PTC Therapeutics, Inc. (PTCT) Earnings Call Transcript & Summary

Okay. Welcome, everyone. We'll continue with the next session. My name is Paul Choi, and I cover the small and mid-cap biotechnology sector here at Goldman Sachs. It's my pleasure to welcome the management team from PTC. To my immediate right, we have Dr. Matt Klein. And at the far end there, we have Kylie O'Keefe. What we'll do is the usual format. Maybe I'll let Matt kick it off with a couple of high-level comments, and then we'll go into Q&A. If anybody in the audience has questions along the way, please feel free to raise your hand, and we'll get a mic to you. Also, for those who are listening on the webcast, if you have any questions, please e-mail them to us, and we'll read them anonymously if time allows. But otherwise, with that, I'll let Matt kick it off here.

Great. Thanks so much, Paul. It's great to be here today. For those of you who don't know PTC, we are a global biopharmaceutical company that discovers, develops and commercializes therapies for rare disorders. We just celebrated our 25th anniversary and are looking forward to a continuing successful next quarter century. We started with a focus on mRNA biology and have subsequently built several scientific platforms where we are able to leverage our unique knowledge to bring therapies forward for patients with high unmet medical need. We have a robust commercial portfolio with 5 marketed products, global, and a 6th product from which we received collaboration royalty revenue in 2023. We're projected to have between $940 million and $1 billion of revenue. So obviously, a key milestone for the company. We also have a robust R&D portfolio with a number of clinical trials that are reading out in the first half of this year and recently shared results from our Phase III PKU AFFINITY trial, where we had really transformative data that will allow us, we believe, to become standard of care and address the still significant unmet medical need in PKU and represent another potential $1 billion commercial opportunity. We have several additional trials still to read out in the next several weeks, including our PTC518, Huntington's disease program from our validated splicing platform, and a number of regulatory milestones coming up in the back half of the year. So really an exciting time at PTC and look forward to answering any questions, yes, Paul.

Great. Thank you. There's a lot to unpack there, but maybe we'll start with this map, which is you have been at the company for several years now, but only recently became CEO. So maybe my first question to you is from your new seat here, how do you -- I guess, think about PTC now from this new seat? And how do you -- how does the strategy and strategic vision for the company, perhaps in your mind, changed from having this new role?

Yes. It's a good question. Obviously, it was an incredible exciting opportunity for me to take over for Stuart Peltz say after his 25 years as a Founder CEO and really at a time where the company was ready to take its next step in growth. As I mentioned this year, we predict between $940 million and $1 billion of revenue. And along with positive trial readouts like from our AFFINITY trial, we're really poised now to think about moving away from a company that has sort of opportunism strategy and needing to take a lot of shots on goal, where we can now be really focused. We can focus our research efforts on things like splicing and bioenergy, which are 2 platforms that we built that, quite frankly, we have scientific knowledge and expertise that very few other companies have and can leverage that expertise in focused therapeutic areas such as neurology and metabolism and oncology. But then also think about being much more strategic in how we deploy our capital and start thinking about as we recently announced a reduction in operating expenses and really thinking how with potentially $1 billion of revenue this year and another $1 billion PKU revenue opportunity, we can think about moving towards breakeven and maybe even 1-day profitability. So it's really, as I take over the role, the time of the company's development where we can start thinking about taking that next step as a company and thinking about being move focused in our strategy, more thoughtful in our capital structure, and our deployment of capital and how we at the same time can still remain that really impressive, innovative and entrepreneurial company that can continue to use pioneering science to deliver therapies to patients who desperately need them.

Yes. It's always a challenging balance. Maybe starting then -- or turning to the commercial piece side of things for either you, Matt, or for Kylie. The commercial execution has continued to be very good over the past year and your DMD franchise reported a very good consensus speed this past quarter. Can you maybe speak to what the recent trends have been for Translarna and for Emflaza in the U.S. and Europe? And then I had a couple of follow-up questions on that as well.

