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

Good day, and thank you for standing by. Welcome to the Translarna (Ataluren) Study 041 Topline Results Call. [Operator Instructions]. Please be advised that today's conference is being recorded. [Operator Instructions]. I'd now like to hand the conference over to your speaker today, Kylie O'Keefe, SVP of Global Corporate and Commercial Strategy. Please go ahead.

Good morning, everyone, and thank you for joining us today for the Study 041 Results Call. Joining me on today's call is our Chief Executive Officer, Dr. Stuart Peltz. Slides are available on the Investors section of the website for you to follow along during the presentation today. I will now pass the call over to our Chief Executive Officer, Stuart Peltz. Stu?

Thanks, Kylie. And thank you all for joining us today. We're excited to share with you results of the confirmatory global placebo-controlled Study 041 trial of Translarna for the treatment of nonsense mutation Duchenne muscular dystrophy. Before we start, let me remind you that today's presentation will include forward-looking statements. Actual results may differ materially from those indicated by the forward-looking statements as a result of various important factors, including those listed on our FLS slides and discussed in the Risk Factors section of our SEC filings, including our most recent Form 10-K. In addition, these forward-looking statements represent the company's expectations only as of today, and we disclaim any obligation to update these statements in the future. On this call, I will provide an overview of DMD and Translarna, discuss the real-world evidence of the Translarna benefit from the STRIDE registry and then share the top line results of Study 041. Let me begin by reminding you of the overview of DMD and Translarna. I founded PTC over 24 years ago to use pioneering science to develop innovative therapies for rare disorders. Our initial research focus was on identifying orally biovailable nonsense mutation suppressing molecule. This work yields our first development candidate ataluren, which became the first-ever therapy developed for children with nonsense mutation Duchenne muscular dystrophy. When we began the clinical studies with Translarna, there was very little known about developing DMD drugs. This required us to pioneer how to develop a drug for DMD patients, while simultaneously studying Translarna. This included both an understanding of the natural history of the disease as well as determining the best endpoints to measure in DMD patients. We're proud to be able to say that Translarna was approved in the European Union in 2014 and was the first-ever approved therapy for DMD boys. Today, Translarna is available commercially in over 50 countries around the world, pioneering a new therapeutic indication with a new mechanism of action and a new chemical entity is challenging. And while there have been a number of successes and setbacks on this journey, we're incredibly proud of our efforts have paved the way in DMD to bring new therapies to patients. Duchenne muscular dystrophy is a relentlessly progressive fatal genetic disorder. DMD is an X-linked muscle disease that affects an estimated 1 out of 3,500 to 5,000 live births. DMD arises by a mutation of the dystrophin gene that leads to the absence of the dystrophin protein, knowing the patient's genotype is very important since, for example, only patients that have nonsense mutation DMD should receive Translarna. DMD is a neuromuscular disorder that leads to relentless and progressive loss of muscle function. This leads to a predictable decline of motor, pulmonary and cardiac function, ultimately resulting in death at far through early in age. Deterioration of ambulation occurs in the first and second decades of life, wheelchair dependency in the second decade and eventual respiratory and cardiac failure with mortality seen in the third or fourth decade. While the precise timing of the event is not the same for each DMD patient, this disease follows the same course. Now dystrophin is an important structural protein in muscle cells that protect them from the stress that occurs during muscle contraction. In the absence of dystrophin, muscle contraction causes an excessive force, leading to breaks in the muscle membrane, ultimately resulting in muscle loss. Restoring dystrophin early delays the progression of muscle deterioration. Translarna works by reading through nonsense mutation to restore dystrophin production. During protein synthesis, a normal messenger RNA is translated by the cellular machinery to make a full-length dystrophin protein. However, a mutation called the nonsense mutation in the DNA is a single point alteration that leads to an mRNA that has a premature stop codon in the protein coding region that causes premature termination leading to incomplete dystrophin production and the mRNAs that rapidly degraded. Translarna works by interacting with the translation machinery to trick the cellular machinery so that instead of terminating translation, an amino-acid at the premature termination codon is inserted enabling the production of the full-length dystrophin protein. Previous Translarna clinical trials demonstrate benefit over placebo across multiple disease endpoints, including the 6-minute walk test and timed function test. The graph demonstrates the positive finding from Study 007 and study 20 as well as the results of the meta-analysis of both studies. In addition, results from additional clinical endpoints, including supine to stand, the North Star and the quality of life measures that both studies also favors Translarna's treated patients. Now I'll turn to the ongoing STRIDE registry, which is the patient registry collecting long-term real-world evidence of Translarna. While clinical trials are designed to capture treatment effect that may predict long-term benefit, the STRIDE