Okay. Welcome to this fireside chat with PTC Therapeutics. I'm Joe Schwartz from the Biopharma Equity Research Team at Leerink Partners, and it's my pleasure to be joined by Matthew Klein, CEO, Pierre Gravier, CFO, and Kylie O'Keefe, Chief Commercial Officer. Thanks so much for joining us at such an exciting time for the company. Perhaps you can start us off, Matt, by laying out the company's key priorities now and what main catalysts we should look out for over the balance of the year.
Terrific, Joe. Thanks for having us. We're excited to be here and share this update. 2023 for PTC was really a year where we made a number of important decisions and changes, including leadership changes, focusing our R&D activities, as well as significantly strengthening our balance sheet, all to provide us with a strong foundation for 2024 and beyond. And as we move into 2024 with a clear strategy, strong balance sheet, we look forward to a number of important catalysts. First, it will be the initiation of our global regulatory submissions for our PKU program. We've talked a lot about Sepiapterin and how this represents clearly a billion-dollar-plus potential revenue opportunity for us, and we'll be submitting the European Marketing Authorization this month and expect to submit our NDA to the FDA no later than the third quarter and possibly the second quarter. So incredibly excited about that, and we have a number of other global submissions at the ready.
We also will be submitting a BLA for our Upstaza AADC gene therapy program this month. We are going to be submitting an NDA for our Friedreich ataxia program before the end of the year we announced recently, which is a really exciting update. We have a number of important data readouts coming. We look forward to sharing data in the second quarter from our PTC518 Huntington's disease program. I'm sure you'll have a number of questions about that, but I think that's now really recognized as the leading program for HD in development right now. We're also looking forward to completing enrollment and then sharing data from our Cardin ALS registration trial with our drug utreloxastat in the fourth quarter. So a lot going on this year, a lot of number of exciting opportunities.
Okay. Great. Well, maybe we should start with PTC518. And can you tell us what we should expect to see when you report the next interim data in the second quarter? And what do you need to see to consider this a win and continue development?
Great question. So for those of you not familiar with the program, PTC518 comes from our splicing platform. It follows on the heels of the successful discovery and development of Evrysdi, which is now the global leading therapy for SMA. We took the learnings from the development, both preclinical and clinical, of Evrysdi and been able to put them to work for PTC518. So we've developed a molecule that is well designed to have the necessary specificity and selectivity that's required for an effective and safe splicing agent. We've also optimized the drug properties so that we can readily penetrate the blood-brain barrier and not get efflux so we can achieve the blood-brain biodistribution that's essential for a drug being developed for a whole brain disease like Huntington's disease.
In our phase 1 program, we were able to gain very valuable data regarding target engagement and mechanism of action, as well as safety and pharmacology, all of which went to inform the design of our ongoing PIVOT-HD phase 2 study. We previously shared initial data last June from the first group of subjects at the 12-week time point where the endpoints were PKPD safety and biodistribution. As we shared at the time, we checked all the boxes. We demonstrated target engagement and dose-dependent lowering of Huntington mRNA and protein and peripheral blood cells, which is really a very important data point to ensure that this drug is doing exactly what it's designed to do and exactly what it has to do to be effective for Huntington's disease.
We were also able to demonstrate that it not only gets across the blood-brain barrier and reaches the brain, but we're achieving levels of exposure in the CNS higher than peripheral. And that's really important because, one, that assures that we're getting enough drug to where it needs to go to have its effect, but it also tells us that the drug dose levels we're studying in the initial cohorts of 5mg and 10 mg are likely sufficient to achieve what we want to achieve, which is a targeted 30%-50% reduction in Huntington protein levels in the brain. The data readout in Q2 is going to include 12-month data from that initial cohort of patients. So in addition to sharing safety and tolerability data over a longer term, we'll also be sharing biomarker data, including data on huntingtin protein levels in the CNS, CNS and plasma NfL levels, as well as volumetric changes on MRI, and data from the clinical scales being used in the trial, such as total motor scale and the cognitive measurement of Symbol Digit Modalities Testi ng.
We'll also be providing 12-week data on a larger number of stage 2, earlier stage Huntington's disease patients, as well as data from stage 3 patients. So that will really help us understand some important potential differences, not only between baseline characteristics and baseline biomarker characteristics of stage 2 relative to stage 3 patients, but also help inform us about potential different clinical effects and other information that will lead in building phase 3.
