Good. Thank you everyone for joining us for the Praxis Fireside Chat here at the TD Cowen Healthcare Conference. I'm covering analyst Ritu Baral and joining us from Praxis, we have Marcio, I don't have you on here.
Am I unknown to you?
Apparently I would. Okay.
Yeah.
Come back. Come back, Marcio. We have to my right, Tim Kelly, CFO, and Marcio Souza, CEO, who I'm sure you guys all know. Let's start right away.
Let's start.
I know, right?
Yeah.
Thank you guys for doing the breakfast this morning. We were really able to get into some of the nitty-gritty, and we'll just keep riffing off of some of that. Let's start sort of higher level. It's gonna be a enormously busy year for you guys. We'll start with the main driver is Ulyxa for essential tremor. You have NDA submitted both for that and relumitragene. You filed, as we started off this morning at breakfast, you filed and will not be requesting priority review. You are anticipating for Ulyxa a standard review process. Can you remind us of the factors that guided this decision? You know, especially addressing keeping your relationship with FDA as strong as possible.
Yeah, absolutely. Appreciate everyone being here. Hope everything.
Mm-hmm.
The microphone is working. Is it working?
Yeah.
Yeah. Just popped on. Yeah.
Yeah.
Is it good now?
Yeah.
Perfect. The multiple factors, right? I think there's a major economic factor here that is definitely drove a lot of the decision to file earlier this year the NDA as standard review. Is the fact that we strongly believe with the markets being as large as it is for essential tremor, addressable at launch, over 2 million patients at peak, much larger than that it would eventually be subject to the IRA mandated negotiations and so on. That at that point in time, which is anywhere between, like, seven years for the negotiation, nine years for the full implementation, as we all know, it would be pretty close to the peak of the drug, if not at peak. Therefore, the impact of the negotiation will be the highest, one would have in terms of revenue.
By negotiation calendar is by calendar year of the approval. So an approval in December takes one year away from the negotiation, so it's very important for us to preserve that since we'll become pretty late in the year, so it's more economically viable to do it in the beginning of the year. I think the second that you touched upon, which is quite important as well, why we take a different view of what's happened on the FDA than most people out there, meaning a less dramatic view, right? We actually believe that for the most part, it's been pretty similar to how the agents operated before. In our specific case, has been, I'm gonna call peaceful, meaning as expected, several meetings, several discussions, two NDAs filed, as you just heard.
We are very cognizant about the reduction in the staff of the agency, particularly when you think about the Office of Neuroscience and the Division of Neurology I and II, there's a lot of applications, there's a lot of stuff under review. When you put the two and two together here, the fact that it economically make a lot of sense for us and then from the agency is just simpler, that was the choice we made to preserve peace on both ends of the spectrum.
Investor focus has obviously been on staffing at the FDA and meeting timelines. In your review team in particular and in the division, can you talk about turnover or any change in leadership?
Mm-hmm
And change in your-
Yeah
Main relationships?
The Ulyxa customize, we call Ulyxa internally, is on DN-1 . It's been always on DN-1 . The all the movements orders are on DN-1 . Since the end of phase II meeting was in June 2023 until today, there's no change in staff, which kind of importance. I wouldn't say it's as fundamental as a lot of people talk about, but it's quite important to have continuity. We had very recent interactions, meaning like December interactions, with them of outside of the regular interactions, like submitting the NDA, receiving the acknowledgement letter, and other things like formal meetings. It's good to see it's the same faces. As you probably know, at the pre-NDA meetings were kind of first time meet the entire review team, right?
It's a little bit of we don't know who are the review team.
Mm-hmm
Until that point.
Yeah.
I know a couple of people. It was good to see that was really everyone kind of we knew from previous interactions as well. Very good continuity on that. On the DN-2 sides, that is the epilepsy part of the business, there was one change last year. You probably know Billy Dunn left the agency. The good news I would say for us is that the replacement was actually the director of DN-1 .
Sorry. Billy Dunn is?
Paul Lee.
Oh, Paul Lee.