Yes, absolutely. So as you said, we had a really strong quarter in the first quarter. We had $170 million for the DMD franchise, which was a 33% growth over the first quarter of last year. So we're continuing that strong double-digit growth across the DMD franchise despite being in market with Translarna for 9 years and Emflaza for 6. So it's quite remarkable for a mature stage product. So if I start with Translarna in U.S., I think there's a number of different drivers that's contributing to the growth. So one of the things that's really reassuring to us is we continue to see growth in existing geographies. So we're not at peak penetration in existing geographies. We continue to find new patients. We continue to ensure that we're broadening access where possible, and we continue to ensure that we focus on high compliance. But in addition to that, we're also looking at expanded geographic areas. So we look -- we've spoke about in the past a number of areas like Brazil and Latin America, other countries in Latin America, Central and Eastern Europe, Middle East and North Africa, and also the common lots of independent states. And that is starting to be a much larger growth driver for us as we continue to expand in these areas. There's still untapped potential for us with Translarna and geographic expansion and there's areas like Asia Pacific, which we're just starting to really scratch the surface on. And so, we continue to project double-digit growth over the next couple of years for Translarna, both in those existing geographies, but also as we continue to expand geographically as well.

Okay. That's great. I mean, it's fascinating because you have a mature -- what people characterize as a mature market between yourselves and Sarepta, yet these patients continue to be identified in other geographies. I guess maybe just on the topic of Translarna for either you, Kylie or Matt, the company has previously stated that you intend to reengage with the U.S. regulators on that front about a potential application? And can you maybe provide us some feedback on what's been happening on the FDA front there?

Yes, absolutely. So what we -- following the readout of Study 041, which was our confirmational study for our European conditional marketing authorization and also being a global placebo-controlled trial, we believe, provided us with data that could support approval in the U.S., in particular, the fact that in the overall population, the intent to treat population. We -- for the first time in a placebo-controlled study in DMD demonstrated statistically significant benefit on the key functional endpoints of disease, including the 6-minute walk test and North Star Ambulatory Assessment and others. We believe that these data, along with the totality of evidence from 3 clinical studies in 700 boys as well as our real-world registry evidence showing that we're able to slow loss of -- time to loss of ambulation and loss of pulmonary function, which are really the 2 key morbid transition points in the disease provided us with a robust package along with the drug safety to meet the unmet medical need in the U.S. for nonsense mutation DMD boys. We had a discussion with the agency in the winter, at which time they suggested that we have a Type C meeting, where we present the totality of evidence that could be in support of an NDA resubmission in the U.S. We said that we're going to request that meeting. We're in the process now of completing some analyses that will address some of the long-standing concerns in the data package as well as provide really new evidence for the agency to consider that reflect the totality of evidence and the true benefit we're able to provide for nonsense mutation DMD. So we look forward to having that discussion with the agency and obviously updating folks as we go through that because clearly, there's a strong desire in the DMD patient community for this drug to get -- get to children in the U.S., as Kylie explained. We've built this robust commercial organization are able to provide this drug nearly every other geography around the world to [indiscernible] in nearly every other geography around the world and obviously, boys in the U.S. and their parents desperately want to get this therapy as well.

Great. Maybe just as a follow-up, any sort of rough framework for when that Type C meeting might occur and when you might be able to provide an update to the market on that?

Yes. So obviously, we're going to work to get their request as soon as possible. And then obviously, it will follow the FDA clocks for a Type C meeting request. So we provide updates as we have them.

Great. Maybe staying on the topic of commercialization. Obviously, you've partnered with Roche on SMA, but you also are -- have recently started commercializing Upstaza as well. Can you maybe provide an update on -- or some color on how that launch is going? Any quantitative measures you can provide like patients identified and treated coverage and so forth and just kind of where the state of the launch is?