registry captures the real-world evidence of long-term treatment effect on key aspects of disease morbidity. The latest STRIDE [ cut ] includes data from 13 countries and 288 patients. Based on the most recent STRIDE data cut, Translarna treatment significantly preserves ambulation in DMD patients. Translarna treatment also significantly acutely preserve pulmonary function. In addition, Translarna treatment protects against loss of pulmonary function. Less than 30% FVC predicts mortality in DMD patients within 2 to 3 years. These are truly clinically meaningful treatment benefits over the course of DMD. As part of the EMA Translarna conditional marketing authorization, we needed to submit annual data reports collected through our post-approval STRIDE registry to confirm the favorable benefit/risk ratio of Translarna, which formed the basis of the initial marketing authorization. We recently shared the positive opinion from the CHMP in support of the eighth annual renewal of Translarna marketing authorization based on the continued safety and clinical benefit captured in our real-world STRIDE study. In addition to the annual renewals, an additional confirmatory clinical trial was required as part of the conditional marketing authorization that is our Study 041. The study was designed as a global placebo-controlled trial of 144 weeks duration, with a 72-week placebo-controlled phase, followed by a 72-week open-label extension, during which all subjects would receive Translarna therapy, but remain blinded to their initial treatment assignment. Key inclusion criteria include genetic confirmation of nonsense mutation, ambulatory baseline with a baseline 6-minute walk distance of greater than 150 meters and a stable use of corticosteroids for a minimum of 12 months prior to the study start. The primary endpoint of Study 041 is the rate of change in 6-minute walk distance with key secondary endpoints of North Star Ambulatory Assessment and timed function tests. Randomization was 1:1, placebo to Translarna at a single daily dose level of 40 milligrams per kilogram. Randomization was stratified by baseline walk distance and type of steroid use as well as time from supine to stand. This was the largest prospective trial conducted in DMD with an intent to treat population of 359 boys with nonsense mutation DMD. As you can see, the treatment of placebo groups were well balanced with regard to age, baseline walk distance and other key patient characteristics. The overall quality of the study was good with very few patients not completing the week 72 assessment, which is pretty remarkable considering the study was conducted during the COVID-19 pandemic in countries that were significantly impacted. I'll now turn to the results for the ITT population. As you can see, there was a statistically significant Translarna effect on the 6-minute walk distance in the overall population of 359 boys. This is the first time that a prospective analysis has demonstrated a statistically significant treatment benefit in DMD. For this analysis, the primary endpoint was the rate of change on the 6-minute walk distance as determined by a mixed effect modeling approach, and we see that there was a 21% slowing of progression by Translarna relative to placebo, a meaningful impact. In addition, almost twice as many patients in the placebo group lost ambulation as compared with Translarna treatment group. These results are slowly declined in ambulation and loss of ambulation are consistent with the long-term treatment benefit that has been recorded in the STRIDE registry across the overall population of ambulatory nonsense mutation DMD boys. Next, looking at the NSAA, we again see a statistically significant benefit of Translarna relative to placebo using both the total score and the weighted linear score. Finally, we see a significant effect of Translarna on the 10-meter walk in stair ascend timed function test. We're thrilled to be able to see this consistent, statistically significant effect of Translarna across the entire ITT trial population. In fact, this population mirrors the population seen in the STRIDE registry, where we also see positive results. Next, we looked at the effect of Translarna on preservation of ability to perform each item in the NSAA in the ITT population. This is an important analysis as it provides more granular data on the meaningfulness of the statistically significant changes recorded on both the total score and linear score analysis. In this analysis, we look at the proportion of Translarna and placebo subjects, who lose the ability to perform each of the 16 tasks in the North Star. As you can see, Translarna had a marked protective effect on the ability to perform virtually all of the North Star tasks, including reducing risk by more than 30% or 40% on several tasks. Again, these data provide important evidence of clinically meaningful treatment. As I said earlier, Translarna has demonstrated a consistent treatment effect across multiple clinical endpoints in a broad nonsense mutation DMD population in previous trials. We also looked at 2 subgroups, one of which was the primary analysis subgroup. In the next few slides, I will discuss how the data from the previous trials and formed the selection of those subgroups. Our analysis of data from Study 007 and Study 020 showed that the DMD patients with the baseline walk distance between 300 and 400 meters baseline group demonstrated the greatest treatment effect relative to placebo over 48 weeks. This was based on the fact that boys with a baseline walk distance under 300 tended to rapidly decline and lose ambulation, not allowing practical demonstration of treatment effect. Conversely, boys with the baseline mark distance over 100 -- over 400 meters tended to be stable over the course of 48 weeks, making it difficult to capture treatment benefit. The 300 to 400-meter baseline group are most likely to decline, but