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

Good afternoon. Thank you all very much for attending the 2024 Citi Global Healthcare Conference, our first time in Miami. Next, with us on stage, I'm happy to have PTC Therapeutics, which certainly had some eventful news over the last couple of weeks. So we have a lot to talk about. I guess if you could start, introduce yourselves, introduce the company. And maybe at the beginning, from a top level, talk a little bit about the evolution of the company over the last couple of years because there's been a lot of changes.

Yes, absolutely, David, thank you for having us. I'm Matt Klein, CEO of PTC; and I'm joined by Pierre Gravier, our CFO. And you're right, it's been an exciting year or so at PTC and since taking over as CEO, we have been intent on evolving PTC from a company that has a very proud 25-year legacy of pioneering drug development on a number of fronts. We wanted to make sure that we took time now to get to company positioned for future success, and that's exactly what we did. We undertook an effort to prioritize our R&D portfolio, focusing on small molecule therapies. We also worked to rightsize the organization. The combination of the portfolio prioritization and the rightsizing led to an approximately 25% reduction in OpEx, reversing years of OpEx growth that also puts us in a position for the first time to talk about being cash flow breakeven in the not-too-distant future. While we reduced -- or rightsized the organization, we were sure to maintain critical elements of the infrastructure, including both in R&D and our global commercial infrastructure. We also cleaned up the balance sheet. We achieved a royalty monetization last year of over $1 billion that allowed us to move some costly debt from the balance sheet, increasing not only our strength -- capital strength, but also giving us increasing operational flexibility, which was very important. As we moved into 2024, we said this was going to be an important year of execution for PTC. And I'm proud to report that we have executed incredibly well across all parts of the company. We continue to deliver strong revenue performance. We recently upgraded our 2024 total year guidance to $750 million to $800 million. And of course, we remain on track to achieve that. We've done that in the context of being maintaining careful OpEx control, which has been very, very important. We're on target to submit 4 approval applications to the FDA this year, which I think is a lot for any company, especially a company of PTC's size. 3 have already gone in, 3 were accepted for review and 1 has already gained approval, and that was our KEBILIDI gene therapy for AADC deficiency. We had the approval come a couple of weeks ago, that came with a priority review voucher, which we rapidly monetized, I reported last week, we received $150 million for that voucher sale. We expect to submit a fourth NDA later this month for Friedreich ataxia with our drug, vatiquinone. And then we also had important developments in the pipeline as well. We -- in Q2, we shared the results of our PIVOT-HD Phase II Huntington's disease trial with our splicing molecule, PTC518, reporting evidence of safety, tolerability, durable biomarker evidence of Huntington reduction and an early signal of clinical effect with dose-dependent benefit on several clinical scales. It's that unique data package, including safety, tolerability, evidence of biomarker effect in early clinical signal that established PTC518 as the leading therapy in development for Huntington's disease and supported the deal we announced just yesterday, which was a collaboration agreement with Novartis for the development and commercialization of PTC518. I'm sure we'll talk a bit more about that deal, but it was obviously quite significant.

On that. There's been a lot of news lately. We had some questions put together, and I have to reorder everything, given what's occurred. Let me start with 518 and the partnership. Could you, I guess, run us to the impetus of seeking the partnership now at this stage post Phase II, you might be looking to try to submit accelerated, but also there's the confirmatory trial going on. What made you do it now? And run us through the process that brought you to Novartis.