Yeah.
Okay. Yeah.
The is Emily Freilich , Dr. Freilich being on both. Now she's DN-1 and DN-2 , in a sense increase the interactions with the same person, with the same overall leadership, allow us to understand a little bit more what they're looking for, how they're operating. I would say for the most part, on any major requests, they met or exceeded the timelines getting back to us. From time to time, there was a few day delays, which I actually consider. I definitely do not submit all my expense reports on time. I understand when there are few like documents that don't get returned to us in, on time if they are not consequential, like things that can take a little bit more time. Nothing consequential has been delayed.
I don't know if it's luck or if it's really, the act of division, but I'll take either. Definitely our experience has been quite positive.
Your NDA submission included the standard titration schedule from Essential3. You also requested that the approval be for clinicians to maintain the 20-milligram dose for an extra week if tolerability issues were seen. This suggestion to hold that 20 milligram for an extra dose.
Correct.
Are there any other titration schedules that are alluded to in your req? Is this a labeling discussion, or is it like a material, a review issue?
Mm-hmm
For the mid label? Like, will you have clarity on this by the time of the mid-cycle review meeting?
Likely. Maybe it's important to reflect on the genesis of the discussion, right? When you give ulixacaltamide to a patient with essential tremor, seven out of 10 of those patients do really well during the titration from tolerability perspective. By week two, by day 14 is the first time that we assess their tremor impacted in their life, and they are basically at full efficacy at that point in time. If you look into the results we've shown publicly, you're gonna see more of that at AAN. Very fast, very effective, relatively safe, since we always call generally safe before a drug is approved, right? In the U.S. at least. For about 30% of them, the impact of dizziness can be problematic from tolerability perspective.
Some of them are discontinue the drug because of that. Not because they're not in the way or getting efficacy, but because of the tolerability. When we were with the agents, the discussion was kind of we like the fact that the vast majority of the patients have good tolerability and good efficacy. It would be ideal in a population that is completely underserved, right? Really nothing works here from a pharmacological treatment perspective to extend to its maximum the ability for our patients to response. The agents had suggested that we should think about it maybe for later in the future after approval to do something.
We have a fair bit of data from the phase II study, and for patients who didn't discontinue the treatment, that gives us the, I would say, knowledge, of course, impression on the case they have to review, that keeping the patients at 20 milligrams would actually resolve this for virtually all of them. We had this discussion with the agency. They said, "Well, if you believe that that would suffice for us to review, include in the submission, include the proposal in the label," which we did. We include in the submission, we include the proposal in the label, and we included a new titration pack-.
Mm-hmm
As an alternative form in case that happens. This is going from 70% of the addressable population at launch to like close to 90%, 100%, depends on how it gonna look. It's our joint objective as company and the FDA to try to help as many patients as possible here. Now, it's always a matter of review, right?
Mm-hmm.
To the last later part of your question. The agent's gonna review, they're gonna agree or not, we're gonna have a discussion or not, but, it's a fairly solid scientific proposal, and we'll be ready to support that.
The other thing, if I can just add quickly too, this was an issue of tolerability, not safety. I think that's a really, really important distinction in there. One of the things that you don't have a chance to do in a clinical trial setting is for a physician to interact with the patient, say, "This is what's typical of this drug. Here's how you're gonna feel. If you don't feel great, call me." That doesn't exist in a clinical trial setting, but it does in the real world. I think that's gonna also be part of our launch and our medical communication as well, that we're working with the physicians on how they can best administer ulixacaltamide also.
One of the things that we've discussed, with KOLs is the idea of the daytime dosing. Like the fact that-
Mm-hmm, mm-hmm.
The, in the trial, the protocol demanded daytime dosing. As we think about like dizziness and brain fog.
Yeah
Is nighttime dosing just something that patients and doctors can just do? Do you want it to be part of the label?
Yeah.
Can it be helpful?
It was done exceptionally in the clinical study and mostly for shift workers.
Right.
Since we actually, dictated, morning, as you said.
