starting and finishing a 600-patient study, 2 studies, but a total 600, on execution that is about 5 times which anyone ever done before, on this space. The issue with benchmarking with medians and means is that we lose sight of high performers, and we never do. So here we are, right, with a phenomenal enrollment campaign that's been very successful for ulixacaltamide. We're very happy on where we are. We're gonna read out by the end of the year.
That's been our commitment. That continue to be, our commitment for, for these patients, first and foremost, who really needs, better drugs, and obviously for all of us, right? For, for Praxis and Praxians, as we call ourselves, and for our, our shareholders and stakeholders at large. That has been, the largest part of the interest, lately. We do have three other programs in the clinic, as you, you know fairly well, and I'm sure we're gonna discuss each one of them. On the backdrop of all of this, all of them advanced, and a few more things advanced as well in the, in the meantime, so incredibly proud, first and foremost, of the team, at, at Praxis, and, and secondarily, right, just on the amazing, progress that we had and looking forward to much more.
Absolutely. That's it. It's been really amazing progress, and I'm happy you've gained a lot of appreciation this year. Beyond just, you know, being on track to read out in the second half of the year, what has kind of been having the demand you've had for enrollment or patients to have ulixacaltamide allowed you to do in terms of your enrollment? Have you been able to get more specific patients?
Yeah, like, appropriate patients for clinical studies should always be the ultimate goal here, right, for companies in clinical developments. So when you end up with the luxury that we have, which I consider a luxury, to have far more patients than we originally expected, interested in this study, not only patients who were interested, but patients who would likely qualify for this study, then you have to remind yourselves that there is a type of patient that we decide a priority, that would like to enroll on that study and then stay steadfast about that. And that's what we've been doing.
So the appropriate patient here, we know, has a certain severity, has a certain characteristic, and we designed in a way that wanted this cohort to be very similar to Essential 1 to our previous study. Multiple reasons for that. One is replication, right? We've seen something very clear in Essential 1 with using the same endpoints, using this moderate to severe patient population, and we believe that that gives us the highest chance of creating value for these patients and for society at large and our shareholders. So that's what we've been doing. So while it's great, right, we would be remiss not to mention the actual numbers. In our last public update, although this is a Reg FD call, I guess I could give you another update here.
We had over 50,000 patients that reached out to us since November. And when I mean reach out, it's a very intense pre-screening that we go through of those, while the vast majority of them would qualify to use an essential tremor drug commercially, just a fraction of them, over 7,000 would pre-qualify at face value to a study. Those are way bigger numbers than we expected, to be honest, last year when we planned this. So we're happy with that. So it turns into the way I've been describing this, and you let me know whether or not it resonates or if it's the correct way to think about it. You move from a science question, right?
Where it's like, what is the best patient population? How do I recruit them? How can you make sure that they are proper, they're gonna stay, they're gonna be compliant, to a little bit of an engineering problem right now. That is scheduling all these patients, collecting all the data we need from them before they get randomized. So I'm glad that at this point in time, we are on that engineering phase, that we really don't need more patients coming in. We're just progressing them throughout the different steps to get them randomized and obviously getting the result after 12 weeks of randomization. So it doesn't really change much, because we stay very focused on the kind of patients we need to show the results we're looking for.
Then in terms of the phase III study, obviously, it's much larger than Essential1 was, but kind of what are the main differences in terms of what you have for the primary endpoint and duration of treatment? And kind of what are some of the key de-risking data you've seen in the development program so far for success in phase III?
Yeah. Being first has great features and has a great responsibility as well that we learned from the past, right? So we are the first one here on a phase III, large phase III program in the essential tremor for pharmacological treatments. So when you look back to Essential1, the vast majority of the criteria we had and the features we had, we would like to keep the same, and that's what we did. So patient population, very similar, looking into the way we're dosing these patients, the way we're monitoring these patients, and so on. But there are a couple of things that as we should, we learned there. We used two scales to assess those patients. One could call two subscales of a larger scale, but one is the TETRAS ADL.
We end up using that scale because the FDA, in one of our interactions we had back then, strongly suggests that we pay more attention to that scale, and I'm very thankful that they did that, and they are absolutely correct on the recommendation. In another scale that's been done throughout the years to assess how patients are doing, whether or not they have essential tremor, what's really the general severity, and that's the performance subscale. What we learned on this study, and the endpoint was a composite of both of those. 11 items from the mADL scale, 2 items from the performance scale. When you isolated each one of those items, and you look into the performance scale items, outside of drug effects, I'm not talking here about drug effects. I'm talking about performance of the endpoints.
It was incredibly clear to the trained eye, to the untrained eye, it's just not an endpoint. It's a good assessment for a one time, for a clinical assessment, for people to feel comfortable on how that patient perform, but it's not stable. It's rather random throughout the different assessments. Very difficult to maintain. So from a clinical study, it's definitely not what should be used. We ran all that analysis on placebo data, not on the drug. We didn't wanna be biased by potential effects here. And then we went through historical data sets, and when you do the same, the answer is there as well. We're just bads as a society, as drug developers on assessing that endpoint. So we abandoned that.