Yes, absolutely. So just for background information, PTC518 comes from our splicing platform, which is really the leading splicing discovery platform in the world. Evrysdi, which was the first therapy, SMA therapy that came from our splicing platform really taught us and the world a lot about the power of splicing and the key attributes of an effective small molecule for treating a whole brain disease and PTC518 has followed in those footsteps. We showed in June, the data that I recently -- I just covered from the interim readout of the Phase II trial. After we shared those data, we had gotten an unsolicited inbound request to talk about a potential partnership. We had talked about being well positioned to bring this forward all the way across the finish line ourselves and commercialize it, but we felt that since we had gotten this offer that we would run a process. As we entered this process, we said if we were to kind of do a deal, there were a couple of things that were really, really important to us. First, we wanted a quality partner that would bring significant experience in neurology drug development and commercialization that could bring more muscle to the efforts, that together with our expertise in splicing and Huntington disease could help get this program further faster and get this drug to patients who desperately need it as quickly as possible. Two, the economic consideration had to be commensurate with the opportunity that one would expect for a first disease-modifying therapy for a disease like Huntington's disease. That included an upfront that would be significant as well as back-end economics that would allow us to share significantly in the upside. And going through the process, it was clear to us that Novartis was an ideal collaborate or partner in this regard given their extensive experience in neuroscience development and commercialization. They have experience in Huntington's disease. They have a great appreciation for the power of splicing. And it was clear to us from the top of the organization from Vas, the CEO, on down. They're fully committed to this program, fully committed to getting a drug to HD patients and believe strongly in PTC518 and its promise. In terms of the economics, we shared that we believe, as far as we could tell, this is the largest upfront for a Phase IIa asset that's ever been there. That certainly supports our desire to have economics commensurate with the opportunity. And on the back end, we have $1.9 billion in development and commercial milestones, of 40-60 profit share in the U.S. and double-digit tiered royalties on ex U.S. sales. So the economics are certainly there. I think in terms of timing, a lot of that was dictated by the desire to have a partner in place as we start thinking about Phase III and the efficacy trial. That's going to be very important because that development will be shared, but the cost will be owned by the partner. And so it's clear that they would want to have input on the design of that study, and that's why the timing is now because we're in the process of getting ready for that. So this is a collaboration that will be from here forward, whether it's an accelerated path to approval or a standard path to a pool. And we're incredibly excited to be moving forward with Novartis.

And going back about a year ago, there was -- people were looking at cash and how that was moving forward -- actually 1.5 years ago, and there was restructured -- a couple of restructurings that occurred and the cash situation is very different now after this partnership. How has that changed, just from a strategic level, things for PTC going forward?

Yes I'll -- first I'll point out, this is not by accident. I mean, I think what we were intended on doing was to making sure that we position the company to build for future success, and that involves having a strong balance sheet, being mindful of operating expenses and being very sure to have some resources at hand that we need. So we sit in a position now that we look to next year with the launch of our PKU drug, which we have a PDUFA date in July and expect the approval in Europe to be in the first half of the year. We've described that as a $1 billion-plus opportunity on its own, potentially $1 billion-plus in the United States, other potential U.S. launches next year. And so we're in a position where we're going to be looking to drive top line revenue, get to cash flow breakeven and do that in the context of having sufficient cash to get there, not needing to think about having to raise capital, but have capital to resource these launches, have capital to invest in our R&D. I mentioned the power of the splicing platform, that's already yielded 2 very promising therapies, one that's not a leading therapy in SMA, Evrysdi, and one, PTC518, which is now the leading therapy in development for HD. We've advanced that platform. We want to be able to continue to resource it so we can continue to grow because we believe splicing could be a source of many, many more powerful therapies for all different therapeutic areas. We also now have resources to think about doing additional business development activities where we can think about complementing both our commercial and R&D portfolio in a strategic fashion as we continue to build the company forward. So we sit here today with a company with incredibly promising near-term future where we can be growing the company towards cash flow breakeven in the very near future. We are going to continue to push the company towards $1 billion-plus revenue again in the very near future. We have a robust R&D engine and we're seeing it in a very strong cash position.

Now with respect to the -- what's happening with 518 going forward, certainly having meetings with the FDA to decide what the current steps from a regulatory perspective are. And there's the pivotal trial -- or confirmatory trial underway. What do we expect to learn about -- when could we expect to learn more about what the actual next steps are relative to the program?

Yes. Let me just clarify. The trial that's underway now is the Phase II trial of the PIVOTA-HD study, where we had an interim data readout in June, and we expect the full readout of that trial to be -- we said last patient [ left ] this will be Q1 of 2025, and then we'll expect to have the data readout likely in Q2 2025. That's a study that's focused on kinetic and pharmacodynamic effect as well as biomarker effect. So that's the trial where we believe we would collect the data that could support a potential accelerated approval based on the Huntington lowering biomarker. We then will be initiating an efficacy trial that would be in the context of an accelerated approval confirmatory study or if accelerated approval is not available, a Phase III trial for standard registration. So the conversation that we're scheduled to have with the FDA later this month is to discuss the potential of Huntington lowering to serve as a surrogate endpoint, given that there's clear evidence from preclinical and clinical studies showing that lowering Huntington protein 20% to 50% has been associated with clinical benefit and we're able to achieve that in clinical studies. And the idea would be that we would begin to get alignment with the agency on the use of that, of Huntington lowering, as a surrogate endpoint is that when we turn the data card over later in the spring, we could potentially have a data package that could support the accelerated approval.