Mm-hmm
Or under approval of the sponsors. We did approve a bunch of those.
Mm-hmm
During the study. We do have actual data.
Mm-hmm
If that is the request from the agents. This is the kind of thing that physicians, as you're hearing, feel incredibly comfortable in making the choice themselves, even if it's not the exact recommendation that's accepted later.
Pre-launch activities. As we discussed this morning, they're well underway. What specific operational milestones need to be achieved over the next six to 12 months to ensure that you are fully ready for the Ulyxa launch? We talking disease awareness? Are we talking about endpoint, awareness, like the meaningfulness of the endpoints? Prescriber identification, you know, the index of suspicion about who your sales force is gonna target, and then obviously sales force hiring, build up, et cetera.
Yeah. If you take a shot.
Of course.
Mm-hmm.
I think the answer is yes.
All the things.
Exactly.
All the things.
We're very excited about the potential of the drug, but also there's a huge amount of work to go into...
Mm-hmm
Ensuring it's successful. I was an economics undergrad, I think in terms of supply and demand. On the demand side, we have talked a lot about how we identified over 200,000 patients with essential tremor interested in participating in the clinical trial over the 15 months when we were doing the recruiting. We wanna get that number up to be multiples of that by the time we get to launch. Things like disease awareness are the type of activity we can continue doing. We were very successful with a particular form of targeted advertising we wanna maintain and now really invest in quite a bit more, that by the time I launch, there's even more patients who are aware that there is a therapy for a disease.
DTC disease awareness in advance of the launch?
Yeah. We call it DSC, but yes.
Okay.
Yeah.
What is?
Like disease states, like education-
Okay. Got it.
And all the parts that's done right now. After AAN, d idn't mean to interrupt, Tim, and then you pick it up again.
Go for it.
After AAN next month, you're gonna see our DSC platform really taking off. Like AAN is like a divider.
Am I gonna get like the Instagram targeted?
Oh, you will.
Yeah. Yeah. I get all my coverage at any time.
Go ahead, Tim. Yeah, but you can see how important that is.
Mm-hmm.
What we found in the study is the average patient had the disease for 30 years. If you can imagine that that's now a lot of what people have accepted in their life, and to say that there's something coming, that's a really important activity for us to build up that demand. On the supply side, we've got the medical community, and it's not only the physicians who we need to ensure we're targeting and finding the right ones, educating them. That's why AAN is so important for us. We're starting with neurologists, and that's where they're all going to be. A hugely important meeting. We also need to work on ensuring that the pharmacies are ready, that the channel is ready, that we're preparing things like patient hub support. We're putting all of these things in place to ensure.
Will you do specialty pharmacy distribution? What's the parameter of the patient assist hub that you guys are thinking?
Yeah. We'll tag team this one. We'll probably talk about pricing in a moment. I think given where we're looking at pricing, that a specialty pharmaceutical or pharma channel does look appropriate for it. Then in terms of hub, we want to ensure that patients are not having any issues. If there is step through, we've conservatively assumed that all patients will need to step through for phenobarbital.
Mm-hmm.
We wanna be sure that that's streamlined. Any other issues they may have with prior authorization, we wanna be ready to go and proactive so that this is a very positive experience for them.
When you look into the scale of this launch, right? Imagine that literally nothing changed between now and the time of launch.
Mm-hmm
In a few months. About 1 million patients being seen by a neurologist every year in the U.S. for essential tremor prescriptions. Not treatments-
Mm-hmm
just you actually get prescription for something. It's about $1 million that was just seen. Nothing else. Markets don't stay static, ignore that for a minute. Take that 2 million patients that are like seeking treatment right now, apply whatever assumptions you want for the first quarter of launch. It's a large volume of patients, right? Wanna make sure they have the best possible experience getting ulixacaltamide. That's why Tim was just mentioning, we're gonna do, I'll say specialty pharmacy and hub support can be completely full white glove, like as you do in a.
Mm-hmm
Gene therapy for a rare disease.
Which you'll do for like-
Relutrogene.
