All right, perfect. Welcome, everyone. I'm Tiago Fauth. I'm a biotech analyst at Wells Fargo, joined today by PTC Therapeutics for a fireside chat. I appreciate you guys making this trip. Overall, I'd like to start with just broad remarks. What's on tap still for 2024? We got some updates yesterday. Can you kinda give us, give us a recap, and then we'll work through some of the main topics?
Yeah, sounds good, Tiago, and thank you so much. It's great to be here. For those of you who don't know PTC, we're a global, biopharmaceutical company. We discover, develop, and commercialize innovative therapies for patients with rare disease. So far, 2024 has been a very successful year, a very exciting year for us. We continue to have strong revenue performance. We recently raised our revenue guidance for the year to $700 million-$750 million. Closed the second quarter with $1.09 billion in the bank, so we remain in a very strong cash position.
We've already submitted three approval applications to the FDA this year, one for our gene therapy for AADC deficiency, where we recently completed a late-cycle meeting with FDA, and that was a very successful meeting, and we're on track for FDA action date of November 13th. That would be very exciting for both the approval of the gene therapy. It's also PRV eligible. We submitted our NDA for sepiapterin, for PKU, for the treatment of PKU. This is a very exciting program, a very strong data set.
Really positions sepiapterin to be the standard of care for PKU, and we've talked about this easily being a billion-dollar-plus revenue opportunity. We resubmitted the NDA for Translarna. We gave a brief update yesterday that FDA has just asked us to modify one of the clinical study reports, and we'll get that right back into FDA in short order and look forward to bringing Translarna to patients in the U.S. We remain on schedule for submission of an NDA for vatiquinone for the treatment of Friedreich ataxia by the end of the year.
We also recently, early in the summer, read out interim data from our PTC-518 Huntington's disease study, with really strong data showing continued safety, durability of biomarker effect, and early signal of clinical benefit. Combination of data positioning PTC-518 now as the leading therapy in development for Huntington's disease. In the fourth quarter, we look forward to reporting top-line results from our registration-directed trial of utreloxastat for the treatment of ALS. A lot going on.
A lot going on, yeah.
We're executing, firing on all cylinders, and having a really strong performance this year.
Oh, perfect, and thanks very much. I do wanna spend most of our time on the pipeline, but I guess given investor inbounds, let's spend some time on Translarna real quick. Again, it sounds like, at least for the U.S. submission, the additional request seems fairly minimal and not really material in the sense of data generation or anything like that.
Right.
It's fairly low-key and probably easy to address. Is that fair?
Exactly, exactly right. This is about presentation of data, not about the data itself. We, we had agreed with the agency that the review for efficacy and for approval in the U.S. would be based on the overall study population, the ITT population of Study 41, with some additional analyses that they asked us to perform, as well as the long-term data from STRIDE.
We provided all that in, in the data package to them. They've asked us to just widen the scope of the clinical study report from Study 41 to also include the other analyses that were part of the protocol, that were not the ones that would be the focus of the review. For us, this is a matter of just rerunning some tables.
Paperwork.
Paperwork and report, QA, QC, and getting it right back into them, which we can easily do in the next few weeks.
Perfect. And again, that's... Historically, there haven't been a lot of expectations on US, so, interesting that at least you have a pretty clear path for submission. Let's pivot to Europe, 'cause again, there's still some debate there. I guess the main question, and I'm not sure you have a clear answer for that, but how much back and forth will there be between CHMP and the EC? Like, what are the exact timelines, I guess? 'Cause investors are just curious of when we might get a final resolution for the topic.
Yeah.
I'm not sure we have an answer for that right now, but can you disentangle the debate for us?
Yeah, absolutely. Look, it's, it's always challenging to have clarity when you're living in a situation that's not, that's unprecedented, right? Having the, the EC turn back a CHMP opinion. We're right now in what's known as the reexamination period from CHMP. That's a 120-day period, basically started in the beginning of July, after the most recent opinion. We expect reexamination will be carried through, probably the October CHMP meeting, where could be a little bit later, 'cause it's up to 120 days. There'll be an opinion then from the CHMP.