Now given, certainly, tominersen and drugs in the past that have gone through the process, previously, the FDA has pushed back on the concept of accelerated approval. Obviously, this data set is different. How would you compare and contrast what the FDA has done in the past? And what's different about this particular therapy?

Yes. I think I pushed back that the FDA has done anything in the past on this because they really haven't. I think tominersen is a totally different drug. It's intrathecally administered. It's very limited in your ability to get pharmacodynamic measurements of Huntington lowering. It's injected into the intrathecal space. So there's no cellular compartment available to understand what the drug is doing in terms of lowering of Huntington protein. So I think that is an open question for the agency and we're the first therapy that's orally administered, that has systemic exposure or full brain biodistribution that allows us to say we can look in the blood and get clear evidence of the vetted particular dose level, how much Huntington protein we could lower in the cell. We could show that we're also getting distribution to the brain with the drug so that we can have confidence that what we're seeing in blood cell lowering is reflective of what's going on in the brain, which then allows us to say that we have that evidence that shows that we're having an effect on meaningful protein in the disease. So I think this is a highly differentiated therapy not only in terms of its route of administration, its biodistribution, but also the strong safety profile we've demonstrated to date and the fact that we've been able to show in the data we have so far that we're not only do we have a reliable measurement verifying that we're lowering Huntington protein in a dose-dependent fashion, but we're seeing that commensurate with lowering in the CSF and we're seeing evidence of favorable effect on clinical markets. That's a constellation of data no one has had before.

Of the downstream milestone payments, is there one associated with the full data coming up from the Phase II trial? Is there potentially one associated with if a determination is made that accelerated approval can go forward, the application, the submission, where obviously -- certainly, it will be one based on the approval itself. But...

Yes. I think we haven't broken out the milestone specifically, but I would say they start more from Phase III and later in terms of approval. I think this was a collaboration that was put together with a full development, a standard approval path as the base case with obvious incentives if there is an accelerated.

Got it. Got it.

And between development and sales milestone, they are roughly equally weighted.

And my last question on this, just from a bookkeeping standpoint. The profit share, just how should we be thinking about in terms of putting it in our models to -- so we're trying to be economically honest.

Yes. Yes. As of now, you -- it will be net, so one line item. So hopefully, that should help you out. That's how we're thinking about it as of now.

Got it. So let's jump on next, sepiapterin. Tell us about where things stand with sepiapterin, the NDA, there's a PDUFA date and what you're thinking about that.

Yes. So we -- we as well as the PKU community is incredibly excited about the sepiapterin opportunity. While there are 2 approved therapies for PKU, there remains a significant, significant unmet need as the vast majority of patients are not well served by the current therapies. Our drug, sepiapterin has demonstrated in Phase III to be able to provide highly significant, not only statistically significant but clinically meaningful effect on phenylalanine levels. And that's really the name of the game of PKU being able to lower phenylalanine sufficiently that patients could have improved symptoms associated with Phe levels as well as be able to liberalize their diet and be able to move away from the highly restrictive and burdensome Phe restricted diet that the patients are forced to have. And some of the Phase III trial, we were able to show that in 84% of the patients, we were able to bring them down to guideline levels of phenylalanine, which is less than 360 micromole per liter. 22% of patients had normalization of phenylalanine levels, which is almost never seen in clinical trials. The mean reduction in phenylalanine levels across the board were very strong, 69% in the more severe classical PKU patients. And we also had a subset of patients who entered the trial on Kuvan. So we were able to understand how much more we can lower phenylalanine relative to Kuvan in those patients, and it was over a 50% greater reduction in phenylalanine levels with sepiapterin, exactly what one would expect based on the sepiapterin mechanism. We then rolled the patients over into a long-term extension study where we've been able to demonstrate durability of phenylalanine lowering over time as well as continued safety and tolerability. And in our Phe liberalization protocol or Phe tolerance protocol, where we're able to specifically study how much patients' diet can be liberalized, we're finding that over half the patients are able to get to protein levels beyond what would be recommended for you an I on a daily basis and still have Phe levels within guidelines. So that constellation of significant Phe reduction, the ability to liberalize your diet for the full spectrum of PKU patients regardless of the agent, regardless of severity is incredibly powerful. And then when you think about the commercial landscape, the fact that they've been therapies before, many of the key pillars for commercial success are already there. There's newborn screening, there's centers of excellence. We know where the patients are, we know where the physicians are. There's a well-aggregated community and the payers are well-informed about what an effective PKU therapy looks like. And so we've said that we think given the fact that there's 17,000 to 20,000 PKU patients in the U.S., the vast majority of them, we said possibly even up to 90% of them are not served by current therapies. The fact that we have a data set that could be -- allow us to access every segment of the patient population, including those currently on therapy and the fact that we have such a differentiated product that enables a premium pricing strategy, we believe this could be a $1 billion-plus opportunity in the U.S. alone. As you mentioned, we've submitted the NDA. It's been accepted. We have a PDUFA date of June -- of July 29, 2025. The MAA is under review in Europe. We expect to have an opinion from the CHMP and adoption of opinion in the first half of 2025. We have files into a number of other regulatory agencies, including ANVISA in Brazil. We expect the JNDA into Japan before the end of the year. So we're well positioned with our current commercial infrastructure for a very successful global launch in 2025.