Relutrogene.
it can be-
Yeah
A middle of the road, where you're actually taking all these barriers away, we're helping the office when they need, but it doesn't burden the system as much either. That's where we're picking right now, the design, and that is gonna facilitate the launch without creating an extra financial burden on us or in the system or on the physician that is prescribing. When you are testing this with providers in general, they think this is great, right? Facilitate dramatically how they're gonna get these patients in. It also gives us control of the experience, which is quite important on the first few months of launch. There is no neurologist in the country has one patient. This is not the kind of disease that it goes like, "Oh, I only have one patient." No.
They have 10, 20, 30, hundreds. Some of them have hundreds of ET they just seen. We want to make sure those first few patients are really going really well, so they can maximize the drug. When we ask physicians, we're having advisory boards, we're having a lot of research being done with them, because the data is so consistent amongst all the subgroups, a priority, they don't have a way to pick which patient would response. The conversation we're hearing back from physicians like, "Well, I will talk to all my patients about this drug," becomes even more important to have the proper parameters, education, when that is the kind of launch we're gonna have.
How should we think about this? like myself, I think, where's Athena? Athena, we're gonna be breaking out your 2027 quarters pretty shortly. as we think about out of the gates, how do you think about going broadly and doctors wanting and having a lot of patients to give it to, but also tightly controlling for a good experience so that the reputation of the drug is positive.
Yeah.
You filed in February, we're thinking standard review. How should we think about 2Q, 3Q, 4Q of 2027? Do you want to limit it or are you just going for it?
No. That, that's why we're putting a little bit of this. We're building expectation in a sense maybe more than we should around AAN, right?
Mm-hmm.
AAN is the first time, number one, the data is gonna be presented in a scientific audience, right? We have multiple presentations at AAN. AAN is the most important neurology meeting in the country, arguably in the world. Virtually every large practice or important neurologist in the country is attending. It's a really concerted efforts to get the first wave of knowledge of the data which exists in several thousand now, but not only 13 or so thousand neurologists that would be the target at launch. From that point on, there is a split. There is a lot of towards patients, and I would say reactivating patients, which we did quite exquisitely for the clinical study, so I think it's more a build on what we've done before. There's a lot of builds with the physicians, right?
For the MSL conversations, for leadership conversations, and just general education between the next quarter. You're going to turn to Q3 and Q4, then there's a lot more certainty on the timing of the approval, right? That's beyond or around mid-cycle call.
Mm-hmm. Yeah.
Like, we'll have an idea on. That's where the deployment becomes like full force towards really the kind of support is gonna be given, education. That's where the last payer discussions start happening as well.
The last payer discussions?
Absolutely.
Yeah.
Like there is a little bit of a misunderstanding. Most medical directors and payer systems don't even get you through the door if you don't have a PDUFA.
Right, right.
'Cause it's a waste of their time.
Sure, yeah.
Right? The, you'd have preliminary discussions right now, have reasonable discussions when.
Mm-hmm
The PDUFA is given, which is soon for us, but we really don't have discussions until they run their numbers.
Mm-hmm
On their claims, and then you can sit down and talk about impacts and everything else, which is.
You need a PDUFA rather than the label to start discussions?
Oh, yeah, we absolutely don't need the label to start discussions.
Okay
To launch the drug, we're gonna need the label.
Okay
In a sense, it's too late to have the conversations.
Mm-hmm
With most of those entities. Of course, after launch is full deployment, commercial campaign, then we're not talking about educating any more about the disease or a potential. We're talking about what is in the label-
Mm-hmm
What's consistent with the label since that's the current legal standards, is consistency with the label.
You mentioned pricing. Does that mean?
I couldn't change it.
what price is it? Yeah.
Yeah.
Give us the whack today.
Yeah.
Yeah.
There were still definitely a lot for us to be looking at.
Mm-hmm.