Yes, absolutely. So looking back to mid-2022, we received [indiscernible] approval for Upstaza and then in the back half of last year, towards the end of last year, we also received [indiscernible] approval. So we're approved in Europe and also in the U.K. So we've talked a lot about the different access pathways that are available to us and how we can secure patients to be commercially treated, and we've been executing on a number of those pathways. So the first is early access programs. We talked about France being a really good example of that. They have the AP program, and that basically replaced the retired [ ATU ] program. And we were able to treat patients very early on. We talked about treating the first patient through the AP program in Q2 of last year, and we've treated additional patients in France since then. There's a number of other countries that also have early access programs. Italy is a good example of that. And then also what we call named patient programs outside of Europe that look to an approval in Europe to be able to have patients treated through named patient programs. The second pathway that's obviously a pretty traditional one is commercial access. We've talked about Germany being the first country has launched through that, and we've obviously talked about treating patients in Germany with commercial access. We've also talked last quarter at earnings about securing a positive recommendation from NICE for Upstaza, and that will obviously help us move forward with treating patients in England and Wales. And we're focused on a number of other countries to bring them online with commercial access. The third pathway and somewhat uniquely a little bit utilized for gene therapy is cross-border health. So that's where a patient is located in the country where there isn't a treatment center of excellence at this point, and they cross the border to an existing treatment center of excellence. And it's a commercially reimbursed patient. So PTC is able to realize the revenue through that cross-border health care. And we talked about at Q1 earnings as well, treating our first cross-border patient that was from the Middle East and was treated in France. And so that has really realized the potential of that pathway, and we'll continue to focus on those areas. So across the board, we're focused on bringing more countries online, so we're able to treat more patients in Europe and continued focus on named patient programs outside of Europe, for example, Brazil, Latin America, other parts of the world that allow that and then also continued registrations. We've talked about a BLA. We're also looking at registration in Brazil and other parts of LatAm and then also in Asia Pacific as well. So there's still continued growth. I think one of the things that people don't often understand is when it's an ex-U.S. launch first, despite it being a centralized registration process, country-by-country, repricing and reimbursement takes time. And so, we're working through that. But we've seen really positive trends and positive discussions with NICE having a positive recommendation. We've had strong ratings across Germany and France, and we're continuing to work through other countries of the back of that.

Okay, great. You brought actually something that would be my next question, which is just on the U.S. BLA status. Matt, can you maybe just remind us of what's going on there and sort of what the key questions are before you continue with the BLA process?

Yes. So we said we believe we'll be in a position to submit that application either by the end of this quarter or early in the third quarter. The last remaining dialogue with the agency has been around the data supporting comparability between the material that was used in the clinical studies and the material that we're going to use commercially. Now one thing that's very important is obviously to demonstrate that they are comparable in terms of key aspects of the therapy, including things like potency, infectivity, viral titer infectivity and capsid -- empty fill capsid. So we provide additional data to the agency to what we believe will fully address their residual concerns. We were just looking forward to their response to that. And once we have that in hand, we look forward to submitting the BLA.

While you're continuing and going to continue to work on commercializing Upstaza like here in the gene therapy space, you also recently announced a decision from an R&D perspective to back off from continuing gene therapy development. Can you maybe walk us through what were the inputs that went into this cost benefit decision and that you announced to the market recently?

Yes, absolutely. Look, we're incredibly proud of the pioneering work that we have done with Upstaza, being able to bring a truly transformative therapy to children and get approved the first-ever gene therapy that's administered through a neurosurgical procedure into the brain. We think that's incredibly important, not only for patients with AADC deficiency, but also for the entire field of gene therapy, particularly gene therapy targeting neurological disorders. We have also, as we said, going to look very carefully at our use of capital and our R&D portfolio breadth. And as I said earlier, we're sitting in a position now with the potential for up to $1 billion of revenue this year and the potential $1 billion product of sepiapterin for PKU. Moving forward, we really think we were in a position where we should say where do we want to thoughtfully deploy capital. And a lot has changed in the gene therapy space over the past few years. Actually, a lot hasn't changed. But I think we've learned a lot more about the gene therapy space in the past few years, a lot of the challenges, the cost that it takes get a gene therapy into the clinic, the cost of development once in -- once in the clinic, the challenges of clinical development for emerging therapies, particularly ones for neurological disorders and what may be by the time you get a therapy approved and uncertain commercial landscape and payer landscape in terms of funding for those types of products. And when we looked at the amount of spend we've had on gene therapies in the past few years, I think we've said and we've shared publicly about $570 million, that's a lot for therapies that are not yet in the clinic and may be very far off to approval. And so for us, it was really a decision of saying, we'd rather not invest any further in those programs, obviously, look to put them in the hands of those who can develop them and really use our resources to focus on our small molecule platforms where, again, we can uniquely discover and develop therapies for really meaningful therapies for patients with high unmet medical needs. So this was really a decision about how best to deploy resources understanding what the return on a very, very large gene therapy investment would look like over the next several years and being in the fortunate position that we have such a broad R&D portfolio and can do so many things, now we have to be very thoughtful about the opportunity cost of pursuing programs that may be incredibly capital-intensive with a very low POS and an uncertain commercial viability.

