Good day, and thank you for standing by. Welcome to today's conference call, CHMP Opinion on Translarna. At this time, all participants are on a listen-only mode. After the presentation, there will be a question-and-answer session. To ask a question during the session, you'll need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your host today, Ron Aldridge, Senior Director, Investor Relations. Please go ahead. Good morning, and thank you for joining us today to discuss the CHMP opinion on Translarna. I'm joined today by our Chief Executive Officer, Dr. Matthew Klein. Today's call will include forward-looking statements based on our current expectations, including with respect to PTC's plans for interactions with the European Medicines Agency and the outcome of any reexamination process. Please take a moment to review the press release that we issued this morning, which contains more information regarding forward-looking statements. Our actual results could materially differ from these forward-looking statements, as such statements are subject to risks that can materially and adversely affect our business and results of operations. For a detailed description of applicable risks and uncertainties, we encourage you to review the company's most recent annual report on Form 10-K, filed with the Securities and Exchange Commission, as well as the company's other SEC filings. With that, let me pass the call over to our CEO, Dr. Matthew Klein. Matt? Thank you, Ron, and thank you to everyone for joining the call today. As you've likely seen in our press release earlier today, the CHMP has unexpectedly given a negative opinion, both on the conversion of Translarna, conditional marketing authorization to full authorization, and on the annual renewal of Translarna. Per EMA guidelines, we will request a reexamination of the conversion and reauthorization decisions. Our request for the reexamination process will follow a standard timeline and will likely run through January 2024. Importantly, as we are requesting a reexamination, the CHMP's decisions will not impact the current authorization of Translarna in Europe. The product will remain on the market, and boys will remain on the drug, pending the outcome of the reexamination process. We expect the opinions following the reexamination procedure to occur at the time of the CHMP meeting in late January. That opinion will then require European Commission ratification within 67 days before becoming effective. The CHMP decision is incredibly disappointing, as it jeopardizes the only available therapy for boys with nonsense mutation DMD in Europe. As many of you know, the regulatory history of Translarna in Europe has been complicated. We have previously gone through the reexamination process to re-reverse an initial negative CHMP opinion and obtain initial authorization in 2014. In 2017, the renewal of the conditional authorization following the completion of Study 020 also required reconsideration by the CHMP. Hence, we've been down this path before with positive outcomes each time. The data from the most recently completed Translarna placebo-controlled trial, Study 041, as well as data from the two previous placebo-controlled trials, Studies 007 and 020, form the basis of the CHMP's current review and decision. Additional supportive evidence of efficacy included robust meta-analyses demonstrating highly statistically significant benefit on several key disease endpoints, capturing different aspects of DMD, including the Six-Minute Walk Distance, the North Star Ambulatory Assessment, and timed function test. In addition, analyses from the real-world STRIDE Registry, which includes 300 boys with an average treatment duration of over 5.5 years, demonstrating that the long-term Translarna therapy delays the time to loss of ambulation by 3.5 years, were included as part of the data package to confirm long-term meaningful treatment benefit. In addition, Translarna has shown a favorable safety profile with over 3,000 patients treated to date. Despite our disappointment and surprise, we will push ahead and fight to keep Translarna's authorization in Europe. We are certain that the patients and physician communities will similarly fight to keep a clearly safe and effective drug on the market. We'll now take any questions you may have on today's announcement. If you'd like to ask a question at this time, please press star one one on your touchtone telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Kristen Kluska with Cantor Fitzgerald. Hi, good morning, everybody. Sorry to hear about this news. I wanted to ask you, on the flip side of the data that you've collected showing the benefits across Translarna, do you also have any studies or findings or sense of what would essentially happen to some of these effects if patients were to stop taking the treatment, given there are very few options available for them? Yeah, Kristin, thank you very much, and that's a great question. We have not formally studied the effects of withdrawing therapy. That being said, over the years, we've collected many anecdotes that consistently share that once boys get off the drug, for one reason or another, sometimes