not lose ambulation. We then look to see if there was a better criteria that could identify an ideal responder population. Based on an artificial intelligence analysis, boys with a baseline walk distance of 300 meters and the supine to stand time of greater than 5 seconds appear to better characterize the responder population. Accordingly, we've designated that group as the primary analysis population for Study 041. I want to now share the results obtained in Study 041 in these 2 populations. First, looking at the 300 to 400-meter group, we again see that Translarna treatment and placebo populations were well balanced in terms of age and baseline walk distance. Similarly, when we look at the 300-meter and greater than 5-second group, we see that there's a good balance in the 2 groups. Looking at the results first in the 300- to 400-meter group, we see statistically significant effects on the walk distance and rate of change as seen within the overall ITT population. I want to point out that the difference in walk distance between the Translarna treatment group and placebo group is much larger in the 300 to 400-meter, which is consistent with our previous trial, in which we identified this group as the one most likely to observe the greatest Translarna treatment effect. Looking at the North Star and timed function test, we again see statistically significant effects on the North Star linear score and the 10-meter and stair ascend timed function tests. However, when the previous study suggested that the 300 and greater than 5-second group would also be able to capture significant treatment effect. This was not the case in this trial. While the results for each endpoint favor Translarna treatment, the results were not statistically significant and were, in fact, a less magnitude than the overall ITT population. Finally, we performed a pooled analysis from the 007, 020 and 041 studies, which includes over 700 DMD boys. This analysis was performed using the 48-week data from Study 041 as the duration of 007 and 020 was 48 weeks. As you can see, there's a highly statistically significant effect across the 6-minute walk distance, NSAA and timed function tests in this analysis, with a p value of 0.0002 for the 6-minute walk distance, signifying a clear benefit of Translarna treatment across a large population of nonsense mutation DMD boys. In addition, and as expected, when pulling the data from all 3 studies for the 300 to 400-meter subgroup, the results were highly significant. And the treatment effect in terms of walk distance was greater, confirming our earlier observation that the 300 to 400 group is likely to show the greatest treatment effect. From a safety point of view, Translarna was well tolerated without any drug-related SAEs, no adverse events leading to discontinuation occurred, and there was no difference in AE frequency between Translarna and placebo. In summary, Translarna is the first disease modifying treatment for DMD to show a statistically significant treatment benefit across the entire ITT population. A statistically significant treatment benefit was also seen in the 300 to 400-meter subgroup as in previous studies. In the primary analysis, 300 meters and greater than 5-second subgroup, while we demonstrated a positive trend across all endpoints, statistical significance was not achieved. Study 041 results adds to the totality of evidence demonstrating clinical benefit of Translarna both in clinical trials and in the real-world study. Lastly and importantly, Translarna demonstrates a favorable safety profile with over 3,000 patients treated. For EMA, we utilized the MMRM analysis, to calculate the rate of change in 6-minute walk distance and other endpoints. The FDA asked that we analyzed the results with an ANCOVA model as the primary analysis with the MMRM model as a sensitivity analysis. The basic difference is that the ANCOVA only looks at 2 time points, baseline of week 72, whereas the MMRM includes all observations for all subjects, which, in our view, represents a much more robust approach to the data analysis. As you can see, when using the ANCOVA model, we get similar or slightly larger estimate of the difference between placebo and Translarna groups on all endpoints, confirming the robustness of the estimate of effect size. Although the ANCOVA model utilizes less information and therefore is less powerful analytical approach, it does confirm the results of the MMRM approach with P values trending towards significance. Importantly, again, we see that all endpoints results favor Translarna. The results for the subgroup analysis were similar with similar estimates of effect as with the MRM -- MMRM, but with a slightly higher p values. I want to point out that the pooled analysis was conducted using an ANCOVA approach given different time points when measurements were collected. These results remain consistent with a statistically significant treatment effect across all endpoints when pooling their results. In conclusion, we're able to demonstrate for the first time a statistically significant benefit of Translarna across a number of disease-relevant functional outcome in the broader overall study population. We believe these results, along with the evidence of real world that have been generated from our STRIDE registry should allow for the continued authorization of Translarna in the European Union and reinforce our strong value proposition with payers in the EU and international markets. In addition, as the study results confirm the benefit of Translarna, we plan to request conversion of the EU conditional marketing authorization to standard marketing authorization. Finally, we remain fully committed to bringing Translarna to DMD boys in the United States, and we look forward to discussing these results and potential path forward before approval with the FDA. I'll now turn over to the operator for questions. Operator?