At that point in time, that will then go to the European Commission to either adopt or not adopt that opinion. It's unclear what interactions they're having. You know, the history here, I think everyone's aware of. The European Commission had sent it back to the CHMP, asking them to pay attention very particularly to the long-term STRIDE registry data.
An expert panel was convened in June, who agreed that we had very well addressed the concerns that had been raised regarding STRIDE, and they stated that the STRIDE data provides strong evidence of efficacy that, quote, "should not be ignored." Nonetheless, the CHMP maintained a negative opinion, so unclear what happens from here. We do know that the CHMP is expecting to elect a new chair in September. We will get new rapporteurs for this procedure. We, of course, remain open to discussions if they become available on how we can have a path forward to keep the drug on the market.
You know, for us, as we've said, we were expecting the withdrawal to have occurred in the first quarter. This is all in months of upside revenue for us and the ability to keep kids on the drug, and obviously, we'll continue to make sure that we have that drug available for as long as possible in Europe.
Yeah, no, that makes sense. And just to wrap up the debate, any noteworthy expected interactions with other agencies in other countries? Like Brazil, what's the status there? Any other regions that could be at risk among the whole debate within the EMA?
We've seen quite consistently that other countries are basically maintaining their independence and doing their own review. Brazil has come up, because just coincidentally, really, the Brazil authorization was up for renewal. It was initially authorized, Translarna was initially authorized in Brazil in April of 2019, and five years later, that expired, so they began their review, and this is still reviewing the dossier.
We've shared that we received a group purchase order from Brazil, government order from Brazil in June and a second one in July, so we take that as good signal that the government is still ordering and paying for the drug. So that, you know, that we think is, again, a good sign on the future of Translarna in Brazil, and we know that Anvisa is intent on doing an independent review with their own KOLs and their own assessment of the data.
Perfect. So let's wrap up that part of the debate and let's focus a little bit more on the pipeline then. PKU, so again, still some skepticism overall on the market opportunity, but let's start by what's the status, both ex U.S. and U.S. from a regulatory perspective, what are some of the next updates we're gonna get in terms of action and, and useful?
Yep. Moving forward, we're getting ready for our global launch. We submitted the NDA at the end of July, so we expect to hear towards the end of September regarding NDA acceptance and also priority review, which we requested. That would, of course, put us in a position with priority review to have approval in the U.S., potentially in March, so 2025. That's really coming quite soon, which is great. In Europe, the MAA was submitted in March.
It was validated in May, and we're right now just going through the CHMP review process, and all is going well there. We submitted the MAA to Anvisa this past week. That's a good step forward, and we expect to submit the NDA in Japan by the end of the year.
Got it. Okay. It sounds like by the middle of next year, we're gonna get a lot of clarity on where you stand across the board. Let's talk about the market dynamics, and perhaps it's a little interesting that for a few physicians or for a few investors, there's still a lot of questions on differentiation mechanistically versus Kuvan, right? What's the case there, and what's the actual clinical evidence to suggest that there is true differentiation between the molecules?
It's a good question because I do think for some people, the market opportunity here is misunderstood. There's an assumption that we're coming in behind another therapy, and therefore, there'll be competition for the market, when the reality is that the vast majority of patients are not on current therapies. It's estimated that as few as 10% of patients are on current therapies. That leaves 90% of, you know, 20,000 or so patients in the United States and 58,000 in the markets that we intend to pursue.
It's a very large opportunity, especially when you consider the data package we've generated so far with sepiapterin and a data package that supports becoming the standard of care, delivering not only meaningful reductions in phenylalanine, but incredibly important, is allowing patients to liberalize their diet. I think what... Another thing that's not very well understood is how difficult it is for patients to adhere to a diet of very little protein. I mean, they may only be able to have, you know, one egg a day, and the rest of their diet is supplements of amino acids that taste horrible, not well-tolerated.