it's to participate in other clinical trials, sometimes it's for other reasons... parents and the boys report a pretty precipitous decline in clinical function, losing muscle function, losing the ability to walk and such. So quite clearly, the withdrawal of the therapy and discontinuation of therapy would have dire consequences for these boys. Okay. And to that point, I'm wondering how you're gonna think about collecting some of these anecdotes, hearing from key thought leaders as you reengage with the agency over the next couple of months, especially as some of these patients you're talking about over 5-6 years on consistent therapy? Yeah, it's been for some of these boys, it's been on the market for nine years. And obviously, this is why this is so potentially devastating. But rest assured, we've got armies, you know, teams of customer-facing teams, our patient engagement teams, our medical teams. Everyone is, you know, very well connected across Europe with the patient community, and it's not even just in Europe, it's worldwide. And you could be sure that we're gonna take every effort to capture every piece of evidence, whether it's hard data or whether it's important stories that need to be shared, of what the consequences of withdrawal could be. That is why we believe, in addition to some of the particulars of how the reexamination process goes, that this education campaign, in terms of educating authorities what the consequences of their decision could be, could very well help in turn this around and reverse the decision in the reexamination process. Okay. Thank you so much, Matt. Our next question comes from the line of David Lebowitz with Citi. Hello, can you hear me all right? Yes, David. Oh, thank you. Could you, you talked about how this has been a road that you've gone down in the past. Could you compare the dynamic of this particular situation with what exactly happened in the prior situations, just so we understand the deltas? Yeah, so David, just to in response to your question, start. So as I mentioned in the presentation, in 2014, the CHMP delivered an initial negative opinion that we then, through the reexamination process, reversed. Again, the feeling at that point was the data did not support efficacy of the drug. I think the safety of the drug has never been in question. As you know, in Europe, the framework through which they evaluate therapies is through what they call benefit risk profile, so you need to have a favorable benefit risk profile. So in 2014, it was about benefit. Again, following Study 020, there was concern that we had not hit the primary endpoint in the trial, which was the same as in Study 007, and there was a question about whether we had sufficient evidence of benefit, given the failure to achieve the primary endpoint in the study. Again, further discussion about looking at the right sensitive populations, helped to turn that around. I think as we sit here today, obviously, we're in a situation, again, with Study 041, where we did not achieve the primary endpoint, but I think overall, we're in a much, much stronger position in terms of totality of data. First, in Study 041, as we've talked about in the overall intent-to-treat population of 359 boys, we have statistically significant benefit across the six-minute walk test, North Star, other endpoints, time to 10% loss of ambulatory function. And then we also have the ability to use meta-analysis, given the strength in the intent-to-treat population, that are able to provide a precise and robust estimate of treatment effect across the 700 boys in the clinical trials. That's really important because the main consideration when you miss a primary endpoint is whether the other benefits you're recording are due to chance or due to therapy. And to be able to use the meta-analysis to provide really strong estimates of treatment benefit with very small P values, tells you that this consistent evidence of benefit we're seeing across the trials is not due to chance. You wouldn't see what we see if it were due to chance. Furthermore, we also have the STRIDE Registry. Now, there were some questions in the CHMP discussions about the robustness of the STRIDE Registry, given that it's a natural history comparative group, which necessarily means it lacks the internal validity one would usually have in a placebo-controlled trial. So I think that nonetheless, we can address, we believe we can adequately, more than adequately address any concerns of bias in that comparison, and then be able to continue to offer the STRIDE Registry as clear evidence of meaningful benefit in the long run. So I think the main difference here, I'll say the similarities, David, is in each case, there's been a question about the efficacy of the drug, given the inability to hit the primary endpoint. But we come now stronger than ever, with much larger data, much more extensive data, and clear evidence of consistent effect, as well as the STRIDE Registry, which we obviously did not have back, either of the times we went through this process. Thank you for that. Toward that end, so, will there be additional data that is being presented to them or reframed in these analyses