[Operator Instructions]. Our first question comes from Kristen Kluska with Cantor Fitzgerald.

Congratulations on these data. So you noted that the last 8 years, the drug was renewed by Europe. So what, in your view, were the key drivers behind the agency decision to do this each year, particularly as the evidence of effect has grown with additional time and additional patients added? And what's the specifics of these data that you reported today do you think will be most important? And I have a quick follow-up.

Please standby.

Oh, sorry, can you hear me? Right. So let me just remind that the approval was in 2014, where we got the approval based on Study 007 on the difference in the 6-minute walk test, timed function test and a whole bunch of other measures where we showed that everything was going in the right direction. And that based on that, we also had the STRIDE registry, which we did. And so we monitor that. And that's real-world data that includes looking at long-term effects, such as preservation of ambulation by looking how much time that a patient goes before losing ambulation, preservation of being able to get off the ground, stand to supine and also the pulmonary function measurements. So it's a combination of the improvement of that. And then we did Study 020. It also demonstrated that was the case as well, where, again, we saw patients, where we saw an improvement in the 6-minute walk test, timed function fests and North Star. So those were the -- so that was there, then we continued to get the STRIDE data set. And the STRIDE data set becomes really quite powerful where we saw at the end of the day, 5.4 years of preservation, 2.1 years of being able to get off the ground and really the pulmonary function data that showed that you've got years of improvement of pulmonary function. And that really most of what we showed you [ on years ] the FVC less than 30% and how substantial that was. Those -- we have 30% that predicts mortality within 2 to 3 years. So then you have all this data. And then you come in with the Study 041, which takes all comers. And what you see is what we're really excited about in the overall population, in the ITT population, which is everybody, we saw statistically significant improvement over placebo, not just also in the 6-minute walk test, but the North Star itself and as well as the timed function test as well. And then if you look in the group, more likely to see a decline, like in the 300 to 400 group, you saw it as well and it was bigger. And then the other thing I think is so telling is that when you do a pooled analysis of 007, 020 and 041, and you see about a 19 meter improvement in the overall population with a p-value of 0.0002. But it's not only that. You see it in the 300 to 400 also gave you about a 30-meter in that pool with a substantial p value as well as the North Star as well and the timed function set. So you put together all of that data and you could demonstrate if anyone is going to say, is there any doubt that this drug is active. You could see it very clearly with the population that even in the overall population, that means all patients that you see clinical benefit relative to placebo and in the population where you can most see the differences, you see even a larger change. So all in all, we think that this is telling us very well that the drug is -- the drug is quite active.

And just a quick follow-up. If you could comment or share any trends related to percent or amount of time for the open-label extension portion of Study 041 and also when you may look to do the next STRIDE data cut.

Sure. So you might remember, it's a 72-week by 72-week follow-up where the people [ dosed ] in terms of the study. People don't know whether they were treated on a placebo. So that will be ongoing. And Matt, you known when is [indiscernible]

Yes. So in terms of the -- so Kristen, again, thank you for the questions. So we obviously we're focused right now on completing the placebo-controlled analysis and will dig into the 144-week data once all those subjects are completed with that portion. With regard to the STRIDE data, we're preparing the next data cut right now, and we'll be planning to present those at the World Muscle Society in the fall.

Our next question comes from Raju Prasad with William Blair.

Sorry, I had some kind of [indiscernible] issue. Did you say anything on when you plan on maybe filing for BLA with these new results?

Yes, sure. So yes, thanks for that question. Obviously, we're really quite excited about the results of this. And so obviously, this will be -- this was a confirmatory trial for the EU. The next steps for the FDA are going to be obviously go and talk to them on this defining the path forward so that we can have a path for bringing Translarna to patients in the U.S. So we want to align on that path for the regulatory process. And so we'll be obviously setting up for a meeting for that discussion that we would then plan and hope to have a foot in the NDA after that.

Okay. And then -- should we anticipate dystrophin results from the study at some point in the second half of the year?

No, there are no dystrophin. There are no dystrophin studies that went along with this particular trial. This is purely on clinical. Like I think this is -- as we know, the dystrophin data, it's a funny biomarker in the sense that no one has ever shown that it actually predicts clinical benefit. So this has been a functional study.

Okay. And maybe one last question. It looked like across [indiscernible] defined characteristics of these patients, roughly 40% were on deflazacort.

I'm sorry, can you repeat that?

Sorry. It looks like in the baseline characteristics, roughly 40% of the patients were on deflazacort, is that kind of similar to the numbers you're seeing in the U.S. [ agent ] with Emflaza?

No, I think this was done -- this study was done in a lot patients around the globe. And therefore, I don't think it's necessarily representative of the deflazacort percentage in the U.S. or Europe.

Our next question comes from Eric Joseph with JPMorgan.

Congrats on the update here with Study 041. Just a question on the hierarchy and endpoint analyses between the subgroups and the ITT population. I'm just curious as to whether having missed that [indiscernible] in the greater than 300-meter and greater than 500 -- sorry, greater than 5-second supine to stand, whether that challenges the, I guess, the veracity of the benefit seen in -- the static benefit seen in the ITT or other subgroups? How are either FDA or the CHMP going to kind of look at the totality of the benefit given that you missed that [indiscernible] on the primary efficacy analysis?