I think what we have been considering is, you're looking at a price that reflects the innovation of what this drug is, the great data that we saw, the safety that it brings as well. I think we have a good analog when we look at some of the tardive dyskinesia drugs who are-
Mm-hmm
Kind of at the low six digits. you know, we've got a lot of range if we wanna go that high. We definitely probably could. I think there's a place more in the midpoint to say as a starting point that gives us a place that, you know, a good place to start from. I think when we go into a future world with IRA, the way discounting is probably gonna be done.
Mm-hmm
It's better for us to start at a higher place where data can inform if we need to take any discounts rather than start low and expect annual inflation increases. Those days are probably waning. We look at a little bit more.
Mm-hmm
At that midpoint to start.
Thoughts on the size of the sales force?
When you deal with the preliminary sizing, you're gonna do like final sizing now.
Mm-hmm.
We just refreshed our. You asked the question before, we didn't properly address. Like, because these markets being, from a patient perspective, established for so long, but for drug, there's no drug, you can literally map patient to NPI, right? You know who has been seeing these patients for all the last-.
NPI is?
Like the identification number for any prescribing physician.
Oh, got you.
Like Charles there has one.
Mm-hmm.
Everyone here who is a prescribing, has their number by heart.
There's one right there.
Right? Yeah, that's what I call him 'cause he's a practicing neurologist. We can just go and run these numbers. These are public. Well, we buy them, and you can just see. We know who is being seeing these patients because we're now going through, as in other disease, we don't know, so we have to run these algorithms to extrapolate. Here's pretty simple. It's a one-to-one relationship, an ICD-10 to an NPI. We know the concentration. The number would say that we should stay around 200 or so to cover well, the country. We will go higher than that. It's a little unusual for companies to say they're gonna go higher at time of launch, but we're gonna go higher for multiple reasons.
One, there are few adjacent, like very large practices outside of neurology that need coverage. The two is we wouldn't want this launch to be limited by not being able to generate the demands on the prescriber perspective. We've seen multiple launches, particularly in neurology, where the company takes the opposite approach, right? We need 200, we'll start with 100, and then at quarter one, it's 125, and at quarter two, it's 200. You're always chasing-
Mm-hmm
The market versus actually right sizing for the success case. You should expect 300 or so-
Mm-hmm
That would cover well, the U.S. would cover well the incentives.
Are you gonna hire them earlier so you can deploy them for a disease awareness, or is this sort of like a conditional offer upon-Approval, the PDUFA date?
The beauty as well here is that we have some flexibility with both drugs.
Mm-hmm
Right?
Also your balance sheet.
Yeah, we're always very careful 'cause money is there until it's not. We have to continue being incredibly responsible. I think it's important to properly invest, at the same time, the more the certainty increase on the timing, it's not if, it's when for the approval of these drugs.
Mm-hmm
That we can deploy more and more, but it can be sequential. We don't have to do a one-size-fits-all here. You're gonna see a lot more people in the fields, the files, and then a few months before launch, it has to be fully deployed.
Okay.
You can't wait for the day, that you have a certainty to actually deploy. It's too late.
I do have to spend a few minutes on relumitragene because that one's gonna get approved first. With the priority review also filed, so that PDUFA is probably Q4. Are you currently building out the rare epilepsy sales force? We talked at AES about a separate targeting effort. Do you need to build disease awareness here? You know, how much do you have to address this issue of the utility of stacking sodium channel drugs?
Yeah
In this population? Because, like, you weren't supposed to be able to do it at all. Some people said it was gonna make it worse, and now it's making. Well, anyway, that thing.
Here we are, and we are wrong again in science, right?
That thing.
First time. It's not an issue whatsoever. I would say patients did really well in this study, both on safety and on efficacy. I think if anything, the community is incredibly excited about this. Very different dynamic that we're discussing on ET. Very different dynamic. There are two major drivers here. One is the number of centers differently from ET, very concentrated. About 10 centers in the U.S. are referral for this patient, so they're very well characterized. They don't see all the patients, but they definitely consult on a lot of those patients, a very good relationship with pretty much all of them.
That's all you need to target, those 10 centers?
That is not all we need to target. Definitely they are the ones that between now and mid-year, we spend most of the time.