when you come back to them in January? Yeah, absolutely. So in a couple important notes, one is in the reexamination process, we can't provide new data per se, but obviously, now having gone through some of the discussions, you know, obviously, it's been a busy week back and forth, and understanding the concerns allows us to be better equipped to proactively address them. The other important change that goes on in the reexamination process, for those not familiar with it, is you're assigned a new rapporteur. The way the European system works is that each program has what's known as a rapporteur, who's the person who is responsible for representing your product in terms of doing the evaluation of the data package, as well as presenting their findings and their impression to the entire CHMP body. During the reexamination process, you're assigned a new Rapporteur who is supportive of the product, so that assures you that you're having a, let's just say, spokesperson or champion, if you will, in the room when things are presented. So in addition to reframing data in a way that addresses concerns that have previously been expressed, you also have some assurances that the person who will be presenting the data in the room and the expert in the room on your program is one who is also favorably inclined towards the product. Thank you for taking my questions. Our next question comes from the line of Alex Xenakis with Truist. Hi. Unfortunately, to hear about the data. We wanted to know, one, how does the results now affect the expansion strategy and the potential investment into SG&A and R&D going into new territories? And then looking into 2024, what type of leverage do you have on the bottom line? Are there any potential cost-cutting measures, either in SG&A or R&D, that could be looked at? Thanks. Yeah, Alex, thanks for the question. Obviously, we're quite new with this result. I will say in terms of our global expansion efforts, that doesn't change. In terms of our priorities and continuing to get Translarna on the market in territories where it's not currently authorized, that doesn't change. Obviously, for now, in Europe, the authorization doesn't change. The boys stay on therapy, and it remains on the market pending the outcome of this reexamination procedure. So, you know, any potential future impacts on any of the questions you had, obviously, these are things we'll look at over time and share updates as they're needed. Definitely. Thank you. Our next question comes from the line of Kelly Shi with Jefferies. Thank you for taking my questions, and sorry to hear this surprising news. I'm curious, how does the CHMP opinion affect your regulatory plan in the U.S.? Yeah. Hi, Kelly. Thank you for the question. It doesn't. We're moving forward. We said we were gonna have a Type C meeting with the FDA in the fourth quarter. That's still on track. You know, I would say if we looked historically, the FDA never followed Europe's lead in anything regarded to Translarna. But, look, I think they're separate regulatory bodies. We again, I want to reiterate, this is a strong data package. We have clear and consistent evidence of efficacy of the product. We have a number of different pieces of evidence to bring forth to the FDA now, including the data collected across the three clinical trials, the evidence of confirmatory benefit in the STRIDE Registry, and we very much look forward to discussions with the agency in the fourth quarter and looking forward to a potential resubmission of the NDA. Thank you, Matt. Our next question comes from the line of Eric Joseph with JP Morgan. So, hi, good morning. Actually, Matt, you anticipated my question about sort of the personnel makeup and during the reexamination process versus the regular review cycle that just concluded. I wonder whether there are any opportunities as part of the reexamination to bring in outside advisors or, I guess, any way in which the sort of discussion might be modified from your side of things. It's good questions, Eric. Look, we are, we to date have always worked with first-in-class experts. We have folks who are experienced in the CHMP process, who've been part of the CHMP, and we'll continue to work with them and any additional folks we can bring to this battle. You know, we've talked about this in a very short period of time, at PTC, since we've gotten the opinion, you know, we're going to battle. The cause here couldn't be more important. It's the lives of boys in Europe with DMD who have no other therapy, and they're on a drug now that's safe and effective, and we're gonna fight and bring everyone to the battle we can to help us win and keep these boys on the drug as patients. Okay. Thank you. Our next question comes from the line of Sami Corwin with William Blair. Hey, there. Can you hear me? Yes, hello. Hi. Hey, Matt. Sorry to hear about the disappointing results. If you are successful in reversing the CHMP opinion, how does that change your strategy in the future regarding submitting for full authorization? And is it possible to have conditional authorization indefinitely? Yep. Sammy, thanks for the question. So I will say it is possible to have conditional