Okay. As part of the strategic prioritization, it sounds like you're definitely thinking a lot more about R&D productivity and to your point on capital allocation here. As you think -- as you and the management team think about this and as well as the Board think about it, how are you thinking about balancing this effort to be productive in the clinic and in R&D versus the move to profitability? And is there a particular time frame or metric that you guys are thinking around in terms of shaping this narrative and communicating it to the investment community?

Yes. Absolutely. And this is something we've talked about since the CEO transition. Look, it starts first with taking stock of what we're doing. What are the programs we should be doing, what should we be prioritizing and what is really the strategic focus of the company. And as I said, I think that really sits in scientific platforms where we have the unique ability to bring forward really important therapy. So it's really focusing down the platforms to things like splicing, which we can uniquely do, and things like the bioenergy platform, again, that we have unique expertise in and say, okay, we focus that down. That obviously brings with it some savings in terms of OpEx. And also, quite frankly, a focus of intellectual capacity and intellectual resources so that we can optimize for success in those programs. And then look again across the entire development commercial portfolio as well through this lens of focus and return on investment. And I think then you get into the situation where you -- obviously, you walk before you run, and we want to think about what our optimal strategy is. How do we get moved towards breakeven? And then obviously, on the other side of breakeven is how you move towards profitability, maintaining the balance, as you said, Paul, then critically important balance is that we have to still be innovative and discover important therapies, which we believe we can. Just when you do that in a more focused way, that's how you do it. Focus your resource spend on programs. We have good return on investment that we can uniquely do and have reasonable probabilities so that when we're deploying capital, it is done in a thoughtful way, and it can bring about transformative success in the long run.

Okay. Great. Maybe turning to other aspects of the pipeline. Congratulations on your recent AFFINITY results for sepiapterin for PKU. Could you maybe highlight some of the key takeaways from the data here and just what you think what is most interesting from your Phase III results?

Yes. First, thank you. I think that we were incredibly excited about the results as are the physician and patient communities, given the fact that even though there's 2 approved therapies for PKU, it still remains a significantly large unmet medical need. The vast majority of patients are not well served by the current available therapies. So the Phase III trial was a placebo-controlled trial, sepiapterin versus placebo in adults and pediatric patients with PKU in the full spectrum of disease, including mild, moderate and severe patients. We first had a run-in phase during which we could identify responders to sepiapterin after 2 weeks of treatment with the drug and had a 66% responder rate. Just to benchmark that in the similar all-comers responder study, Kuvan had a 19% responder rate. So right away in that first 2 weeks, we again were able to demonstrate that we have an ability to provide a meaningful impact of many, many more patients than the standard of care Kuvan or BH4. We then took those patients that we had the 65% -- 66% that responded. And by the way, that included a number of classical PKU patients, 16 classical PKU patients that had a mean reduction of 60%. Again, a tremendous magnitude of reduction in the most difficult-to-treat patients. We then randomize those patients to receive sepiapterin and placebo for 6 weeks. And we've had a highly statistically significant finding with an overall reduction of 63%, a mean reduction of 63% in the treatment group. And obviously, minimally -- minimal change in the placebo group that had a p-value of 0.00001. So highly statistically significant and clinically meaningful magnitude of effect. But when you dig deeper into that, you see really other pieces of impressive data. When you look at the subset of classical patients, we had a mean reduction of 69%. Again, a tremendous reduction -- magnitude of reduction in the hardest to treat patients. And then we also were able to bring 84% of patients -- 84% of patients to below the clinical target guideline of 360 micromolar per liter. That's really significant in its own right. But also, when you compare that with the numbers from Kuvan, which is in the 30s percent, I think it's 34%. And furthermore, we've had 11 patients -- 11 patients who achieved normalization of phenylalanine levels that's below the 160 micromolar per liter normal level. So those are really phenomenal data. And then the last piece that was really significant is we were also able, again, as we did in Phase II, look at how sepiapterin performed in patients who were on Kuvan. So we had 27 patients who entered the study on Kuvan. We were able to get their Kuvan-associated phenylalanine levels. They then got washed out and then treated with sepiapterin for 2 weeks. And what we found is that we had a 48% reduction in phenylalanine levels from their Kuvan treatment level. So that, again, is saying that in patients who are on Kuvan that sort of may be served by Kuvan, we're able to provide significantly greater benefit. So when you put all these data together, they really support a product that was safe and well tolerated and can provide meaningful benefit not only to those who aren't served by available therapies, but even those who may be because we're able to achieve such greater reductions of phenylalanine, and that's really the name of the game in terms of providing neurological benefit to patients with PKU.