In terms of the question you asked about what would be sort of a go-no-go at this point, I would say that we've already gathered the valuable information we needed from the first data readout to know this program is moving forward. I would think the only thing that could come out of this data readout, which would make us rethink that decision, would be a strong adverse safety signal. But we're quite confident based on the safety profile we reported last June and what we've seen to date that that's not going to be an issue as the drug continues to demonstrate a favorable safety profile. So for us, this is going to be about learning, learning about are we at the right time point yet that we can start to appreciate some of these biomarker effects. But we've gotten a lot of the really key data we needed so far in terms of target engagement, mechanism of action, confirmation, and biodistribution confirmation for this program to continue to move forward.
Yeah. Okay. One of the questions we get a lot from investors is on the FDA's clinical hold. So could you bring us up to speed on where you stand in terms of the ability to resolve that?
Yeah, absolutely. So this is a partial hold that had been on the program from the non-clinical data. We were at a point when we were getting the study up and running that the FDA had wanted additional data to support the dosing and duration that we wanted to use in PIVOT-HD. That was in contrast to the regulatory authorities everywhere else in the world who allowed the program to go at the doses and for the duration we wanted 5mg and 10 mg dose levels and even a higher dose level of 20 mg.
We made the decision based on the FDA feedback that we would collect the clinical data as part of PIVOT-HD, take those data demonstrating drug safety in humans, which is obviously probably most relevant to the condition more so than doing any non-clinical work, take that back to FDA and unstick the hold. We had a discussion in the fall where the agency looked at the safety data that we had generated so far at the first 12-week time point. They communicated that those data would be sufficient for starting for the 12-week portion, but they wanted to see six-month data in order to let us go for the entire length of the study. Obviously, we're going to have those data in short order. We look forward to sharing them with the agency. As I stated earlier, all the data we're seeing so far confirm a very favorable safety profile. We look forward to having that discussion and unsticking the hold.
What have you done, when you've designed 518, to avoid the potential for off-target effects? Can you talk a bit about its design and how comfortable you feel with the ability to avoid anything that was seen with Branaplam, for example?
Yeah. No, it's a very important question, Joe. This really goes back to having expertise in the development of splicing molecules. The discovery and development of Evrysdi for SMA not only was pioneering for the field of splicing, but also taught us, gave us the playbook of how do you develop a safe and effective small molecule that's going to do splicing and deliver a meaningful effect to patients. The core elements of that were selectivity and specificity. You want to make sure that you have a molecule that is selective for the Huntington, in this case, the Huntington pre-mRNA, but also specific so that it's really doing its work where you want it to and nowhere else. So that was really important. When we're developing splicing molecules, we have as a very early stage gate, a very strict threshold for selectivity.
We've published some of our work around this. So anything that would move close to the clinic, we know already has those necessary attributes of selectivity and specificity. The other part is on biodistribution. I talked a little bit about this earlier. Obviously, if you have a disease like Huntington's disease, which affects every single part of the brain, if you're going to affect that disease, you're going to need to reach every part of the brain at sufficient levels that you can have beneficial effect. So that was another key component to the design of this molecule, ensuring first that it gets across the blood-brain barrier and then second, making sure it's not effluxed.
Obviously, by seeing the results we've seen in phase 1 and phase 2 thus far, it was like to say we gave our medicinal cannabis an A+ because this is getting across the blood-brain barrier and we're seeing higher exposures in the CNS than we're seeing peripherally. So when you put those things together and you want to benchmark to, say, a molecule like Branaplam, which was initially developed for SMA, then was developed for HD, I think that tells you right away you fail the specificity because if it could be developed for two different diseases, obviously working at many different places. And then I think also the elements of crossing the blood-brain barrier and not being efflux is an important differentiator. And the proof is in the data. When we looked at our 12-week data, we saw no evidence of NfL spikes.
We've had no reports of peripheral neuropathy, all of which I think were seen quite early at the Branaplam data readout. So I think that gives us a very important check that the things that we knew were critical to the success of this molecule are there and the data are supporting that. And that's why we can comfortably say we look forward to treating more patients for a longer period of time and start to really tell the story of what this drug can do in the long term.
That's a great segue. So when you see the data at 12 months, what would be a win? Are you comparing to natural history and doing propensity matching in order to show a difference from that on the different endpoints? Can you talk a little bit about what you're hoping to see?