authorization permanently. How the procedure will play out, in terms of its, the processes being aligned as they are now, which was they looked at the conversion of full approval and the renewal together as one. It was two different opinions, but they were joined. They were inclined to not look at one without the other. And so obviously, we'll explore options as we move through the re-examination process. But as a separate point, historically, there have been drugs that remain conditional in Europe forever. Great, thank you. Our next question comes from the line of Brian Abrahams with RBC Capital Markets. Hey, good morning. Thanks for taking my questions, and sorry to hear the news. So in the past, CHMP found the STRIDE registry and the real-world evidence to be convincing, and Study 041 clearly showed some positive signals. So I guess I'm trying to understand what happened here or what changed. Was there a change to the personnel or the rapporteur who, and their perspectives? Anything changed with regards to the STRIDE data itself, or the underlying natural history comparators? And I guess I'm also wondering whether did you have an opportunity to address some of the CHMP's issues on STRIDE and 041 in sort of a rolling real-time basis during this review process? Is there any back and forth, or was this unilateral and the opportunity to address these will come now in the re-examination? Thanks. Brian, thank you for your questions. You know, it, this is part of the reason we were so surprised. Again, the strength of evidence in Study 041, quite strong. The STRIDE Registry, which has been a reliable source during the renewal process, those data only continue to get stronger over time as the length of follow-up grows. We now have 300 boys with an average treatment duration of 5.5 years, and the benefit in terms of delaying loss of ambulation is 3.5 years. I'll also say that the initial preliminary assessment report we received when this procedure started, was supportive of benefit, of consistent benefit as shown in the past. So again, this is why this all became a bit surprising to us. We did have, as was made public by the CHMP, a SAG, a scientific advisory group, as well as an oral explanation that allowed us for some discussions. I, I think part of this was a concern when they looked at the primary endpoint of the three studies, particularly study 41, not achieving the primary endpoint in the subpopulation of boys with a walk distance of greater than 300 and supine-to-stand time of greater than 5 seconds, that there was a question of whether they could use a STRIDE registry with natural history comparator to overcome a failed primary analysis, and I think that's where a lot of the discussion was. I think we are quite confident that we can continue to allay, now maybe not in a reactive mode, in terms of questions when you come before the CHMP in an oral explanation, but more in a proactive mode to demonstrate the rigor of the STRIDE comparison, and again, be able to reiterate the strength of the data from the clinical trials, that the evidence of benefiting the ITT population cannot be overlooked. The consistency across endpoints in Study 041, the consistency across studies, all speak to the fact that the treatment effect is real, reproducible, and not due to chance. So I think, just to circle back to the spirit of your question, it was surprising to us, and we look forward to the opportunity to incorporate concerns that they voiced during our back and forth over these past days and weeks, and bring them to bear, as we go through the examination process. Thanks, Matt. Our next question comes from the line of Joseph Thielen with TD Cowen. Joseph, your line is now open. Our next question comes from the line of Jeff Hung with Morgan Stanley. Thanks for taking my questions. You touched upon this, but can you remind us about your decision for designating a different primary analysis subgroup in Study 041 than subgroups in studies 007, 020? And what gives you confidence that the EMA may ultimately find the argument compelling? Thanks. Hey, Jeff, thanks for the question. So just to walk back in time and discuss the etiology of the subgroups. So following Study 7 and Study 20, which both had as the primary analysis population, the overall intent-to-treat population, it became quite clear that the Six-Minute Walk Distance, which was the primary endpoint in both studies, really did not detect differences similarly across all different patient subgroups. As in all neurodegenerative or neurodegenerative neurological disorders, patients progress at different rates, and if we're going to be able to demonstrate treatment benefit in terms of delaying disease progression, we're gonna need, we're gonna need to find those boys who enroll in the trial who aren't so early in their disease that they don't progress at all during the clinical trial, so that you can't demonstrate benefit relative to placebo. And we found that that was true for boys with a baseline walk distance of over 400 meters. Similarly, there are patients who are so far in their progression that they decline too rapidly towards loss of ambulation, again, making it very difficult to