To be able to have a therapy that can allow kids and adults to start taking regular diet would be incredibly valuable. What we're seeing in our long-term extension study is that we have 60% of the patients are tolerating levels of protein that would be recommended for you and I, and still having within-range phenylalanine levels. That, that's transformational. We're seeing things on social media of, you know, kids eating a hamburger, you know, hashtag sepiapterin, and saying, like, "I've never been able to have a hamburger before and still have phenylalanine under control."
This is transformational for patients, and this is why there's so much excitement, so much pull from the patients and the physicians for this drug. To answer your question about mechanistic differentiation, it's pretty simple, actually. Kuvan or BH4 is basically the cofactor for the enzyme that is broken in PKU, the enzyme known as phenylalanine hydroxylase. The idea behind Kuvan was if we give the cofactor for the broken enzyme, we can get more function out of it and therefore reduce phenylalanine levels. That's a very well-established approach to metabolic disease.
The challenge is that, Kuvan is when you ingest it, when you take it, it gets oxidized, and then most of it gets excreted. That which isn't excreted and gets absorbed, gets to the cell, but doesn't get into the cell very well. Yes, you have this ability to provide a cofactor that can increase enzyme function. It's just a lot of it isn't getting there. What you see clinically is exactly what you'd expect. Yes, you're having some small effect for patients, mostly in patients who have a lot of healthy enzymes, so less severe patients.
When you challenge patients on Kuvan with more protein in a diet, it's not always allowing them to liberalize the diet. That's the challenge. Sepiapterin is different. epiapterin is a precursor to that cofactor. It's readily absorbed from the gut, and it's actively transported into the cell. Once it gets into the cell, it has two distinct functions. First, it's able to—it's converted into the cofactor BH4. Right then and there, you're in a situation where you're having much more cofactor available for the enzyme. It's just a much more bioavailable cofactor approach.
Second, it has an independent chaperone effect. What a chaperone effect is, is it's able to attach to the enzyme, stabilize it, help improve its shape so that it functions better. What you see with sepiapterin is exactly what you'd expect if you had a more bioavailable therapy that had an added mechanism of action. That is a greater response in terms of lowering phenylalanine, a greater ability to drive enzyme function, even in the more severe cases like classical PKU.
When you challenge patients with more protein in their diet, they can deal with it because you're providing a therapy that's allowing the enzyme to function even with more protein being presented. From a mechanistic standpoint, it's perfectly rational why we're seeing what we're seeing from an efficacy standpoint with, you know, in the phase III trial with classical PKU patients, the more severe patients having an average reduction of 69% in phenylalanine.
The overall population, we had 84% of patients come within control, with target levels for control of phenylalanine below 360 micromolar per liter. We had 22% of patients have normalization of phenylalanine levels, which is something you really don't see in clinical trials. I already mentioned the data that we're seeing in the long-term, open-label extension, where we're seeing patients be able to liberalize their diet and still have phenylalanine in control.
All of these factors together really allow us to have the potential to become the standard of care and provide an effective therapy for the majority of PKU patients. Now when you zoom back out and talk about that population of patients who are not on therapy at all or are not well-served by current available therapies, you start saying, well, math becomes quite simple to why this could become a billion-dollar opportunity, perhaps even in the United States itself.
No, that makes sense. I guess, let me push back a little bit on that, so we can get a better understanding of the market. I guess, once markets with relatively low rates of treatment are generally associated with lower severity of disease, let's say, right? Let's say, based on your numbers, 10% of patients are actually on therapy, there's 90% that are not, and the assumption is they don't have to be.
Therefore, having a better drug may not necessarily grow the market as much. What is the misconception on assuming that, and how to break down currently patients that use Palynziq, patients that use Kuvan, and where sepiapterin is going to actually fill in that need?
Yeah. Good question. I think this, again, goes to some misunderstandings of this marketplace. First, let me just also frame that being, we're coming into a disease where all the pillars for successful commercialization are already there, right? There's newborn screening, so all the patients are identified. There's centers of excellence identified in the United States. Patients are associated with these centers, so even if they're not on therapy, they still are tied to these centers for diet management, which has been their—that's really the standard of care now is diet management.