So do you think there's a disconnect with the investment community? They -- on one end they look at Kuvan and they know it's going generic. And on the other end, they see Palynziq, which is in the classical population. And they're just -- they kind of sit back and they're not really sure on either end of the spectrum, what it looks like. There's clearly a sweet spot. But as it drifts further and further into those other ends, they become increasingly tentative.

Yes, I think there's a disconnect on the surface. I think if you dig deep, it makes -- the opportunity becomes quite clear. The first disconnect is that it's a well-served community. So while you have a therapy on one end, you mentioned Palynziq, which can be for classical patients, it's used by a small portion of the population. It's an injectable that has a tolerability profile that patients say is very difficult. There's a high anaphylaxis rate, over 20%, patients are advised to carry EpiPens. It's very hard to titrate the therapy, and so -- and it's available for adults only. So you're talking about a very small segment of the population that's actually using it. On the other end, you mentioned there's Kuvan, but I think even has been discussed previously in other forums, at any time it may be less than 10% of the population on Kuvan because for many patients, it's not providing sufficient lowering of phenylalanine to allow liberalization of their diet. So if you're taking a therapy, but you still have to maintain a highly restricted diet, there's not a lot of perceived benefit to taking that therapy. So yes, on the surface, while one could say that Kuvan had peak revenue of $560 million, which was principally in the U.S. and Palynziq has revenues a bit less than that, that we automatically can't be higher than that is false because it's only a very small portion of population addressed by those 2 therapies. In fact, it's the fact that those 2 therapies have garnered that level of revenue that gives us confidence in what we say we can achieve in revenue because we're able to access so much larger portion of the population. And offer an oral small molecule that has demonstrated to date that's been safe and well tolerated, that has significant phenylalanine reduction, including for classical patients. It allows diet liberalization including for classical patients. So this is why we believe we can access every segment of this population. And with the pricing that we've talked about and the size of the population in the U.S. of being 16,000 to 20,000, we would need modest penetration to get to $1 billion in the U.S. So on the surface, I can see why there's a disconnect, but if you dig deeper and understand the true reality of the landscape and the opportunity, it becomes quite clear that our view of the revenue potential is quite real, and this could be a very meaningful product.

With respect to Kuvan historically, what do you think that the original data for the drug actually said? And how much could be attributed to the compliance of therapies to the drug and how their clinical, I guess, their results actually?