Yeah, absolutely. So the design of PIVOT-HD for 12 months is placebo-controlled. So we do have a placebo group. We do have a 5 mg dose group, and we do have a 10 mg dose group. We have, of course, availed ourselves of the robust natural history data that are available on Huntington's disease patients at this level of severity. So we have some understanding of what changes one could see. But I think, again, this is a first glance, right? This is a small data set. So I think it's really an example of we're going to be looking to start to understand where can we see effects relative to placebo and relative to natural history on which biomarkers are sensitive to change in this short amount of time in patients with this disease severity.
I think we talked a lot about the design of the study and thinking very carefully about which patients we're including in the clinical trial. I think it's well understood in most diseases, but certainly in neurodegenerative disorders, that there's probably an ideal patient population that's not so early that they're not progressing. So if they're not progressing, how are you going to show you're slowing progression? And they're not so late that they progress so much that when you're acting upstream of the disease like we are with PTC518, it really the causative aspect of the disease, mutant huntingtin protein, cat's out of the bag. Yeah, that's too late. You can't really affect things. So we did a lot of work to try and have that right severity population, which is another thing we're going to learn in this trial, so that we're seeing things move sufficiently over this time course that we can start to benchmark what we're seeing with PTC518 against natural progression.
Okay. Great. Very helpful. Let's switch gears and talk about sepiapterin. Can you talk a little bit about your market research into the PKU market and what does that look like to you and where do you see the biggest opportunity for sepiapterin to play a role?
Yeah, absolutely. So I think starting sort of in the helicopter, it's about 58,000 patients globally with PKU, and less than 10% of them have their needs met on current therapy. So large unmet medical need. I think when you sort of look at the patient segments within the PKU market, there's the classical PKU patients, and many of those are represented in the therapy-naive bucket. They've not been on current therapies. And then if you look at those that have trialed Kuvan, you have 70% of patients in the U.S. that have tried Kuvan.
70% of those initially fail, 30% show a response, but 60% over time are poorly controlled and come off the drug. And so when you sort of start from the 58,000 and get to those that are well controlled, it's less than 10%. So huge unmet medical need. And I think when you look at the response rate that we've seen in the APHINITY study with north of 60% of patients having a 30% or greater Phe reduction coupled with 63% Phe reduction in the all comers and then 69% in the classical PKU, which has not been seen in the past. And then when you look at the Phe tolerance data and you say, "Not only are we able to bring patients into target Phe guideline levels, but then they're able to liberalize their diet and they're able to exceed the recommended daily allowance of protein intake that you and I have," then this is changing the face of PKU as it's known. And I think from that perspective, when you look at that coupled with the fact that this is a well-trodden marketplace, there's newborn screening. So we're not going out to look for the patients.
They're diagnosed at birth. The treatment centers of excellence are very well known. We know the metabolic specialists. We know the dietitians that work with the metabolic specialists or the geneticists depending on the country. We know the patient advocacy community very well. They're well-coordinated, well-consolidated. The disease pathophysiology is well-documented from a payer point of view. It's well understood. All of these aspects that you normally spend substantial time doing pre-launch are all done. So what we need to focus on is differentiation and understanding why this drug has a potential in a broader patient population. That's what the teams are doing.
Okay. And now that Kuvan is generic, how does that influence the opportunity set for sepiapterin? Is there compelling data showing the benefit of sepiapterin instead of or in addition to Kuvan?
Yeah. So I think I would look at this in sort of two ways. We do have data that shows that sepiapterin has worked in those patients that were previously on Kuvan. So there's two parts of that data. One is we have a phase 2 head-to-head study that showed superiority of sepiapterin over Kuvan. And then the second part of the data is that we secured as part of the Affinity study where we had 27 patients that were on Kuvan at study entry were washed out. At study entry, they had baseline Phe levels of 581 micromolar per liter. When they were washed out off Kuvan, 681 micromolar per liter, and then post-treatment of sepiapterin came within guideline Phe levels, so less than 360 micromolar. So a big difference, right? Because coming into the guideline Phe levels then allows them to look at potentially liberalizing their diet. So that data shows benefit over Kuvan.
But I think in addition to that, if you think about the landscape that I just talked about, the vast majority of patients have tried and failed Kuvan or have tried and have been poorly controlled over time, setting up what's called medical documentation for step edits, right? So they have those documents in place that say that they've tried and failed. Even in the case of a payer requiring that step edit to be reinstituted or redocumented, it's a quick and easy task. It's a blood test, so it's objective. And they would only need to go on a couple of weeks of therapy, complete that blood test, see that the response rate is not where it's expected to be, and then step through to sepiapterin.