The third is, it's a very well-aggregated patient and physician community, and the fourth is payers understand the disease. You're coming into a preset, optimized commercial landscape. Now, to your question, if only 10% are on therapy, what about the other 90%? They're living with a choice every day. They're either having highly restrictive diets where they can't have, you know, maybe five or six grams of protein a day, you know, an egg a day, along with horribly tasting and expensive medical foods. That's their life. This is the life of a kid who has to go to school and not eat lunch like all the other kids do.
Can't go to a birthday party and have cake and pizza, or make the choice that you're going to do those things, have horrible brain fog, cognitive impairment, and a whole host of other problems. This is not like a lifestyle drug. This is a horribly debilitating disease for patients, and if they're not on... And the reason they're not on a therapy is because the therapy is not changing the morbidity of the disease.
It's not like, okay, you know, 10% are on a, or a small percentage are on a drug, and the rest are just okay, and life's okay. No, life is miserable, and the reason they exist with this miserable diet is because the therapy hasn't allowed them to get off it. All right? Why would you take a therapy if it's not allowing you to change that part of that's so debilitating? That's why there's such promise for sepiapterin. Now, you talked about the market segments, and we view it in, you know, there being really three main segments.
Those who are therapy naive, who never tried a therapy, and those tend to be patients who are more severe, whose physicians or who patients believe there was not gonna be no benefit to be derived from current available therapies. Those that have tried therapies are either failed or suboptimally treated... and a third of those who are currently on therapies. You know, when we started, we thought that the first kind of low-hanging fruit would be the patients who are therapy naive, who are waiting, and their physicians know who they are.
We're in touch with the KOLs and the specialty centers, and they've got lists of patients who they think could be eligible for the drug. That's a market segment we'll go for right away. What we've also heard from physicians is that they're also interested in switching patients on existing therapies. You know, some of the data we have confirms, again, what one would suspect with a more bioavailable and potent cofactor approach, which is patients that who've been on Kuvan previously or BH4 previously, have a much greater response to sepiapterin.
We saw that in, in the AFFINITY trial, where we had 29 patients who came into the study on BH4. They got washed out and then put on sepiapterin, and they had a 48% greater reduction in phenylalanine levels, with a mean phenylalanine level below 360. That means under control. So those data really confirm, this idea that we could provide greater benefit to those on therapy, and the physicians are aware of that.
We had a KOL speak last year on a deep dive on the PKU opportunity, Anja Muntau, who's one of the leading KOLs in the world, and she basically said, "Look, I'm trying all my patients on this drug as soon as possible from each of those segments." Again, when you put all of this together, it's why we believe, first of all, that those not on therapy are imminently accessible.
They're diagnosed, they're tied to centers. We know who the centers are. We know who the prescribers are. We know... We know all that information. They're wanting a therapy that can improve their quality of life, allow them to liberalize their diet, and that's, I think, a lot of reasons why we could easily push back on the pushback as well.
There you go. And I guess you already partially answered the next question, but it's just related to, given availability of generic Kuvan, like, even though the product profile might be differentiated in some features, what should be expectations in terms of payer management, reimbursement, access? Again, that's an additional concern that we usually hear from investors, and I don't know what kind of work you've done so far to de-risk that part of the commercial launch.
We've done a lot of that work already, and, you know, to be clear, a generic version of a therapy that's not broadly adopted and that we're, you know, it doesn't—we're still more effective than generic. The other thing here that's really important to note is that even if a step at is required, in PKU, it's several days of therapy, a blood test, and you could document responsiveness or not.
Yeah.
It is much... I mean, we have the team, you know, our teams are, are ready and to go. We have the commercial infrastructure set. There's no building we have to do. We have in the U.S., you know, our team that's been commercializing Emflaza. I think their, their quality and their performance is well documented in how well we've been able to maintain Emflaza revenues in, in, in a generic world now. Also, this is a team that's used to trying to have to step through prednisone and DMD, where it could take months to prove, you know, PKU is a few days.