We made the clear justification to the FDA, and we abandoned that. So de facto, the only change is removing those two items that shouldn't be there to begin with, and everything else is exactly the same. When you look into the effect size we're seeing on the endpoint we're using right now, there is no other modification, there is no subgroup analysis here. All of this is done on the same exact MITT population. The effect size is actually much bigger than we expect to see on Essential3 . And maybe I shouldn't say expect to see. We expect to see a very clear effect. What the trial is powered to see to demonstrate for Essential3 , there's a recruiting program.
We feel, we feel very good about all the steps we've done since you don't really need to believe on a lot, but just follow the science to attribute a very high probability of success for the upcoming readouts.
To that point, on some level, too, you've shown in placebo-controlled study and withdrawal study, which is two components of the Phase III, that ulixacaltamide works in ET.
Well, oh, yeah, we obviously fairly clearly believe this drug is active and is helping patients. We wouldn't be. I certainly wouldn't be here advocating or continuing this program if I thought otherwise. So we decided that the best way to inform an NDA or a generation of the evidence for effectiveness for the drug was to apply both a parallel group design, as we did before with Essential1. Also like how patients are treated with the design. The FDA and other agencies being for a while suggesting that more companies do studies that replicate how patients are gonna be taking a drug, and randomized withdrawal are great for certain drugs, not for all drugs, for this one, for certain. And so the second study is a stable responder randomized withdrawal for eight weeks.
Then patients are randomized to either stay on drug or go on placebo for 4 more weeks, and we assess the ones that maintain the effects. We ran 2 pilot studies with the same design. The results were overwhelmingly positive for those 2 studies, so obviously we have very high confidence here. When you first asked about the duration of these studies, I just realized that I haven't answered your question. The essential one was an 8-week study. When we talked to the agency, they strongly recommended we go to 12 weeks. We look into our data, what we had in terms of the transition to drug for patients who stayed beyond 8 weeks. It was very clear there was additional gain for patients on drug when that happened.
So we decided there was very little to no risk to extend. It gives us a little bit more safety data, and quite importantly, because we're not counting for that extra effects, it's indirectly increased the power of this study as well. So it was a win-win-
Absolutely
- in multiple places.
Now, so we're somewhat on the precipice of that data, maybe more towards the end of the year than now. But, say, it hits patients potentially have this new therapy, how meaningful would this be to the essential tremors market, and, how well served are these patients?
There are 7 million of us, and I mean us because I am certain some of us in this room have the condition walking in the United States right now with different degrees of essential tremor. A portion of that, around 2 million, have the condition deteriorating so much that they really need assistance in different ways. So let's call the term to be 2 million patients here. There is only one pharmacological treatments that is widely used or attempted to be used. That is propranolol. I think we all know as a beta blocker, but it's used here.
60% of the patients who start propranolol discontinue in the first 4 weeks, and only 50% of the patients can start because of concomitant conditions and comorbidities, and so on. So when you compound those numbers, you'd see that there's a lot of people who needs to be treated, there's a lot of people who wants to be treated, and there are very few who are treated. If that is not the very definition of unmet need, I'm not sure what it is. Then take our latest data points as a surrogate. We are. We're a small company. We work very hard, and we deploy resource really well, but we still have limited resource. We're able to mobilize over 50,000 patients in a matter of months.
And I challenge anyone to show me an example that that happened on a disease that there were marginal unmet needs. It's incredibly clear how big the unmet need is here, and I'm incredibly proud of our ability to actually help these patients, 'cause that's why we do what we do. That's absolutely why I do what I do, is to help them.
Well, that's, that's amazing and, anyways, we're really all excited to see that data. But, another thing that's really well appreciated about your company is that, it is diversified and that you are CNS focused, but you have a number of assets with very good data. Earlier this year, you presented some data on PRAX-628. So maybe, we could segue now from ulixacaltamide to that asset and kind of, what do you show in PPR?
Mm-hmm.
Why is that important for focal epilepsy?
Yeah. So the way and maybe for everyone to level set here, one could argue that a drug like 628, which is very clearly active on preclinical models, those preclinical models tends to be incredibly predictive of efficacy, that wouldn't need to have an intermediate study to go directly to a confirmatory or definitive efficacy study in focal onset seizures. We took the step to. Yep, that is absolutely valid. We applaud the people who did that, but would feel more comfortable if we had an additional data set here. This is pure comfort and capital allocation. It's the combination of both of them, scientific comfort and the allocation of capital. So last year, we decided to run this intermediate study in patients with epilepsy.
So there was an additional data there, PK, safety, and so on. It was seeing, very clearly what we wanted to see. What we wanted to see was very simple. Like, is this drug reducing the signal that happens, when there is an electrographic discharge on these patients, when you stimulate them with lights, with certain frequencies?... and can we reduce or remove that signal? That's because then the drugs in the brain is engaging, is doing something. Nothing more, nothing less. That was the objective from the beginning, because there is very clear evidence that when that's true, but everything else has to be true, the animal models, the therapeutic index, the safety, that those drugs end up being quite successful. And we've seen the results, like we talked about the results, earlier in the year.