It's a very different world in the PKU space to the one that we're living today, which is step edits through prednisone to Emflaza, which the team has done an incredible job of managing. That's a lengthy process and a subjective endpoint. They're very much looking forward to a short process with an objective endpoint.
Okay. Great. And then can you give us an update on your regulatory submissions? How much do you understand now what the pathway is in the U.S.? It sounds like Europe, the clock is ticking, and we're in the waiting phases. But what about in the U.S.?
Yeah. So the European submission, Joe's reference, will go in this month, which is great. We're very excited about that. And for the FDA submission, it'll either be late second or third quarter. We're finishing up the animal study we needed to finish, the in-life portion in June, and we'll look at the potential for submitting around that time. If not, then it'll be in the third quarter.
Okay. Should we expect to hear when the carcinogenicity study is completed? Well, is that something that you'll update us on?
It'll be done in June. How about that? We know. It started in December. It's a 26-week study, and everything's going on schedule.
Okay. Great. And well, let's switch gears and talk about vatiquinone in FA. I guess, what analyses will you be preparing, and what interactions will you be having with the FDA ahead of the potential NDA filing? And I guess, how are regulators feeling about the single components of mFARS versus the overall mFARS?
Very good question because this was really the thrust of our discussions with FDA and getting alignment around an NDA submission. And the mFARS is a composite disease rating scale. It has four different parts. And it turns out what wasn't known when we started the MOVE-FA study, but is very clear now through a number of papers written by FA researchers, as well as the results, interestingly, of an FDA grant to look at Friedreich ataxian children, that at different stages of the disease, different parts of that scale are relevant. And for the patients that we had in MOVE-FA who were ambulatory patients, who were pediatric teenagers, young adults, that upright stability scale, that one part of the mFARS, just that one part, is the only one that matters. In natural history, it's the only one that progresses. And if you look at the placebo group in our trial over 72 weeks, it's the only one on which there was any progression.
The others were flatline. And of course, it's on that Upright Stability Score that we had a statistically significant benefit with a p-value of 0.021 and about a 40% rate of slowing of progression. And so when you think about it in that framework, that on the only part of the scale that you could have shown benefit, you did, and you showed a meaningful benefit and statistically significant benefit, I think the agency was then able to appreciate that, yeah, this is actually very robust. And yes, we had pre-specified it not as a primary endpoint, but it had been pre-specified. But then again, it was very clear that this couldn't be happening by chance. So that was very compelling.
Then when you look further into the upright stability subscale itself at specific items, you again see changes and benefit of treatment that make sense in terms of what the natural history says as the progression of these different items towards loss of ambulation. So really, another piece of evidence that says that we have pretty persuasive data. And then we could look, of course, to some of the other endpoints and seeing consistency on the changes in upright stability with walk tests, changes in upright stability on the functional component of the modified fatigue scale, fatigue being one of, if not the most significant burden, some symptom of the patients. So when you put all that together, you have a 72-week placebo-controlled study with persuasive evidence of effectiveness, which, of course, is what the FDA wants to see. They then asked for some additional analyses for confirmatory evidence.
We're going to be able to offer several different pieces of evidence, including analyses from longer-term extensions from our first Friedreich ataxia study done years ago, as well as the open-label portion of the MOVE-FA study, which is ongoing. We're continuing to collect those data. So we look forward to putting that data package together. We look forward to having a pre-NDA meeting with the agency prior to submission just to align on some of the details and specifics of the submission.
What will those analyses entail? Will we see that? Will you make an announcement and share those broadly, or is it just for the FDA?
I know there's a lot of interest in those analyses. And of course, we're going to do so first and foremost, we're going to even though we've done a prior analysis of the open-label data from the first study, we're going to do it again, but first develop an analysis plan, have a predefined matching criteria from the robust Friedreich ataxia natural history database, define how the model, basically everything you would do in an analysis plan. We're going to do that for the old data, and then we're going to do that for the new data. I expect that we'll have the results of the new analyses I'm sorry, have the results of the analyses of the old dataset sooner. And we look forward to sharing that with folks. And then obviously, as we have more data, we'll share that with the agency and as necessary with others who are interested.
Okay. Great. And if you're successful in winning approval, where do you see vatiquinone being used relative to omaveloxolone or Skyclarys?