Yeah.
We don't see that as a problem at all. In fact, that's also why we thought that patients, that segment of patients who failed previous therapies would also be a more easily accessible initial segment because there's already documentation that they were not well addressed from the available therapies.
Perfect. No, that makes sense and sounds like that's gonna be the big driver in 2025. Let’s move to Huntington's, AS. Again, so far, in our opinion or been on print, saying that feels like this is the best asset to test the therapeutic hypothesis of mutant huntingtin lowering, leading to clinical benefit. There's still a lot of skepticism from investors overall, despite the differences relative to all the tents, like, you haven't really seen any of the safety concerns we've seen in the past. From your investor feedback and just interactions with KOLs, what's the mismatch between exci tement around this program?
Yeah, I think Huntington's disease traditionally has been a very challenging disease to tackle. That's why there are no approved disease-modifying therapies for Huntington's disease. That's also the opportunity, of course. When you think about neurodegenerative diseases, Huntington's disease is unique because we know what causes it. It's a monogenic disease that's a mutation in a huntingtin protein, leading to a huntingtin gene, leading to a mutant huntingtin protein that's toxic.
That's the cause of the disease in every patient. We don't have that in other neurodegenerative diseases. We're not sure what causes it in the majority of patients. One, we know what causes it, and two, we can attack that, and we're leveraging splicing to do that. We've talked a lot about how the PTC518 program follows on the heels of the successful discovery and development of risdiplam for SMA.
Okay.
That's really important. That taught us how to design and develop an oral small molecule that is highly selective, highly specific for the target, in this case, huntingtin gene or the huntingtin pre-mRNA, and also have the important qualities to ensure broad bioavailability to the brain. Huntington's disease is a whole brain disease.
Yes, at certain times of the disease, the striatum may be more important, but it's the whole brain over the course of the disease. If you're gonna successfully tackle the disease, you really want to have a therapy that is going to get to every single region of the brain and have effect there. As you said, Tiago, correctly, this is the therapy to test the huntingtin lowering hypothesis.
Yeah.
You know it, you know it works. By the way, we can tell it's working because we can take a blood test and show the pharmacodynamic effect. We can establish PK/PD relationship in blood cells. That's so important. We know exactly what we're doing with lowering. We can then measure brain fluid and say, "Yes, it's getting to the brain." We're actually getting higher exposure in the central nervous system than the blood. We have a drug that we know is doing what it's supposed to do.
It's getting where it's supposed to go, and what we're seeing now in the data and what we showed in June is we're seeing the effects that we need to see. We're seeing durable Huntington lowering. We're seeing dose-dependent lowering of Huntington, the CSF. In thirty patients in twelve months, we're seeing dose-dependent effects on clinical measures. That's as good as you can get. And on top of that, the safety profile, which is incredibly important. We have no treatment-related NfL spikes observed, and we're seeing safety and tolerability thus far.
All of the key components are there, and we've talked now about next steps being starting those discussions with FDA about the potential for accelerated approval based on Huntington lowering. We're in the process of requesting the special type C surrogate endpoint meeting with the agency and providing the dossier that supports why lowering Huntington disease, Huntington protein is likely to provide clinical benefit. There's a strong scientific literature supporting that. There's also just basic scientific logic, that this is the protein causing the disease.
Lowering it is probably a good thing, and it's applicable to all patients. You know, we're incredibly excited about the data we have so far. We're very interested in seeing if we can align with the agency on a surrogate endpoint that could put us in a position that when, you know, PIVOT-HD reads out its entirety next spring, we could be in a position to look towards an accelerated approval application.
Got it. I do wanna talk a little bit more about that, but if that doesn't turn out to be the case, what is the alternative regulatory path for the program, and what does that imply in terms of additional trials, timelines? And again, the risk there is always how can you power the trial? How can you be confident you can hit on some of the functional endpoints? What's the backup plan?