capture treatment benefit. And those are boys who had a walk distance of under 300 meters at baseline. So that became what we talked about as the quote-unquote 300-400 meter subgroup, those that were not too early and not too late, in whom the 6-minute walk distance was most sensitive to treatment effect during the course of a clinical trial. That's really key because obviously all boys will pass through that stage at some point in their disease course, but we're really in a time-limited situation with a clinical trial, and we need to make sure that boys in the placebo group are going to move at the right rate so that we can record a treatment benefit relative to placebo. So this is, this was demonstrated when looking back then on Study 7 and Study 20, that in that 300-400 subgroup, there was nominal significant benefit and a large, and again, the largest magnitude of effect in that subgroup. We obviously believe that Translarna has benefit for all boys with DMD. This is really just a question about magnitude of effect over the course of a clinical trial. So the idea then was in Study 41, to test the hypothesis that the 300-400 subgroup, that sensitive population, would demonstrate not only statistically significant benefit, but also capture the greatest magnitude of treatment effect over the course of a clinical trial. The decision was made as Study 041 was being set up to modify that 300-400, based on some data from 007 and 020, that suggested that an additional disease measurement could be introduced to further optimize that sensitive population. The decision was made to replace the upper bound, the 400-meter, with the second disease variable, supine-to-stand time. So the primary analysis population for Study 041 became boys with a baseline walk distance of over 300 meters and a supine-to-stand time of greater than or equal to 5 seconds. Unfortunately, that was not the most sensitive population. That is why we did not achieve significance in the primary endpoint. In fact, the magnitude of change in that group was smaller than the ITT population. Once again, though, the 300-400 group did demonstrate itself to be the most sensitive population with the greatest magnitude of treatment effect in Study 041, as well as a nominally statistically significant treatment effect. You know, obviously, the primary analysis population was a concern to the CHMP. I think we will continue to, in our discussions and reexamination, emphasize that in this particular situation, that the lack of statistical significance on a subpopulation is, does not mean lack of efficacy. In fact, when you look at the consistent evidence of benefit in the overall population, which is most consistent with the indicated population, as well as the population that was the primary analysis group for the other two studies, and is not a select post-hoc subgroup, but it's rather the superset of all patients, this ITT population. I think that that's a very compelling argument, and we look forward again to having a discussion around the value of that population as being more worthwhile and more informative, in fact, than the subgroup that was the primary analysis population. Thank you. Our next question comes from the line of Joseph Dome with TD Cowen. Joseph, your line is now open. Our next question comes from the line of Danielle Brill with Raymond James. Hey, guys, this is Alex in for Danielle. Thanks for taking our question. We actually wanted to ask about a different continent, about Brazil. Will this decision trigger any re-review in Brazil? Or do you expect that they will act in parallel with the EMA? And also, if so, what do you expect the timing? You know, just walk us through the regulatory process there, you know, if it would happen after a formal decision in January. Yeah, Alex, thanks for the question. Let me be clear that the Brazil rightly prides itself of being an independent regulatory body, and I'll also point out that the authorization in Brazil is full authorization. It, it's not conditional, it's not contingent on Europe. It's a full independent... It's an independent assessment resulting in a full market authorization. So we do not anticipate impact in a regulatory sense from certainly not at this point in time, given the fact that the CHMP opinion is now on hold, given, pending the reexamination process. So there'll be no decision now on Translarna in Europe, till we go through the reexamination process, which will complete in January, and then that opinion still have to go through centralized EC adoption of the opinion. So I think it's premature for us to think that things are over in Europe, but it's certainly, when we look to other countries like Brazil, that, as I said earlier, pride themselves on independent regulatory processes, and they have a full approval, not subject to re-review, as a conditional would be, we don't see any impact here. Okay. If I can sneak in one follow-up. How much of your revenues are coming from Brazil? As you know, Alex, we don't actually break out country-by-country revenue. I think last year we had a total of $288 million of Translarna revenue. While the commercial revenue started in Europe, we've actually, as