Okay. Great. In the wake of your data results, I think one of the debates of the investment community is trying to understand the data versus the approved therapies on a like-for-like basis and given -- set the patient numbers and so forth. Number of classical patients, different baselines and maybe understanding what data looks like from your perspective on an apples-to-apples basis. To that regard, I guess, what would you say that the data suggests in terms of where sepiapterin would be most applicable and just understanding how to contextualize maybe some of the data results, let's say, in the classical patients, particularly?

I guess maybe I'll make a couple of comments and Kylie maybe you can talk about the commercial because I think you mentioned the different -- apples-to-apples is always hard. These studies were conducted years later. And that's why I think when you have data in patients who are on Kuvan and then look at what they do when they're on sepiapterin are very impactful and having that 48% greater reduction is really important. We also had a number of patients who were documented as Kuvan failures who responded to sepiapterin. So that's pretty good and that's subject to maybe changes over time. You mentioned the question of, well, maybe our baseline levels of phenylalanine were a little lower than the Kuvan studies, that actually just raises the bar. So if you can have greater magnitude of reduction, both in absolute phenylalanine reduction and percent magnitude than volume reduction, that means that we perform better when the bar was higher. So I think, again, all of these data put us in a position to address all the different segments of the population, and that's the feedback we're getting from physicians as well, even those who have patients on Kuvan. Kylie, I don't [indiscernible]...

Yes. I think it's well said, Matt, I think across the board, what we're hearing from both physicians and patients is a substantial unmet need, and we knew that going into the trial. Despite there being 2 therapies available, there's large proportions of patients and patient segments that are not being served. Now that might be because they're therapy naive, and that includes that classical subsegment you just talked about. But there's additional therapy naive patients. That might be patients that have tried the standard of care but have failed or patients that have tried the standard of care, tried to liberalize their diet and come off the drug because they've been not well controlled, right? So there's many pockets of pretty large unmet need. And so, the question going into the study from our perspective was what are the data points that we believe could be the proof in the pudding, so to speak, as to our ability to meet the needs of those patients. And I think coming out the back of the AFFINITY readout, I think consistent feedback has been that this is far exceeding the belief of what is required to meet the needs of those patients in many of the segments. If we think about -- you touched on classical PKU, right? These patients have traditionally been unable to go on therapy. They're entirely managing the disease through diet management, and this is highly frustrating for a patient, particularly with very severe disease. And they're desperate for therapies. And so, the ability for us to show a 69% fee reduction or 523 micromolar in absolute fee reduction, that's very substantial for those patients. You think about what 69% means if you're a patient with a baseline fee level of [ 1,000 ], it's very substantial fee reduction. So from that perspective, it's a quick and I'd say more hanging fruit that has a lot of unmet need, but we don't see that as the only opportunity or we're stopping there or we don't see it as the primary opportunity. We see also the patients with -- that have tried the standard of care and failed. So they've not [ shown ] a response. And as Matt just talked about, we were able to show a 66% response rate. So there's a big gap of patients that have failed Kuvan that would show a response on sepiapterin, and we had some of those patients in the trial, and that will be another large opportunity in very quick succession at launch. And then the third is also those that are just not well controlled. Do you think about what control means to a patient? It's about liberalizing the diet. So fee reduction is one thing. But understanding what fee levels you're able to maintain while you have an increased fee intake is really important to the physicians, to the patients, and to the payer. And that's a big part why we put feet tolerance into our long-term extension study because it's one thing to say we have 69% fee reduction in classical petitions or 63% in a broader patient population. But then, if a patient comes down into target fee levels, 360 micromolar as an example, but they're not able to liberalize their diet, what does that really mean? And so having an ability to show that we not only bring them into that target fee level, but then over time, they're able to have an increased fee intake and maintain those levels is truly what's going to be one of -- in my opinion, from a commercial perspective, one of the most differentiating elements of this drug.