Yeah. We've started that too. We're doing this in parallel. We're pursuing the discussions around accelerated approval, and we're working to align with the agency on the endpoint strategy for an efficacy trial. Whether that efficacy trial is done as a confirmatory trial in the context of an accelerated approval, or whether that efficacy trial is done as a phase three registrational trial.
We're also now requesting a Type C meeting with the agency to talk about endpoint strategy with a proposal where we can have an endpoint that we can sufficiently power in a reasonable duration of the study, demonstrate that clinical efficacy that would be needed to support an approval in the context of a standard pathway.
Got it. And thinking about news flow, there are a couple of different things here. The first one is gonna be just when we're gonna hear about accelerated approval. I'm assuming you're probably gonna wait for formal minutes of whenever you get the meeting. Also, just additional data for the program. You haven't been enrolling additional stage two, stage three patients.
Yep.
What, what's the news flow?
Yep. We plan to have those two meetings with FDA regarding surrogate endpoint and regarding an efficacy endpoint in the fourth quarter. As always, once we have clarity, whether that's at the meeting or after the meeting—
Mm-hmm.
We'll share with people. I think we would... You know, we define success for that surrogate endpoint meeting as getting the FDA's alignment, that this is a possible surrogate endpoint. And that would be success there. That is Q4, those meetings. We have said already that the last patient, last visit for PIVOT-HD, when all 140 patients are across the 1 2 month time point, will be in March of 2025. We then expect to share data in the second quarter of 2025.
Got it. Again, if you get an accelerated approval alignment with FDA, that puts you in a place to potentially submit registrational package in the second half of 2025. That's there, the back of the envelope math.
Yeah, we haven't provided, we haven't formally guided to that, but that's how the math would look like. We would expect that the data from PIVOT-HD could stand.
Got it.
Obviously, that's an incredibly exciting opportunity in the not so distant future.
Of course. Yeah, no, and again, we're gonna talk about your capital position and allocation, but it seems like even a phase three in this indication is not gonna be necessarily overly strenuous on the balance sheet or timelines, right?
You know, and we built for that.
Yeah.
I think we, we've talked a lot about having the infrastructure to run a global trial for HD, and ultimately to commercialize HD with our global commercial infrastructure and experience. As I mentioned in the opening remarks, we closed Q2 with $1.09 billion in the bank.
We're in a very strong cash position, and we said we did a lot of things last year in terms of right-sizing the company, reducing OpEx, using a royalty monetization to get some very costly debt off the balance sheet to give us cash and flexibility, both of which we have now. We're in a cash position where we can move HD forward, get PKU launched, which I mentioned already, is really no incremental cost to us-
Mm-hmm
... since we have the commercial infrastructure, and start moving towards cash flow break even. We've talked about that being the goal. We've talked about how PKU alone can get us to cash flow break even. It'll take a little longer if it's just PKU, and if we get FA through or Translarna in the US through, that would move that date forward and get to-
Yeah
- cash flow break even a lot sooner.
Got it. Perfect. Now, that makes a lot of sense. Unless you minute, just I wanna talk a little bit about FA, but also about ALS. Maybe let's start with FA, 'cause again, that feels like it's more of getting visibility on the regulatory path, and if the additional analysis from the data generated so far is enough to support approval, what, what's the case that you're making? When can you get visibility on a formal interaction with FDA around submission?
We had very productive discussions with the agency and in our most recent discussions that we had earlier this year, they were aligned that we could have a submission based on the placebo-controlled data from MOVE FA. A lot of that is around the importance of upright stability. Upright stability is one of the four components of the disease rating scale, and it is the component of the disease rating scale that is most sensitive and most relevant to pediatric and young adult ambulatory patients, which was the primary analysis population of MOVE FA.