Yes. I think the issue, if you look back historically at the data, First of all, the clinical trials, the first trial was an all-comer trial to see what portion of patients could have a greater than 20% lowering of phenylalanine -- greater than 30% lowering of phenylalanine levels, and that was 20% of the population's all-comers. We did a similar running in our Affinity trial, and we had 2/3 of the patients had over 30% reduction, 75% of patients had over a 15% reduction. So right away, that tells you that we're across the board at an all-comer population having a significant benefit for a much larger portion of the population. When you look at the -- in their pivotal trial with Kuvan, I believe the mean reduction was 29% across the board. Ours was, again, over 60% and 69% in the classical PKU patients. We've also shown significant data thus far, supporting the ability for patients to liberalize their diet. So just on the surface, the strength of the data is much more stronger. And also when you think about the mechanism of sepiapterin, it has 2 different mechanisms of action. One is as a cofactor. So sepiapterin gets actively -- it gets easily absorbed from the gut, actively transported into a cell and in the cell, it can get can get converted into BH4. We are achieving much, much higher levels of BH4 in the cell. That's why what we've seen is if the patient does respond to Kuvan and they're going to have a much greater response to sepiapterin because they're getting more cofactor. It then has a second mechanism of action, which is a second chaperone effect that is not related to BH4. So that means we're able to provide benefit to mutations that are not "BH4-responsive." So when you think about this mechanistically, it supports why if there's been benefit to Kuvan, and we would have a much greater benefit and why we're able to provide benefit to a much wider population.

That's very helpful. Let's jump over to vatiquinone. There's an NDA coming up before the end of the year, which is also coming up.

Very fast.

The trial -- the MOVE-FA trial did not succeed in this primary endpoint, but you saw data within the study, specifically upright stability, subscale of mFARS as the primary endpoint that was that was positive. How would you -- what would you say to the predictive nature of that particular aspect of the endpoint?

Yes. I think it's really interesting, right? This is an example of evolving knowledge in the field. When we started the MOVE-FA study, it was believed that the mFARS scale, which is a composite scale of 4 different subscales that look at different parts of the disease was the best outcome for Friedreich's ataxia study because it was able to capture disease progression on all different patients regardless of their age and regardless of their stage. And so we went ahead and started the trial and designated that as the primary endpoint, and we've designed the study to focus on kids, pediatric patients and adolescents and young adults, primary analysis population was age 7 to 21. What was learned while we were doing the trial through a number of research efforts in the Friedreich's ataxia community as well as interestingly, a study partially funded by the FDA in children with Friedreich's ataxia was that the mFARS was great in theory, but different parts of that scale were relevant to different patients based on their age and stage. And if you're focused on a pediatric age group as our study was, it's the upright stability scale, that's the only part of that scale that's sensitive to change over time. It's the only -- it's the part of the scale where the patients progress the most. And thus the only part of the scale where you could register a treatment benefit in disease modification. And that was borne out in our results. So what we saw on the mFARS is if you look at the placebo group, who for over 72 weeks received placebo, we look at each of the 4 different subscales, it's basically flat line, no change on 3 to 4 scales. But if you look at upright stability, there's clear progression over the course of 72 weeks. And what that does is it supports what the researchers we're learning at the same time, which is for the patient population enrolled in MOVE-FA, the most sensitive and reliable measurement of treatment effect was the upright stability scale. And we had a statistically significant benefit as p-value of 0.021 on that. We had a 50% slowing of progression on that scale. And a lot of work has been done to look at the predictive nature of that scale on future risk of loss of ambulation. And the treatment effect we had over the course of 72 weeks translates to about a 9-month delay in loss of ambulation. And so this was something that, again, was emerging knowledge. So in our discussions with FDA, they have become very understanding of the fact that for the patient population in our study and for pediatric studies in FA in general, upright stability is the right outcome. It is the reliable outcome. Now of course, we were also able to show other really important data points that supports the reliability of that finding. First, we -- in addition to the overall scale having significant effect, we also were able to show that the individual items in the scale, which are lost progressively as a patient moves towards loss of ambulation, were preserved in a progression fashion. In other words, what we saw in the effect on the individual items is exactly what you expect to see if you had a therapy that was slowing disease progression on upright stability. We also showed concordance of changes in upright stability with the 1-minute walk test, again, suggesting that what we were seeing in upright stability in terms of slowing loss of ambulation is manifesting itself on a direct measure of the ambulatory function, the 1-minute walk test. We also had a significant benefit on the modified fatigue scale and of course, fatigue being the #1 patient symptom complaint in FA. So when you put that efficacy package together along with the strong package of safety we have particularly in children with vatiquinone, we were in a good position to have that discussion with the agency about being able to submit an NDA for Friedreich's ataxia.