Okay. Maybe just one more on this, which is sort of what are the items left to check from a pre-NDA perspective? And then secondly, as you think about the commercial rollout here, what steps have you taken in terms of either sales force build-out and or payer engagement?

From a regulatory standpoint we're -- as we said, we're going to get a [ meeting press ] ready, send it in and look forward to the pre-NDA discussions and have an NDA submission by the end of this year as well is the target. Yes.

And then from a commercial infrastructure point of view, I think one of the things that we've been very deliberate about, Paul, is building a commercial infrastructure and engine that is plug and play for many of our opportunities and PKU is no exception to that. So we have a global commercial footprint that's been built to be able to commercialize, not just the DMD franchise, not just Upstaza, not just Tegsedi and Waylivra, but also sepiapterin as it comes to the marketplace. And so, whether it's patient engagement, whether it's payer engagement, whether it's physician engagement, all of our customer-facing activities and infrastructure is built and ready to go. And in many cases, we've started a lot of this work. So we've been engaging with the well-known centers of excellence. We've been engaging with the patient advocacy groups. And to your question about payers, we've also been engaging with payers. We have done a number of different scientific advice meetings in advance of data readout to understand what does the package look like that payers would be interested in? And how does that differ from U.S. to ex-U.S.? And I think one of the aspects that's reassuring to us is, as expected, payers were very interested ex-U.S. in fee tolerance data because they want to understand how is the therapeutic operating alongside diet management. And so that was reassuring for us because obviously, we've made a deliberate decision to go forth with that. And I think from a totality of evidence point of view, we have a Phase II head-to-head study, and that gave us a lot of good data points and confidence we have the Phase III AFFINITY study as well as the long-term extension. And within that data package, we also, as Matt talked about, have patients that were on Kuvan were washed out and went on to sepiapterin. And so, across the board, we feel like we've got a really strong data package to be able to continue those payer discussions. But there's nothing come up so far in payer engagement that would provide us any cause of concern.

Great. Maybe if we could discuss the MOVE-FA study results in vatiquinone for a moment here, while not meeting the primary endpoint after you announced the top results. You did mention that you want to engage with regulators on a potential discussion here exploring a path forward here. Can you maybe comment on what you've seen in the data that underpins this potential move to gauge on a regulatory discussion here?