What was not—that fact was not known at the time that we designed the trial, but it's something that has become quite clear from several studies over the past couple of years, including, interestingly, a study funded by the FDA. The FDA funded a study that looked at Friedreich's ataxia in pediatric patients. It's called the FA Child Study, and the results of that study were just recently published and showed again that upright stability, if you're gonna want to understand disease progression and therapeutic effect in those younger ambulatory patients, you need to look to upright stability.
Then when you look at our data, that confirms that, because if you look at the placebo group, at the four sections of the mFARS, it's flatline on the other three sections. You only see progression on upright stability. That tells you the only way you're gonna register a disease, effect on disease progression is on upright stability. Having that discussion with the agency and bringing their own funded data to them as well, I think they got very comfortable with the fact that we had the statistically significant effect in upright stability is persuasive.
When you look at that effect in upright stability, along with a corroborative effect on the walk test and fatigue scale, it puts together a story that we have persuasive evidence of efficacy on MOVE FA. That was part one of the NDA. Part two of the NDA, or the other component of the NDA, is the confirmatory evidence, and we agreed with the agency that we would provide three pieces of confirmatory evidence.
First would be a set of mechanistic studies that confirm that vatiquinone is having a relevant effect on, markers of ferroptosis that are both confirmatory of the mechanism action of the disease and also referable to the disease itself, to disease pathology. Second, we had a previous placebo-controlled study that was done years ago in adults, and we have 24 months of treatment data that we're gonna compare to a natural history comparator group from the robust Friedreich ataxia natural history study. The third would be a comparison of long-term data from MOVE FA against a natural history comparator.
We have aligned with them that that would be a package that they would review. I think that's very, you know, it's a great place to be. The plan now is to complete those long-term analyses. We had to submit analysis plans to the FDA to get their agreement, run those. We'll have a pre-NDA meeting in the fall just to align on the contents of the package in terms of specifically how do we pool safety from a whole bunch of different studies, how do we pool efficacy.
Yeah.
-and a few other things, and we remain on target for submission by the end of the year.
And you partially addressed that, the question already, but I guess the pushback would always be, Skyclarys is, again, kind of a contentious submission on itself for other reasons, but again, they showed a benefit on that as far as you're using a subset. The answer is basically just a different kind of population that were enrolled across different values.
Yeah.
Is that the main difference here for that question?
Yeah, look... Actually, if you look at the mFARS data from Skyclarys, their effect was driven on one component also, upper limb.
Yeah.
Which is the part of mFARS that is relevant in older patients assembly.
Makes sense.
In fact, it's different populations. I'm very excited about being able to have a label based on preservation of ambulatory function. That's relevant to all ambulatory FA patients. We, of course, also have data from the older study, that long-term open label data I mentioned. Again, we show what Skyclarys shows, which is effect being driven by upper limb. Again, adult populations.
Got it. Okay. All right. I think that's a fair distinction that is sometimes lost in the minutiae. We have just a few seconds left.
Okay.
I guess I'll keep it very brief for ALS specifically. Again, most programs fail, probably the success, super low. The corollary to that is the bar for clinical meaningfulness is also on the ground. So why, why should an investor assign any credit at all for ALS?
It's a, it's a tough field. What we've talked about is we have a mechanism of action targeting ferroptosis, just simply Google ferroptosis and ALS. This is well understood to be an important pathway. We have preclinical data that shows we, we move markers of, of ferroptosis. We've benchmarked it to edaravone, which has a similar, it not similar, but also looks at oxidative stress, and we have 25x-80x the potency. And we know we have biodistribution to the brain. All those boxes are checked. We have a study design that is well-established, so we're using a well-established study design.
Anything that we could have done at this point to have confidence, we have. Obviously, this is still the first in disease trial, so it's a phase two trial. We're just in a unique position that if it's positive, it's registrational, as you said. I think there's a lot of things that give us confidence, but of course, ALS is tough. We got that. But, you know, I think we look forward to that data set and being able to potentially make an impact in a disease where an effective therapy is really needed.
Perfect. No, I think we covered a lot of ground, so yeah, we can leave it at that. Thank you so much again for joining us at conference.
Thank you.
Appreciate it.
Thank you.