Now you recently put out a press release, you said that you reached alignment with the FDA on key aspects. And I know that certainly the FDA has the nimbleness of shifting relative to what was a predetermined result objective of a trial to positive findings within the trial the FDA has not always been easy to work with in that regard. What makes you feel confident that the FDA will look at this submission with -- I guess, through the new lens.

Yes, a few things. First, this wasn't like we missed the primary endpoint, and then cherry-picked out a positive finding. This was a part of the primary endpoint that was collected and analyzed with the same rigor as the primary endpoint. And in fact, that this specific subscale was prespecified as an exploratory endpoint, but nonetheless, it was there, the fact that we were acknowledging there was emerging understanding of the importance of that subscale. So that's important. It wasn't like we looked elsewhere for something that we weren't even considering as a primary efficacy measure. The other part is we also were aligned on the confirmatory evidence. We discussed that in addition to MOVE-FA. We've been finding several sources of confirmatory evidence. First was the long-term data collected as part of MOVE-FA and that included an analysis of patients treated for 3 years, 72 weeks in MOVE-FA and an additional 72 weeks in the open-label extension that we would compare that treatment effect in those patients to a natural history cohort from the robust Friedreich's ataxia natural history database akin to what was done in Reata's confirmatory evidence for omav or SKYCLARYS now. And what we were able to see in that long-term analysis is that over 3 years, first of all, we hit the prespecified endpoint in the -- which was looking at the overall mFARS over 3 years. It was highly statistically significant with a p-value of less than 0.0001. We had a 50% slowing over 3 years of the disease progression. And that was really impactful in saying that what we observed in the short term is manifesting in the long term as a significant effect on disease slowing. We also were able to look at risk of loss of ambulation because we said if we were looking at MOVE-FA and said that we had significant effect on upright stability, which is suggestive of potential slowing of loss of ambulation, let's now directly measure that over 3 years relative to natural history. And again, we found a statistically significant reduction in risk of loss of ambulation over time, providing further direct confirmation of what we observed in MOVE-FA. We also agreed that we will provide confirmatory evidence from the second long-term study, which was the open-label extension or 24 months of treatment data from a placebo-controlled study than many years ago in ambulatory and nonambulatory adults and the results of this long-term analysis over 24 months, we had a 4.8% benefit on the mFARS scale, which translates to roughly 2-year saving disease progression. And again, this was highly statistically significant with a p-value of less 0.0001. And finally, we said we'll be able to provide mechanistic data from both preclinical and clinical studies that provide important evidence of biomarker effect on measurements that are relevant both to the mode of action of the drug as well as FA pathology. So the alignment with the agency was that we would submit a package that would support efficacy from those sources. And what gives us confidence is one of the discussions we had with the agency, and they've made it clear to us that questions they have about the efficacy will be matters of review, which to us was very encouraging that this file should get accepted and be reviewed very carefully.

Now let's jump over to Upstaza or KEBILIDI. Did I get that right?

Yes, KEBILIDI. Yes.

These names always kill me. Biotech names are tough. Tell us about the approval, how the launch in Europe and what we can learn from that relative to the United States?

We're incredibly excited about this approval. This is another example of how we've been able to pioneer a field of drug development. I talked about slicing earlier. That's obviously an incredibly powerful source of drug development in treating diseases. And what we've done with KEBILIDI or Upstaza, depending on where you are, was being able to get approved the first-ever direct-to-brain administered gene therapy, combining a specialized neurosurgical procedure, stereotactic neurosurgery with a gene therapy that's been able to demonstrate transformative effects on patients. AADC deficiency is a disease where children are growing without the ability to make dopamine. They lack the enzyme needed to make dopamine. We provide a gene to the exact spot in the brain where dopamine is needed, and we're able to see a few months after the administration of gene therapy that kids are able to start making dopamine. And then over the course of the next several months, we should then begin to attain motor milestones. First, the ability to lift their head and to sit up and to crawl and even walk. And so I think this is an example of a therapy that's not only pioneering but also one that delivers on the promise of gene therapy that with a treatment, you could truly transform the life of a child with an otherwise fatal disease. Given that this is a novel approach to drug therapy -- drug delivery through a brain surgical procedure, we clearly had to make a lot of learnings in the European launch. This is not as simple as a patient going to the doctor, getting a prescription and having their treatment. It requires significant coordination within the hospital, reserving operating room time, time in the radiology suite, preparing the nurses how to handle things in the operating room, the pharmacy has to be ready. And then we also needed to have all the important aspects of postoperative care, not only in the intensive care unit, but physical therapy and other things that are really important to ensure optimal success in therapy. When we launched in Europe, we said we would be relying on 3 avenues for commercialization. One would be through early access mechanisms, which we leveraged in the -- in several countries, traditional pricing and reimbursement, which we accessed in several countries as well as cross-border health. That is since we had centers of excellence of delivery of gene therapy in certain countries, it was literally easier to move a patient from one country to another rather than just set up another center of excellence in another country. We learned a lot from all of that. So as we -- KEBILIDI was approved in the U.S., we had already done the work of getting centers of excellence identified. We had -- we're still in the process of conducting a clinical study that supported the approval. And what we did in that study was have study sites, our key centers of excellence. So when we now come to launch the drug, we know that we have centers that have that experience already. They understand what's involved in the surgical planning and the surgical conduct of the procedure. There are teams of physical therapists and ICU know how to manage the patients in the perioperative and longer-term postoperative period. So we're now well-positioned to have a successful launch and get patients treated as quickly as possible.