you know, done an excellent job of diversifying revenue sources and that geographic expansion beyond Europe to include Brazil, other countries in LATAM, Middle East, Commonwealth of Independent States, and now as we're moving into Asia Pac, gives us a very broad base of revenue contribution from geographies worldwide. Got it. Thanks so much. Our next question comes from the line of Tazeen Ahmad with Bank of America. Hi, can you hear me? Tazeen. Hello? Yeah. Hi, Tazeen. Okay, great. Thanks for taking my question, and sorry for the update. I was just curious, Matt, if you could tell us what the current penetration is for Translarna in the addressable European population and what your thoughts might be for any new patient that might be starting therapy during this period between now and January, whether or not you think doctors would have a harder time getting those patients on, just given this result? Thanks. Yep. Thanks, thanks for the question, Tazeen. We've not given penetration numbers in the past. We've said that we are not near peak penetration in Europe. There's still absolutely room for growth there. As we talked about, we look at growth both within existing territories like Europe as well as geographic expansion beyond Europe. In terms of new patients and patients on drug, I think, look, this is, you know, on a physician level, this is the only drug they have for their patients. This is not like this, this may not be available, I can give them this other drug over here. You know, we've actually, even in this short period of time since we've had the opinion this morning, we've heard from a number of our physicians who are similarly in no way, shape, or form, looking to discontinue their patients and are gonna look to continue to add new patients because they realize that this is a therapy that's safe, this is a therapy that's beneficial, and there's no other alternatives. I will say that, of course, a great amount of effort on our part is going to go on in the next few weeks to support our physicians in this process to clarify any confusions that could arise from a CHMP negative opinion and reassure them that nothing has changed in terms of the authorization status or their ability to prescribe this drug for new patients. So obviously we'll take a lot of efforts to ensure that, but I think it's gonna fall on very receptive ears as physicians who prescribe Translarna believe in its safety, believe in its efficacy, and want to be able to offer something to these boys who have a fatal disease with no other treatment options. Okay. And then as it relates to countries outside of Brazil, which are the ones that tend to, make their decisions based on what the European status is? So for example, I was just curious about Germany as a standalone and any other large countries. Yeah, so I think the countries within the European Union at this point all follow the centralized procedure, which is they follow CHMP. Now, if we walk down the road and go through reexamination, negative opinion, EC ratification later in the first quarter of 2024, could individual countries reference an existing authorization like MHRA or some other country and say they're gonna approve it in Europe? You know, we'll look at that as a contingency, if it were to get to that. But in terms of countries outside of Europe that aren't under the jurisdiction of the European Medicines Agency, none of them are contingent on the European approval. They're all independent. Okay, great. Thank you. Our next question comes from the line of Gena Wang with Barclays. Hello? Hello, can you guys hear me? Yes. Oh, hi, it's Tony on for Gina. So- Hey, Tony. Just wondering with regards to the process for withdrawal, if in the event that the CHMP does hold its negative opinion, what are the steps and timelines look like for that, and how does that really happen? Yeah. So, Tony, thanks for the question. I think we're a long way from that. Obviously, we said that this reexamination process, if it follows... Please stand by. Can someone get me on? Yes, you're connected. Thank you. Can folks hear me? Yes, we can hear you. Okay, sorry about that. There was some just power failure here. So just to finish the question, Tony, I believe it's we're a little too soon in the process to be going through those timelines. We look forward to focusing now on the reauthorization, the re-examination process. Okay. Got it. Thank you. That concludes today's question and answer session. I'd like to turn the call back to Dr. Matthew Klein for closing remarks. Yes, thank you all again for joining this morning. Obviously, this news was surprising and quite disappointing to us. Our teams are now 100% focused on going through the reexamination process. We are looking to the past and see that we've been through this before and successfully. We believe we're armed with much stronger data than we've been in the past and very much look forward to the reexamination process to keep this drug on the market for the boys in Europe. So thank you for joining the call today, and we look forward to speaking with you at earnings. This concludes today's conference call. Thank you for participating. You may now disconnect.