Mm-hmm.
They have all, like, the understanding and the data, and most of them have already. It's just like complementing a little bit. The second wave is really the community neurologists that have been carrying on the day-to-day for these patients, right? Pediatric neurologists, particularly just connecting with them. There's also a smaller number. There's only a few thousand patients, like 5,000-10,000 patients addressable at time of launch here.
For the SCN2A-
2A and 8A.
AA. Yep.
The last one after that, patients who were born on the last 10 years, in the U.S., which are most of the addressable here, they all have gene, genetic diagnosis. You know, there is like sometimes people talk, oh, the identification has been pretty much solved in the U.S. right now, but the previous ones don't. Really getting that referral to make sure they get diagnosed, that the second wave of the launch is important that we start earlier as well. We know we are responsive to certain sodium channel blockers, so it's likely, but you haven't done a gene panel, it's important for that as well. We do see, when you, in this case, triangulate medical records, EMR, with other data that.
Mm-hmm
There are far more patients that don't have the final. We are not currently including them on the term, but we know they are there.
Sorry, the final genetic diagnosis?
Correct.
Okay. Got it.
For 2A and 8A. Yeah. Older ones. Most importantly, right, there's like we're running the EMBOLD study. It's going really well. That would expand the markets towards-
Mm-hmm
The larger gene.
By how much?
By 20-fold.
20-fold. That's gonna need expansion of the sales force at that point. Yeah.
Yes. Yeah. Absolutely.
Next data catalyst is POWER1 though, and that's for vormetragine for focal. That data is due Q2. Let's talk about expectations around what median seizure-
Median, yeah
Reduction rate you're going to show with top line and what your expectations for placebo are.
Yeah. If you look into the last 10 years or so of epilepsy drug developments, not the narrative, the actual data, it's been pretty stable, placebo. It varies anywhere between 0% and 20%. 20% is probably the most conservative someone should pick, and that's why we picked, that's what other picked as well, to calculate. I think that's a good point to start with a drug showing anywhere between, like, I would say double of that to as the lower end, to triple of that on the higher end. Anywhere between 20 and 40, and 60. 40 and 60. Sorry. I do know basic math. That would be reasonable here. We use 30% placebo-adjusted as the target, but nothing wrong.
I know others in this space been talking about their drugs that reading out soon, possibly being as low as 40. I don't think it's a problem, actually. I actually think. I agree that would be a good benchmark for them, and it's a good benchmark for us, but everyone is looking for the 50s as the go-to here. Very large markets, like over 2 million Americans with focal onset seizures, the majority of them by far having breakthrough seizures every year. Not a minority as some of the literature tends to refer to. In our very extensive research using electronic medical records, claims analysis, tokenized data, it's over 60% of the patients that have breakthrough seizures require medication change in a given year.
One, two, three, 10 drugs new in this space, they all do really well. This looks a lot more like the MS markets than the historical epilepsy market, where there is a space for several drugs, several modalities.
Mm-hmm
Several ways to do it. We just feel very excited about the new wave of epilepsy drugs in development, but particularly for vormetragine.
Great. Last question. I can't forget about elsunersen.
Yeah
Phase III.
Good yeah.
Is ongoing. How is enrollment going?
Good. You might recall that back last month, I guess, last quarter now, passed very quickly, the FDA suggested we remove the sham.
Mm-hmm.
It was originally sham controls. They strongly suggested to use that we remove. We actually strongly agree with them, and we removed the sham from that study, made an emergency amendment to the protocol so the patients could be switched, and it's going well. We also have a proof of concept study, I would say proof of concept plus reading out in Q2, which has nine additional patients on the sham controls cohorts that we've done. That would further, in our view, de-risk this opportunity for elsunersen, then between later in the year, beginning of next year, should have the results of the phase III. We'll be filing for another NDA, hopefully in the next 12 months as well.
Great. With that, we are over time. Thank you, Marcio.
Okay. Thank you.
Who wasn't supposed to be here. Thank you.