Yes, Eric, Matt here. Thanks for the question. So clearly, the reason we think about looking at subgroups is trying to find a population that would be most sensitive to change in the conduct of a clinical study, knowing that it's very difficult in a heterogenous disease, like Duchenne muscular dystrophy, to be able to demonstrate a statistical effect in the broad population. Obviously, I think it's a much stronger data able to show that work, particularly in this population, statistical significant improvement in walk distance, in North Star [indiscernible] test. And in many ways, the ITT population is consistent with the broad label we currently have and also sets the foundation for being able to go to the FDA and have discussions about being able to, for the first time, the statistically significant functional benefit. In terms of your specifics on statistical analysis, since [indiscernible] 300 and greater than 5, that subgroup didn't hit significance, we then go to a different [indiscernible], which is the broader population and conduct those analyses without having the need for multiplicity at all. So those data stand, those p-values stand. And again, they provide really for the first time, [ creation ] of statistically significant benefit on the key endpoints in DMD [ walk test, North Star ].

Our next question comes from Tazeen Ahmad with Bank of America.

Just a point of clarification. As far as EU is concerned, what was your agreement about this study, about 041, that achieving statistical significance would be sufficient to get it permanently approved? Or are there additional data points that the European Union would look for before granting that permanent approval?

Sorry -- So yes, thanks for the question, Tazeen. The -- what they -- what the EMA was looking for was looking for the totality of the data, right, because -- so they -- as you noticed, it's a study, it's a broad study of patients of 5 years -- 5-year-old and older within the study period. And so we took all comers. So I think that's what they wanted. They wanted us to look at how people did across the disease progression line. And so -- the good news here, I think that's what so [ stellar ] here is that the study was large enough that we were able to see in the overall population that we were able to see a statistically significant result of 19 meters, which was consistent with the Study 020. And that furthermore, in the group that I think is pretty clear now is the right group to look at foreseeing where it's more [indiscernible] declining. In the 300 to 400 meter, you also saw a larger increase in that as well. And then the fact that the North Star demonstrates improvement and statistically significant as well as the timed function test, I think that's a pretty good package demonstrating that. Then when you put that in line with the STRIDE registry, which if you think about -- what's so interesting about the STRIDE registry, from my point of view, is that a clinical endpoint was to predict long-term outcomes on patients, right? So you're looking at 6-minute walk test, North Star, 16 or 17 different functions, the timed function tests going up and down steps. And in essence that -- those are endpoints. And then the outcomes are preservation of walking, the preservation of being able to get off the ground, the preservation of pulmonary and cardiac function. And what the STRIDE registry showed is over -- and that's a 5-year study, where you're looking at those hard endpoints, where you saw a 5.4-year improvement in preservation of walking, approximately 2 years in terms of getting off the ground, FVC-30, which predicts mortality, you see in our patients virtually no mortality relative to -- or growing lower than 30% relative to natural history. So you put all of that together with the data that we have, along with the natural history -- and by the way, this is somewhat historic from the point of view of like our endpoints in the Duchenne trial demonstrating statistically significant. But you put that all together, obviously, what we're going to do is not only work with the EU, it's strong proposition with payers, the international markets, but it gives us opportunity to go from a conditional marketing opportunity to a normal -- a standard one.

Okay. So just to clarify, just based on the data that you have in-house, do you think that EU will grant you a permanent approval in Europe?

Yes. So what we think is -- what we're going to be requesting is conversion of the EU conditional marketing authorization to a more standard marketing authorization.

Okay. Okay. And then what kind of agreement do you have with the U.S. on what this data needed to show, I guess, coming into the data? And can you talk about the importance of being static on MMRM versus ANCOVA?

Sure. Obviously, again, I think my own view is, I think that, firstly, we're obviously quite excited about the notion, that Study 041 in the broad ITT population demonstrated benefit, was better in the 300 to 400, the NSAA statistically significant in those populations as well as the [ ITT ]. Obviously, when you think about the MMRM versus the ANCOVA, the ANCOVA uses baseline and the last week, week 72. So you're only using really 2 data points to get to that answer. Then on MMRM. The MMRM uses all the data points. And that's why you get better [ confidence ] in terms of the variation, and that's why I think you get a better idea of what the statistical significance is. They, however, asked us to do ANCOVA, but do then do a sensitivity analysis with the MMRM. Now I would point out to you that the MMRM is not something that's fore into the FDA, they use it quite a bit. And so we use both analysis. We think that MMRM allows for more precise estimate, which is why you have lower standard deviation. And it's been used, if you look like the [indiscernible], they talked about the using -- they performed the MMRM there as well. So I'm not -- my guess is they're quite knowledgeable of this. But that's going to be the conversation as we talk to them about it.

Okay. And this would be my last question. Just to clarify though, FDA did ask for ANCOVA as the analysis preferred over MMRM?