Yeah, absolutely. I think one of the things that's well known is what remains is an unmet need in the pediatric space, right? If you look at the label indication, it's 16 and above. So we know that the average age of diagnosis sits around 10, and I expect that to become even less as you start to see more and more work in the space that focuses on the importance of the correct diagnosis and shortening the gap between age of symptom onset, which occurs much younger, and age of diagnosis. And so I think that's an easy space for us to be able to own because there is nothing else there.
I think also in addition to that, as we continue to show the evidence around vatiquinone, whether that be an upright stability that, as Matt talked about, shows that delay to loss of ambulation, that's extremely important as you look at the sort of adolescent and adult population as well. So I think it's sort of unknown what will happen in the adult space, but we don't expect to only be in the pediatric space. But that's a space we can own. And then we can have data-driven discussions around where we would sit in the adolescent and adult population.
Yeah. Okay. That makes sense. And then if we stay with you, Kylie, can you talk a little bit about some things that are going on with the existing commercial programs? I know Emflaza lost its exclusivity in February of 2024. Are there any generic threats now? And what steps are you taking to address that?
Yeah, absolutely. So as you said, loss of exclusivity for Emflaza is incurred in February. We have seen one generic entrant. But I will say it was relatively slow to hit the marketplace from sort of full approval to hitting the distribution channels. One of the things we've talked a lot about is the steps that we've put in place and the strategic initiatives that we have put in place prior to loss of exclusivity to do everything that we can to protect the business. What I would say is on an overall basis, we expect that to sort of withstand the pressure of one generic entrant. So what are some of those initiatives? Making sure that we're contracting with specialty pharmacies, making sure that we're contracting with payers, making sure that we're putting other strategic initiatives in place to ensure brand loyalty.
So making sure that patient support programs are very robust, making sure that we partner with physicians and patients to understanding what's driving that brand loyalty and making sure we're continuing those programs. So that coupled with a continued focus on clinical differentiation against prednisone has been the work the team has been doing leading up to this. It was obviously not a surprise by any means. And so building this infrastructure in place to be able to protect the generic entrant was important. And by infrastructure, I mean programs. So that has occurred. And I think what we feel confident around is while there's one generic entrant, we can withstand that and protect a good portion of the tail through 2024 and beyond. If we start to see other generic entrants, then we'll look at how we then further strengthen those walls.
Okay. How much ground do you think Translarna could hold onto outside the U.S. following the EMA's final decision to remove its exclusivity or remove it from the market? What other territories reference the EMA's decision?
From that perspective, everything outside of Europe, we expect to maintain. We've talked that we have a number of independent approvals that stand alone, and they've done independent reviews from a safety and efficacy point of view. And we expect those areas to continue. Within Europe, we've also talked about the fact that we're looking at a number of opportunities through early access and through named patient programs that could allow us to extend the longevity of the revenue within Europe. But I think the way that we've tried to think about revenue guidance for 2024 is that would be an upside. So we've looked at removal of the European revenue, maintaining the revenue outside of Europe, and then driving as much as we can to keep some opportunities for revenue within Europe.
Okay. Great. And then Pierre, you haven't been at the company for all that long, but we've already seen you do some things such as a royalty agreement to shore up the cash balance and extend the runway. Is there any more ammo in this regard, or is there any room for operating efficiencies to be realized at the company, if any of the pipeline programs don't pan out? How does the company view the cost structure? Is it optimized?
Yeah, of course. So look, last year, obviously, we did a number of things. We deprioritized some early-stage assets on the gene therapy side, as you mentioned it. We did the royalty financing. We also cleaned up the balance sheet. So you mentioned the word optimizing. Optimized, that was important to us. Obviously, as part of the financing, we used some of the proceeds to retire the very expensive Blackstone that we have, which was a very high cost of capital. So this was step one. Now we enter phase two this year, 2024, with a very, very strong balance sheet to get through all the activities that Matt and Kylie mentioned: PKU submission, of course, of Upstaza submission, HD, Translarna in the U.S. potentially, and then FA. And that is really important.
We are really well positioned to get through all these activities, launch PKU, which is going to be a billion-dollar-plus opportunity. That's really the focus that PTC has now. We'll always look for opportunities, obviously, to make sure that we deploy our capital where there's a high return on investments.
Yeah. Great. All right. Well, I think we're out of time, but thank you so much for the update today.
Thank you, Joe.
Thank you.
Thank you very much.