Yes, absolutely. So the primary endpoint in this study, MOVE-FA, which focused primarily in children, which we were able to do given the safety of the drug was the disease rating scale, which has 4 parts to it. One of the 4 parts -- actually -- so we had some nominal significance on 2 out of the 4 parts, and it turns out on the 2 parts that most reflect clinical meaningfulness. One is upright stability, which has been shown to be very important in terms of time to loss of ambulatory function, which obviously is a key -- transition point of the disease and a second is bulbar, which reflects speech and swallow. So the fact that we had significance on the 2 key parts is element number one. Number two is if you look at the pediatric patient population, the part of that scale that's actually moving. The one that actually progresses the most over childhood, adolescents and FA is upright stability. So now you're saying, okay, on the most meaningful one to kids, you registered the strongest response. Obviously, we also had data on the fatigue scale, which met significant fatigue being the #1 complaint -- symptom complaint of patients with FA and at the external led patient-focused drug development day was the one symptom -- was the #1 symptom patients they want a drug to target. And then, of course, the safety of the drug and the fact that [indiscernible] is approved for basically adult patients. So this remains this unmet medical need. And in our discussion with the KOLs and the patient community leaders, they felt very strongly given the unmet need in kids and the fact that we actually impacted the -- the one thing that is important in kids on that scale, upright stability certainly warranted a discussion with the agency and whether that means they would view the upright stability data as an intermediate clinical endpoint, which is one of the pathways of accelerated approval is a discussion worth having because certainly, when you think about what an intermediate clinical endpoint has to do, it has to say, one, that it is something that is known to be important in terms of the long-term clinical outcome of the disease. And then two, you made a movement on that, that's significant well when look at the literature, it clearly establishes the relationship between changes in upright stability and time to loss of ambulation. So obviously, it's an intermediate step on a very meaningful clinical endpoint. And then look at the magnitude of change we had, it's really consistent with that about reducing by half what a patient would lose in a year. So that actually over the long term, could be quite meaningful. So we believe it's worth then to just have a discussion to see if we could avail ourselves a pathway.

Okay. Very good. We're coming off on time here, so I want to maybe spend our remaining time talking about Huntington's and 518 here. I think our conversations with investors suggests that they're very impressed by what they see in terms of the drug in the serum, but they have challenges connecting it to what it could translate to in terms of Huntington changes and then further what that means from a clinical meaningfulness perspective. Can you maybe provide your view and help us connect the dots on how to think about that? This is a very important year in terms of updates in the Huntington space between yourselves and care, and so forth. So you maybe just frame for us what we should expect from the data and how you'll present it.

Yes, absolutely. Look, we're in a pretty unique position in the neurodegenerative disease that we have an understanding of one of the key causes, which is the case of Huntington's disease is the production of a mutant disease causing toxic protein. So to be in a position where you know what the cause is and to be able to target that effectively really sets up a treatment hypothesis, which is quite sound. And obviously, this program where -- comes from our splicing platform, where we've learned a great deal from the successful discovery and development of [indiscernible] for SMA in terms of what needs to be in a molecule to ensure that it is selective and specific really important for splicing, gets to the brain and broadly buy -- distributes to the brain, which obviously is incredibly important for a whole brain disease like Huntington's disease. Now taking that path from being able to have something in a lab to something in human volunteers to be able to translate that into ultimate clinical benefit, obviously, is a many step path, and we're -- our whole development program is proceeding in that way. So we've gone through Phase I and now in the PIVOT-HD study, what we plan to show in the data before the end of June is looking at the dose-dependent reduction of Huntington mRNA in -- and protein in the blood, very important because we're in a position with a systemically administered therapy that we can actually go window into the brain from looking at the blood. We can uniquely do that because it's an orally administered therapy. And we know that what's going on in the cellular machinery of a blood cell is the same on what's going on in the neuron. We know that we've shown that preclinically. And so what we really have is a very special way to get a window into what's going on in a neuron. So those data will be very important one, in terms of confirming what goes on in the cellular machinery; and then two, coupled with exposure data showing that we're getting the drug across the blood-brain barrier in sufficient quantity and it's not being e-fluxed tells us that it's getting into the brain, and we have every reason to believe then at this early stage that we're going to have an effect on Huntington protein in the brain. Then the next step comes when we start looking at biomarker data like NFL, which obviously is an important marker not only of safety but also effects on neuronal inflammation and renal cell loss and ultimately Huntington protein in the CSF and those biomarker data set, we said [ will come ] at 12 months, will begin to tell that story of how we are doing in terms of having an impact on things that really matter. -- in Huntington's disease. So I think it's really a stage-gate approach that we need to walk along and get the most information we can at the right time. So at 12 weeks to be able to get important PK/PD peripheral data and CSF exposure data, which tells us that we're getting into the brain and affecting the cell machinery are really critical first steps along that path.

Okay. Great. Exciting times in Huntington's. Okay. We've run over here. So my thanks to Matt and Kylie for joining us, and we'll end on that note. Thank you very much.

Thank you, Paul.

Thanks for having us, Paul.