No, no. Okay. You got to be very clear because I don't want it to be [ written ] as just the ANCOVA. It's both. They asked for both, the ANCOVA and the MMRM.

Our next question comes from Robyn Karnauskas with Truist Securities.

Congratulations on the data. I just have a couple. I guess, first, just to follow up on the last question. The FDA asked for both. Do you think that you want both to be positive? What is the precedent for like how the FDA treats both the statistical analysis? And what was the primary for statistical analysis plan? And the second question was given that $300 million to $400 million was not a part of the primary analysis population, how do you think the FDA will view that subset analysis of more than 300 and greater than 5? And I guess lastly, third, what is that percent of the population if they were to make a more restrictive label?

So the question is -- so was it the ANCOVA was the primary, MMRM was sensitivity analysis. So -- but they use both. So in my view, we'll be talking to them about that. The 300 to 400 is something that we had defined now and published in multiple publications, right, because when we think about -- when you think about the -- what are we trying to do in this case? And why is this the group that shows the greatest change? It's because patients greater than 400 tend to be stable for that period of time, whereas patients -- and patients less than 300 often tend to go [indiscernible] and it's hard to stop, right? So between those 2, the 300 to 400 group seems to be a group that is -- what we've seen is the group of patients that are in the decline phase, but are less likely to [indiscernible] right? So it gives you a better indication of looking at, in a sense, what's the largest effect that one can see, right? So that's the -- that lets you get look at that effect. So you can see in the ITT population, what's nice about that as you now know that it helps all the patients within that we've tested for 5 years and greater, right. And then what's a larger effect, you can see in patients that are all declining, you get to see that in the 300 to 400. And then it's consistent with the NSAA and the ITT, they all come to be -- they all were positive. So when you -- and then you look at the test, I think what's interesting about the ANCOVA and the MMRM is they actually gave you the same numbers basically, right? And that's a good thing because we know what the treatment effect is. The question is in terms of the variability. Now we all know the MMRM is better at looking at all the data, so it gives you a better fit. The ANCOVA gives you a less good fit, and that's probably why the p values were a little bit larger. But that being said, they're not the -- they're not that much larger. What I think what you've seen when they've talked about P values, well, they're not at 0.05, they're not unduly large. So I think they can look at that as well. So I don't think that we're going to -- we'll see in our discussions, but we don't expect issues with this, nor do we expect the restricted label because of the observations we saw in the overall ITT population.

Got it. And just on Slide, I think, 22 at the bottom, you talked about the ITT population was not the primary analysis population, that seems like the entire data set that looks the most clean, what was the primary analysis population for the study? So it says at the bottom, the ITT population is not the primary analysis population. This is first Study 041. I was curious like what was the primary analysis population?

Yes. So Matt here. Thanks for the question. As we mentioned earlier, when you -- given the heterogeneity of DMD, we would have expected to see a significant effect in the overall ITT population. So in our previous studies, we had done some work to try to identify the group that's most sensitive to the change of the trial. And so that work yielded first 300 to 400, then we look closer and identified 300 and greater than 5 is having a greater fit treatment recorded in the previous study. So we designated that group, the 300 and greater than 5 as the primary analysis population. We had the unexpected and quite frankly, excellent results of having now shown statistically significant effects in the broader overall population, which again is consistent with what we've observed in STRIDE and consistent with the broad benefit in slowing disease progression and DMD boys now recorded in a double-blind prospective trial on the with walk test, with North Star with timed function test.

Got it. I got it. It just seems like I guess in the FDA conservative nature that they're in today, the question is like, do you think that they will -- or if you've had discussions with them about what happens if that were to [indiscernible] that was a very unexpected result, I guess, is more a robust response in ITT, but then that subpopulation, if you don't exclude the stable patients isn't as ideal for the primary. So like how -- given that we're all nervous about the FDA, could you give us like maybe some [ nuggets ] to make you feel more comfortable that they'll be more open to looking at all the analysis you presented today?

Yes. So let me first start with EMA and emphasize again that this finding in the ITT population is consistent with the label we have in Europe, which is demonstrating a significant benefit across the broad population of DMD patients. And as Stu emphasized, this is really consistent with what we see long-term STRIDE. We can now piece together the slowing of progression in the course of a clinical trial with a slowing of loss of ambulation, loss of pulmonary function in the real world. That's an incredibly powerful data set, which is quite unique, and we think very, very compelling. Turning to the FDA. I think it becomes equally compelling. Again, we do clinical trials to try to get an idea of how a drug will perform in the real world. The FDA talks about using potentially enriched populations to try to capture clinical [indiscernible] course of a trial, particularly in heterogeneous rare disorders, like DMD, where they believe it's quite a challenge to demonstrate an ITT population statistically significant effect. I don't think anyone has shown in a double-blind, placebo-controlled of DMD, a functional -- statically significant functional benefit. And so we're in a situation where we did say that we'll look primarily at a subgroup. However, we actually, again, have the unexpected, but we think quite important finding of statistically significant benefit across entire population. When we look then across the 3 studies in a pooled analysis and have a highly statistically significant effect, now with 3 prospective double-blind, placebo-controlled trials in the entire population and then we can marry that with real-world evidence, which demonstrates that the slowing progression recorded in this trial is consistent with slowing of loss of key functional milestones over the lifetime of DMD patients, and those are very compelling arguments to regulators everywhere.