We very clearly passed that bar to move forward, which gave us extra confidence to start late-stage studies, which we are starting later this year, the first one. We intend to read out that study next year and start the second study next year for focal onset seizures. It's a market that there is a renaissance, I would call.
Absolutely.
A lot of people interested there. It's pretty obvious why, there is virtually no one really controls. The general statistics, 30%-40% of patients are not controlled. I think what they miss when they quote that statistic is at any point in time, meaning the patient's not controlled today, and the ones not controlled tomorrow are not the same. So this market is really massive, and it's a fatal disease, right? The next seizure might be the last one.
Yeah
...that individual has, so it's very important to develop. So we're starting that. We're excited about all our programs, to your point, and we're creating more and more value as we continue to move these drugs forward.
Not only that, but you may have plans to move 628 forward in generalized epilepsy as well?
Yeah, absolutely. So 628 is a functionally selective drug, meaning it really works and show its beauty when those neurons are not behaving as they should, right? When they're misfiring, I would call. So obviously, focal onset seizure is a great place, generalized is a great place, and we are not considering, we are planning to be in generalized. So we haven't announced when we're starting that study because we don't have the firm date yet, but you can expect very soon that we're gonna announce when we're gonna start that study. But it does not stop there. The 628 is very potent, only have NaV 1.7 and NaV 1.8. I think we all know the link between NaV 1.7 and NaV 1.8 to other indications, primarily pain.
That might be something we explore in the near future. I think the market needs, and again, others are doing this and doing really well, but it needs drugs with the profile of 6, 2, 8s there as well, and other things in the future. So we continue to look. Discipline is our number one tenet here, so we're gonna continue to be incredibly disciplined. But yeah, it's going places for sure.
Awesome. And then I know we don't have too much more time, but, one of the programs I think is most underappreciated in your pipeline is, PRAX-562 and DEEs, and just your whole DE program in general. Why do you think 562 is particularly suited for SCN2A and SCN8A? And what are some expectations, we should have heading into the data for that program in the Q of next year?
Yeah, so next quarter, we have the readout, as you just said, for 562. One interesting way to look into the molecule. So patients with a very extreme case of developmental encephalopathy, I would call them more classical because they are really very extreme, the classical ones, especially SCN2A, SCN8A, a few others, KCNQ2, KCNT1, you name it. They really don't have an option from what is available right now. So the best you can do is to push the available drugs to toxic levels. They're still having seizures, they're still having significant comorbidities. You halt the development of these kids, partially because of the disease, but I strongly believe partially on why and how you're treating them. Those drugs are not exactly benign.
562 is the first disease-modifying drug ever developed for this condition, right? When we are looking to the actual dysfunction in the channel and considering how can we modulate that quite precisely, and what is the biggest link, the simplest link to measure? So precision modulation, we achieved that. The preclinical works are in our website, in the resource page. I encourage you to see it, completely eliminate seizures, restore wild type, on those genetic models. That was straightforward. That's very clear. But then the question that comes to us is, what happens when you give this to incredibly fragile kids? Those are not 25-year-olds. Those are not 50-year-olds. With all due respect to all of us on their brackets, definitely some closer to the 50 than to the 25 here.
Those are incredibly severe young kids. What happens when you give to them? Can you actually bring them closer to the true disease modification, which it is? Remove everything else that doesn't matter, that is only impairing these drugs, control their seizures to the maximum we can do, and allow the, the person who is inside the kids, who could not manifest themselves, to start manifesting themselves. And we are incredibly confident that we're gonna start to see this next quarter, and you're gonna see even more of that as 562 continues to develop. So, I agree with you. We don't talk enough about it, and, and it's a, it's an incredible drug that is already making, meaningful changes on these patients' lives, and it's gonna make even more.
Excellent. And then maybe just lastly, your company is very well capitalized. What are you gonna do with all this capital?
Number one, pretend it's not there. And I'm not even joking. Tim is right there, and we're great partners in crime on this. It's very tempting when you have more capital than you look like you need, that you just start, like, using in places you shouldn't, right? We're again proud of being disciplined. We have four programs in the clinic. We have three programs about to be declared preclinically. Each one of them have to pass very stringent bars to continue to move forward. We have a very small structure. Maybe I shouldn't say small. We have a right-sized structure, about 80 or so people in the company. Every single one that joins have to go through this filter of really caring about this and being very competent.
We're not gonna overgrow. I'm a strong believer that overgrow is worse than undergrow. We're gonna develop all these drugs to the next value creation. Of course, I expect that all of them are gonna go through, but if one doesn't, we're gonna be definitive as we were before. We're gonna preserve those resources, and we're gonna be very respectful to the money that is not ours. It's our shareholders', and we take great care of-