Now if we jump over to Translarna, there's 2 ends of this. There's the -- I don't know, merry-go-round that's going on right now with Europe and the CHMP. Certainly, what's going to happen next because the CH -- or could the EC once again pass it back for another review causing more of a long-term dance. And then, of course, in the U.S., similar but different, the FDA submission, it's -- will be going in again soon. And how should we think about that?

Yes. So a few points. I think what gets lost in a lot of the back and forth and the seeming confusion over the regulatory pathways is the patient -- a group of patients with nonsense mutation DMD who desperately need a safe and effective therapy and the fact that over the years with Translarna, we've accumulated a strong dossier of data that supports both efficacy and safety over the long term. And so that's really, really important. On the European front, the discussions at CHMP were really about the structure of the confirmatory study, Study 41, and the fact that in the prespecified subpopulation, significance wasn't reached on the primary endpoint, but in the overall population, the ITT population of 359 boys, which is also what's in the label population we had significant effect across all the endpoints, and they had taken a very strict view that the primary analysis population had to be positive to confirm a conditional authorization. The European Commission disagreed and sent it back to them and said, please consider the totality of evidence not only within Study 41 but from the STRIDE registry, which demonstrates that over 5 years, we're having a significant delay, 3.5 years of loss of ambulation, a significant delay in loss of pulmonary function. Nevertheless, in this last procedure, the CHMP again remained narrowly focused on this primary subpopulation. In fact, in their own opinion, which they published, they acknowledge that there was significant benefit in other parts of the dossier, but that they weren't able to look at it, weren't allowed to look at it because we missed the primary endpoint. Of course, there's no law saying they couldn't look at it. That was the position they took. And so we'll now see how the European Commission weighs in. On the FDA side, we're very happy that we resubmitted the NDA, and that has been accepted for review by the FDA, and so it's under review right now. That NDA is based on the findings of significant benefit in the overall population, the ITT population of Study 41 on 6-minute walk distance, North Star Ambulatory Assessment, time function tests, time to 10% loss of baseline walk distance, all key efficacy measures in DMD and the confirmatory evidence provided in STRIDE that says these findings is a significant effect over 72 weeks in Study 41 are manifesting over many, many years and significant delay in the morbid milestones of disease such as loss of ambulation, loss of pulmonary function. So that package of safety and efficacy, we believe is quite strong, and we look forward to collaborating with the FDA during its review of the application.

Supposing the EC were to withdraw, have there been any stockpiling or anything of that nature because the patients will still want drug. And so there might be an element of trying to stockpile before any potential withdrawal.

Yes. So one thing that's been very clear that the voices of the patients, the families and the physicians in Europe have been loud. Loud in their belief in the drug, they're loud in the desire to maintain availability to the drug. It's hard to know about stockpiling and how that works and in terms of what's authorized in certain countries. What we're focused on now is, of course, making sure that we get drug to patients as long as it's authorized and we remain authorized and also exploring avenues to continue to make the drug available commercially to specific named patient mechanisms or other local mechanisms in different countries in the event that the drug is withdrawn.

Got it. Thank you very much for your time.

Thank you, David.

Appreciate it. Always glad to have you.

Thank you.

Thank you.