Our next question comes from Brian Abrahams with RBC Capital Markets.

Congrats on the totality of the data here. With a couple of housekeeping questions, and I apologize if I missed this earlier, but what was the p-value for the primary endpoint for the primary analysis population using ANCOVA?

What is it?

ANCOVA [indiscernible] 300?

Yes, the 300 and 5 -- the 300, 5 population, the primary analysis?

Yes. And that is 0.36.

Got it. And then I know it sounds like the FDA is going to consider both ANCOVA and MMRM potentially. Was 1 of the 2 the prespecified statistical methodology in the statistical analysis plan? Or do you sort of -- are kind of both looked at in these types of studies equally?

Yes. So both were included in the statistical analysis plan as they wanted the primary ANCOVA with supporting sensitivity done with MMRM to one, obviously, examine the robustness of the estimates of both models and then allowing for the variability, which is not typically accounted for an ANCOVA, but provides a robust estimate for the MMRM. So [indiscernible] the same treatment effect, but when you have a more robust analysis, you have decreased variance, and they're statistically significant.

Got it. No, that makes a lot of sense. And then can you clarify -- and just as a follow-up maybe to Eric's earlier question, the ITT group, was that a prespecified analysis group, even if -- I know if you didn't hit on the primary analysis group, the statistics, you don't kind of continue necessarily with the hierarchy, but was the ITT group among those -- those groups that were prespecified in the analysis?

Yes. And you always do the ITT. In our view, if you hit the ITT, where you're demonstrating all patients with the Duchenne muscular dystrophy, that was a big deal.

Yes. Perfect. Makes sense. Maybe 1 more quick 1 if I could squeeze it in. Just any sense as to what the FDA or U.S. KOLs are looking for with regards to clinical meaningfulness on the magnitude of benefit here? And just obviously, you're showing overall consistency across several of these studies now. But just sort of wondering if there's -- if that hadn't been discussed at all in your meetings and discussions with them. I'll hop back in the queue.

Well, that's the beauty, I think, of clinical -- of having the STRIDE registry that goes along with the clinical -- taking the clinical end points that what we have here, which we saw, if you look in the overall -- like if you take all the boys in the pool, you're getting about a 30-meter difference in the 6-minute walk test larger in the -- you're right. So that's good. But what tells you where things are in the STRIDE registry, where when you see the results that you have now, and what are the end points that it's giving you, it's -- we're seeing, what greater than 5 years in terms of preservation of walking, years in terms of preservation of being able to get off the ground and also really in cardiac and pulmonary function in FVC years of [ loss of 60 ] and really virtually no loss of FVC 30 in our case, which is really the measure of ultimately mortality in that case. So I think that's actually pretty strong data demonstrating clinical benefit for these patients. And then could you take that off the [indiscernible]. Then the -- the -- we also looked in the preservation to perform the NSAA. And what we did is when we looked in the ITT population, in North Star, right, the 16 or 17 measurement, which is you can do it, do it with trouble or change, we saw in that particular group of 20% stabilizing a function within that group over the period of time that we studied in all of them. So this also shows strong improvement in terms of functional outcome measures as well. So we use the end point in these studies to look at ultimate functional consequences of that. And in the North Star, we show that they preserve functions as well. So the combination of the STRIDE data, looking at the NSAA data and the clinical outcome measures, I think, give a pretty strong measurement in terms of what's the effect of an outcome. And let's put it into perspective. Where the group that actually has the data and what are the consequence of -- we can actually make the connection now because of the STRIDE data that we have, what is the effect of ataluren on patients for a really hard endpoint based on the data that we got now. So what you're able to say is that with the data and the results in the STRIDE data is having a pronounced effect on the outcomes of these [ kids ]. So that's what's so exciting. I mean, it isn't just like a prediction, we have the data.

So. That's super helpful. And Matt, just wanted to clarify on my earlier question, the 0.36 p value, I think that's listed in the slides as the MMRM p value. Is that also the ANCOVA p value as well for the primary endpoint?

Yes. Brian.

Our next question comes from Joseph Thome with Cowen & Company.

Maybe in your historical interactions with the FDA around Study 007 and 020, did you ever present MMRM analyses of those trials to the FDA? Or are those just ANCOVA based? And just trying to figure out when in the FDA's history, they decided to incorporate this new metric? And then second, in terms of FDA interactions, if it is decided that maybe this trial isn't sufficient for a submission. I guess what is PTC willing to devote to Translarna further in the U.S.

Yes. So obviously, I think we're thrilled with the data in terms of the overall ITT population. But -- I mean even in the ANCOVA while it missed in terms of -- it certainly trended in the right direction it's -- with the MMRM. And so our -- obviously, our goal is to talk with the FDA and just convince them that we should move forward with this. So that's what we're what we're doing. The MMRM is not a new measurement. It's what we've done in the past. So I think -- and actually, they like MMRM, right, because it's a standard methodology that people use that take into account the data. So and the matter of fact that they wanted us to do it both as a sensitivity analysis. I mean I think they're good at this. So the repeat measures helps you get an idea of what's the best fit for the data that gives you the best p value. So I think at the end of the day, they'll look at this quite carefully. And the totality of the data and the [indiscernible]. The other thing is when you're using all of the data from Study 007, 020 and 041, right? So your -- that should also give you confidence in the -- and actually the data is pretty consistent. We're seeing, what, 14, 15 meters here and 19 meters, 20 or so, 30 meters in 007. It's not actually -- they're not that far off and there's consistency within the results within the data itself. So when you look at that nice consistency throughout the different trials, I think it keeps adding to the confidence that this drug is active. So I think we feel we're in pretty good shape there.

Just 1 quick one, maybe, obviously, great to see that everything is trending in the right direction. But in terms of -- you've been with this patient population for a long time, is there a bar for sort of clinical meaningfulness for 6-minute walk or NSAA that physicians are looking for, just to kind of put the data from the overall population in perspective?

Yes. I think that's a great question. And that's why I was harping so much on the STRIDE data because at the end of the day, those are outcome -- those are clinical endpoints that predict outcome, right? And the outcomes are what you anticipate is preservation of function, right? At the end of the day, that's what you want the 6-minute walk test, the North Star, all these other things to do. And so what we've shown is that from the STRIDE data that we saw preservation of ambulation by a substantial number of years. We saw preservation of pulmonary effect. We saw the FVC less than 30, state that patients who are treated with Translarna didn't see those sorts of reductions compared to natural history. So those are less likely to survive longer. So I think what you're seeing is that the results shown here showing a profound effect in terms of functional outcome. And then consistent with that, even within using -- because if you think about what is the North Star, it's a set up functional 16 different functions that you measure, like a 10-meter walk, going up a step, going down a step, so they're all functions. And not only do we use that to get the score from -- to get a score from the NSAA, you could take that individual data where, as I said, it scores 2, 1 or 0, where 2 is going to do it easily, 1 is difficulty, 0 is can perform the function. So what we often do with this data is look to see for patients who lost function. And we can see within the -- and that's what that slide, what slide number was that where we showed the data where we saw substantial percent protection, in Slide 23. And what that shows you, I think, so nicely is compared to placebo, how many patients were able to do those who would still be able to do who didn't lose function. So when we do the calculation, we think it's approximately about a 20% reduction in loss of function in that sense. So very strong. So again, consistent with what we've seen in the 6-minute walk test, timed function test, overall North Star scores, we're doing what patients need, which is preserving function. Does that make sense?

It does. Perfect.

Our next question comes from Gena Wang with Barclays. Gena Wang, your line is open. Please check your mute button. Our next question comes from Judah Frommer with Credit Suisse.

Thanks for all the detail today. Just a quick 1, and kind of interactions with the agencies, both Europe and FDA more recently. Any sense for how they're viewing 6-minute walk versus North Star. It seems you've had kind of conflating 6-minute walk results in other trials. So just curious how they might be thinking about functional endpoints for this population.

Yes. I think they like the 6-minute walk test. I think they've also been talking and liking North Star assessment as well. So I think those are 2 endpoints that, at least when I read there regulatory guidelines, they seem to like. They like the NSAA, I think, because of multiple tests on that. The 6-minute walk test has been used a lot in trials, so they understand it. And that's good. So if you look at the overall ITT, that's where we're showing 6-minute walk and North Star, you have a good examples of them doing well in these studies.

Thank you. And I'm currently showing no further questions at this time. I'd like to turn the call back over to Stuart Peltz for closing remarks.

Great. Well, guys, I really appreciate that you've been on the phone, and thank you for taking time to join the call today. I think what you can see from the results that we presented today that this is clearly exciting time for PTC. As we move forward to use these favorable results from Study 041 to help strengthen Translarna's position in the EU and other international markets, we're also excited to engage with regulators in the U.S. and other potential new markets to bring Translarna to additional nonsense mutation DMD patients in need. We're especially pleased with the progress we're making in helping patients with serious rare diseases, enjoy longer and more productive lives. Thank you for being here.

This concludes today's conference call. Thank you for participating. You may now disconnect.